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Sample records for hiv therapeutic possibilities

  1. HIV Neurotoxicity: Potential Therapeutic Interventions

    PubMed Central

    Wallace, David R.

    2006-01-01

    Individuals suffering from human immunodeficiency virus type 1 (HIV-1) infection suffer from a wide range of neurological deficits. The most pronounced are the motor and cognitive deficits observed in many patients in the latter stages of HIV infection. Gross postmortem inspection shows cortical atrophy and widespread neuronal loss. One of the more debilitating of the HIV-related syndromes is AIDS-related dementia, or HAD. Complete understanding of HIV neurotoxicity has been elusive. Both direct and indirect toxic mechanisms have been implicated in the neurotoxicity of the HIV proteins, Tat and gp120. The glutamatergic system, nitric oxide, calcium, oxidative stress, apoptosis, and microglia have all been implicated in the pathogenesis of HIV-related neuronal degeneration. The aim of this review is to summarize the most recent work and provide an overview to the current theories of HIV-related neurotoxicity and potential avenues of therapeutic interventions to prevent the neuronal loss and motor/cognitive deficits previously described. PMID:17047310

  2. Conotoxins that Confer Therapeutic Possibilities

    PubMed Central

    Essack, Magbubah; Bajic, Vladimir B.; Archer, John A. C.

    2012-01-01

    Cone snails produce a distinctive repertoire of venom peptides that are used both as a defense mechanism and also to facilitate the immobilization and digestion of prey. These peptides target a wide variety of voltage- and ligand-gated ion channels, which make them an invaluable resource for studying the properties of these ion channels in normal and diseased states, as well as being a collection of compounds of potential pharmacological use in their own right. Examples include the United States Food and Drug Administration (FDA) approved pharmaceutical drug, Ziconotide (Prialt®; Elan Pharmaceuticals, Inc.) that is the synthetic equivalent of the naturally occurring ω-conotoxin MVIIA, whilst several other conotoxins are currently being used as standard research tools and screened as potential therapeutic drugs in pre-clinical or clinical trials. These developments highlight the importance of driving conotoxin-related research. A PubMed query from 1 January 2007 to 31 August 2011 combined with hand-curation of the retrieved articles allowed for the collation of 98 recently identified conotoxins with therapeutic potential which are selectively discussed in this review. Protein sequence similarity analysis tentatively assigned uncharacterized conotoxins to predicted functional classes. Furthermore, conotoxin therapeutic potential for neurodegenerative disorders (NDD) was also inferred. PMID:22822370

  3. Personalized Therapeutics: HIV Treatment in Adolescents

    PubMed Central

    Rakhmanina, NY; Capparelli, EV; van den Anker, JN

    2009-01-01

    Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends on multiple factors. The continued use of higher (weight- or surface-based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV-infected adolescents. PMID:18830226

  4. Novel therapeutic strategies targeting HIV integrase

    PubMed Central

    2012-01-01

    Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds. PMID:22498430

  5. [Therapeutic possibilities of hereditary diseases in dermatology].

    PubMed

    Schnyder, U W

    1983-01-01

    Several years ago the therapeutic possibilities for the treatment of inherited skin disorders were rather restricted; recently new possibilities have been developed and successfully applied. The author discusses the indications for a surgical procedure in basal cell nevus syndrome and the satisfying results revealed by dermabrasion in sebaceous adenoma of Pringle. The use of a low phenylalanine and tyrosine diet in case of palmoplantar keratosis with tyrosinemia is of theoretical as well as practical interest. However, a most striking therapeutic success is obtained by the treatment with drugs. The substitution of zinc in acrodermatitis enteropathica is very effective and not expensive! The positive effect of phenytoin in epidermolysis bullosa cicatricans is based on the partial inhibition of collagenase activity by this drug. Finally the author discusses the advantages of a treatment with retinoids in different hereditary keratinization disorders. PMID:6666938

  6. [A possible complication of therapeutic plasmapheresis].

    PubMed

    Shafro, L I; Tsimermane, G I; Krivulis, D B; Andreev, G N

    1991-01-01

    Possibility of citric intoxication as a complication of therapeutic plasmapheresis is being discussed on the basis of two clinical observations. Hemodynamic reactions to sodium citrate administration have been noted during reinfusion of auto red cell mass. It is suggested that the development of collapsoid reaction, accompanied by a significant decrease in the total peripheral resistance at a stable cardiac output and cardiac index, is determined by the transition of the ionized calcium of the blood into calcium citrate, and thus the violation of the processes regulating the excitement and constriction of the muscular cells in the peripheral arteries. On the basis of further observations (360 therapeutic plasmapheresis procedures) gradual injections of small calcium quantities are recommended for the prevention of citric reactions during reinfusion of auto red cell mass. PMID:1767964

  7. [Therapeutic possibilities for multiple caries in children].

    PubMed

    Oka, A E; Kattie, A L; N'Cho, K J; Bakayoko-Ly, R

    2003-09-01

    The exaggerated consumption of sugars under its various associate shapes to an insufficiency of mouth and tooth hygiene could drag some tooth decays. These tooth decays, when they demonstrate, leads to a destruction of the temporary teeth, with for corollaries of the aesthetic and functional problems. The therapeutic are not always apparent especially when there is coexistence of coronary destruction to juxtapose to the gum without reaching pulp with some precocious a toothlessing. The authors, across some cases clinics treated to the breast of service of Paediatric Dentistry shows different types of therapeutic possibilities in function of the shapes clinics. He was about conservative treatments or of extraction, of prothesis restorations to the aide of the Crown order form, of infantile removable prosthesis and of composite prosthesis. PMID:14705377

  8. Putting an 'End' to HIV mRNAs: capping and polyadenylation as potential therapeutic targets.

    PubMed

    Wilusz, Jeffrey

    2013-01-01

    Like most cellular mRNAs, the 5' end of HIV mRNAs is capped and the 3' end matured by the process of polyadenylation. There are, however, several rather unique and interesting aspects of these post-transcriptional processes on HIV transcripts. Capping of the highly structured 5' end of HIV mRNAs is influenced by the viral TAT protein and a population of HIV mRNAs contains a trimethyl-G cap reminiscent of U snRNAs involved in splicing. HIV polyadenylation involves active repression of a promoter-proximal polyadenylation signal, auxiliary upstream regulatory elements and moonlighting polyadenylation factors that have additional impacts on HIV biology outside of the constraints of classical mRNA 3' end formation. This review describes these post-transcriptional novelties of HIV gene expression as well as their implications in viral biology and as possible targets for therapeutic intervention. PMID:24330569

  9. Fighting HIV/AIDS: is success possible?

    PubMed Central

    Okware, S.; Opio, A.; Musinguzi, J.; Waibale, P.

    2001-01-01

    The fight against HIV/AIDS poses enormous challenges worldwide, generating fears that success may be too difficult or even impossible to attain. Uganda has demonstrated that an early, consistent and multisectoral control strategy can reduce both the prevalence and the incidence of HIV infection. From only two AIDS cases in 1982, the epidemic in Uganda grew to a cumulative 2 million HIV infections by the end of 2000. The AIDS Control Programme established in 1987 in the Ministry of Health mounted a national response that expanded over time to reach other relevant sectors under the coordinating role of the Uganda AIDS Commission. The national response was to bring in new policies, expanded partnerships, increased institutional capacity for care and research, public health education for behaviour change, strengthened sexually transmitted disease (STD) management, improved blood transfusion services, care and support services for persons with HIV/AIDS, and a surveillance system to monitor the epidemic. After a decade of fighting on these fronts, Uganda became, in October 1996, the first African nation to report declining trends in HIV infection. Further decline in prevalence has since been noted. The Medical Research Council (UK) and the Uganda Virus Research Institute have demonstrated declining HIV incidence rates in the general population in the Kyamulibwa in Masaka Districts. Repeat knowledge, attitudes, behaviour and practice studies have shown positive changes in the priority prevention indicators. The data suggest that a comprehensive national response supported by strong political commitment may be responsible for the observed decline. Other countries in sub-Saharan Africa can achieve similar results by these means. Since success is possible, anything less is unacceptable. PMID:11799443

  10. Gene therapy: a possible future standard for HIV care.

    PubMed

    Abou-El-Enein, Mohamed; Bauer, Gerhard; Reinke, Petra

    2015-07-01

    Despite undeniable accomplishments in developing cell and gene therapeutic strategies to combat HIV infection, key social, economic, and policy-related challenges still need to be overcome for any future commercialization efforts of these novel therapies to be successful. Here, we address these challenges and structure a framework for eradicating HIV/AIDS using gene therapy. PMID:26088914

  11. A proposal to use iterative, small clinical trials to optimize therapeutic HIV vaccine immunogens to launch therapeutic HIV vaccine development.

    PubMed

    Shapiro, Stuart Z

    2015-01-01

    The HIV cure agenda has rekindled interest in the development of a therapeutic HIV vaccine. An iterative clinical trial strategy that proved successful for the development of effective cancer chemotherapies in the 1960s may be applicable to the development of a CD8 T lymphocyte-based therapeutic HIV vaccine. However, while cancer chemotherapy development could begin with iterative clinical trials to improve the use of active drugs, the first step in therapeutic HIV vaccine design should be discovery of immunogen constructs with potential for activity and their optimization to meet the challenges of HIV-1 sequence diversity and human polymorphism in T cell antigen presentation. A strategy for doing this is discussed in this article. The proposed strategy relies on a major commitment by funding organizations to fund organized and coordinated manufacture and clinical testing of a series of first- and second-generation constructs to test basic concepts in product design. This is presented as an alternative to funding a more traditional competition among private manufacturers and product champions of individual, already designed products. PMID:25286142

  12. Nanotechnology as a New Therapeutic Approach to Prevent the HIV-Infection of Treg Cells

    PubMed Central

    Jaramillo-Ruiz, Didiana; De La Mata, Francisco Javier; Gómez, Rafael; Correa-Rocha, Rafael; Muñoz-Fernández, Mª Ángeles

    2016-01-01

    Background HIV-1 has proved to infect regulatory T cells (Treg) modifying their phenotype and impairing their suppressive capacity. As Treg cells are a crucial component in the preservation of the immune homeostasis, we researched that the antiviral capacity of carboxilan dendrimers prevents the HIV-1 infection of Treg and their effects. The phenotype and suppressive capacity of Treg treated or non-treated with carbosilane dendrimers were studied by flow cytometry. Treated and non-treated Treg from healthy donors were infected with HIV-1NL4.3. The infection of Treg cells by HIV-1, and protective effect of two dendrimers were determined by measuring antigen p24gag in the supernatant of the culture and intracellular. Results The Treg cells were treated with cationic and anionic carbosilane dendrimers. The results showed that both dendrimers did not modify the phenotype and functionality of Treg cells compared with non- treated Treg cells. Anionic dendrimers showed high biocompatibility with normal activity of the Treg cells and in antiviral assays. These dendrimers were highly active against HIV-1 preventing the infection of Treg, and were able to protect the Treg from the Foxp3 downregulation induced by the HIV-1 infection. Conclusions This is the first work showing that the in vitro use of anionic dendrimers prevent the HIV-1 replication and the infection of expanded Treg cells in culture, which raises the possibility to use Treg cells therapeutically in HIV-1-infected subjects. PMID:26785250

  13. Understanding HIV infection for the design of a therapeutic vaccine. Part II: Vaccination strategies for HIV.

    PubMed

    de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A

    2015-05-01

    HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. PMID:25528627

  14. The structural biology of HIV-1: mechanistic and therapeutic insights

    PubMed Central

    Engelman, Alan; Cherepanov, Peter

    2013-01-01

    Three-dimensional molecular structures can provide detailed information on biological mechanisms and, in cases where molecular function impacts on human health, significantly aid in the development of therapeutic interventions. Over the past 23 years, key components of the lentivirus HIV-1, including its envelope glycoproteins and capsid, and the replication enzymes reverse transcriptase, integrase and protease, have accordingly been scrutinized to near atomic scale resolution. Structural analyses of the interactions between viral and host cell components have moreover yielded key insights into the mechanisms of virus entry, chromosomal integration, transcription and egress from cells. Here, we review recent advances in HIV-1 structural biology, focusing on the impact these results have had on our understanding of virus replication and the development of new therapeutics. PMID:22421880

  15. Possible transmission of HIV Infection due to human bite.

    PubMed

    Deshpande, Alaka K; Jadhav, Shivaji K; Bandivdekar, Atmaram H

    2011-01-01

    The potential risk of HIV-1 infection following human bite although epidemiologically insignificant, but it is biologically possible. There are anecdotal reports of HIV transmission by human bites particularly if saliva is mixed with blood. The oral tissues support HIV replication and may serve as a previously unrecognized HIV reservoir. The HIV infected individuals have more viruses in blood than saliva, possibly due to the potent HIV-inhibitory properties of saliva. The case presented here is of a primary HIV infections following a human bite where in the saliva was not blood stained but it got smeared on a raw nail bed of a recipient. The blood and saliva of the source and blood of the recipient showed a detectable viral load with 91% sequence homology of C2-V3 region of HIV gp120 between the two individuals. The recipient did not receive PEP [post exposure prophylaxis] as his family physician was unaware of salivary transmission. The family physician should have taken PEP decision after proper evaluation of the severe and bleeding bite. Hence it is necessary to treat the HIV infected human bites with post exposure prophylaxis. PMID:21453452

  16. Parasitic infections in HIV infected individuals: Diagnostic & therapeutic challenges

    PubMed Central

    Nissapatorn, Veeranoot; Sawangjaroen, Nongyao

    2011-01-01

    After 30 years of the human immunodeficiency virus (HIV) epidemic, parasites have been one of the most common opportunistic infections (OIs) and one of the most frequent causes of morbidity and mortality associated with HIV-infected patients. Due to severe immunosuppression, enteric parasitic pathogens in general are emerging and are OIs capable of causing diarrhoeal disease associated with HIV. Of these, Cryptosporidium parvum and Isospora belli are the two most common intestinal protozoan parasites and pose a public health problem in acquired immunodeficiency syndrome (AIDS) patients. These are the only two enteric protozoan parasites that remain in the case definition of AIDS till today. Leismaniasis, strongyloidiasis and toxoplasmosis are the three main opportunistic causes of systemic involvements reported in HIV-infected patients. Of these, toxoplasmosis is the most important parasitic infection associated with the central nervous system. Due to its complexity in nature, toxoplasmosis is the only parasitic disease capable of not only causing focal but also disseminated forms and it has been included in AIDS-defining illnesses (ADI) ever since. With the introduction of highly active anti-retroviral therapy (HAART), cryptosporidiosis, leishmaniasis, schistosomiasis, strongyloidiasis, and toxoplasmosis are among parasitic diseases reported in association with immune reconstitution inflammatory syndrome (IRIS). This review addresses various aspects of parasitic infections in term of clinical, diagnostic and therapeutic challenges associated with HIV-infection. PMID:22310820

  17. Parasitic infections in HIV infected individuals: diagnostic & therapeutic challenges.

    PubMed

    Nissapatorn, Veeranoot; Sawangjaroen, Nongyao

    2011-12-01

    After 30 years of the human immunodeficiency virus (HIV) epidemic, parasites have been one of the most common opportunistic infections (OIs) and one of the most frequent causes of morbidity and mortality associated with HIV-infected patients. Due to severe immunosuppression, enteric parasitic pathogens in general are emerging and are OIs capable of causing diarrhoeal disease associated with HIV. Of these, Cryptosporidium parvum and Isospora belli are the two most common intestinal protozoan parasites and pose a public health problem in acquired immunodeficiency syndrome (AIDS) patients. These are the only two enteric protozoan parasites that remain in the case definition of AIDS till today. Leishmaniasis, strongyloidiasis and toxoplasmosis are the three main opportunistic causes of systemic involvements reported in HIV-infected patients. Of these, toxoplasmosis is the most important parasitic infection associated with the central nervous system. Due to its complexity in nature, toxoplasmosis is the only parasitic disease capable of not only causing focal but also disseminated forms and it has been included in AIDS-defining illnesses (ADI) ever since. With the introduction of highly active anti-retroviral therapy (HAART), cryptosporidiosis, leishmaniasis, schistosomiasis, strongyloidiasis, and toxoplasmosis are among parasitic diseases reported in association with immune reconstitution inflammatory syndrome (IRIS). This review addresses various aspects of parasitic infections in term of clinical, diagnostic and therapeutic challenges associated with HIV-infection. PMID:22310820

  18. Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways.

    PubMed

    Spear, Mark; Guo, Jia; Wu, Yuntao

    2013-11-01

    The human immunodeficiency virus-1 (HIV-1) infects helper CD4(+) T cells, and causes CD4(+) T-cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV-dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4(+) T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post-entry migration has led to the nascent model of virus-host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway-based anti-HIV drugs that are currently in development or testing. PMID:24117829

  19. Novel anti-HIV therapeutics targeting chemokine receptors and actin regulatory pathways

    PubMed Central

    Spear, Mark; Guo, Jia; Wu, Yuntao

    2013-01-01

    Summary The human immunodeficiency virus-1 (HIV-1) infects helper CD4+ T cells, and causes CD4+ T-cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV-dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4+ T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post-entry migration has led to the nascent model of virus-host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway-based anti-HIV drugs that are currently in development or testing. PMID:24117829

  20. Toward a cure for HIV--Seeking effective therapeutic vaccine strategies.

    PubMed

    Autran, Brigitte

    2015-12-01

    This review article focuses on the rationale and evaluation of therapeutic vaccines against HIV. This strategy has been developed in order to restore or restimulate HIV-specific immunity in patients treated with antiretroviral therapies. Despite the lack of good candidate vaccines against HIV, two objectives have been targeted during the past 15 years. Therapeutic immunization was first proposed to help control virus relapses during treatment interruptions. More recently, the concept of therapeutic immunization has been boosted by efforts to reach HIV remission or cure, in combination to HIV reactivating agents, to help purge HIV reservoirs in a "shock and kill" strategy. This review analyses the rationales for these strategies and the results of the most widely therapeutic vaccines designed to generate T-cell immunity, i.e. recombinant viral vectors and dendritic cell-based strategies, while extremely few strategies targeted HIV-specific Abs. Only marginal control of HIV was obtained with cellular-based strategies, suggesting that approaches targeting or using broadly neutralizing Abs, should be of benefit for future efforts of therapeutic immunization against HIV in the quest toward a cure for HIV. PMID:26542079

  1. HIV Testing Among Teens Attending Therapeutic Schools: Having a Personal Source of Information About HIV/AIDS Matters!

    PubMed

    Swenson, Rebecca R; Houck, Christopher; Sarfati, David; Emerson, Erin; Donenberg, Geri; Brown, Larry K

    2015-06-01

    Being informed and using positive coping strategies are associated with engaging in health-promoting behaviors. We assessed whether the type of information source about HIV (personal or impersonal) and coping strategies (optimism, avoidance, or emotion-focused) are associated with HIV testing among adolescents attending therapeutic schools. Participants were 417 adolescents, ages 13-19, who attended one of 20 therapeutic day schools for emotionally/behaviorally disordered youth in two US cities (Providence, RI and Chicago, IL) and completed a baseline assessment for an HIV prevention study. Among adolescents in the study, 29% reported having been tested for HIV. Adolescents were more likely to have been tested if they were older, female, Hispanic, identified as non-heterosexual, came from lower SES households, and had recently had unprotected sex. Additionally, youth who endorsed greater use of optimistic thinking and emotion-focused coping, and who reported having been informed about HIV by more personal sources, were also more likely to have been tested for HIV. In a multivariate analysis, having had recent unprotected sex and having more personal sources of information about HIV/AIDS were independently associated with HIV testing. Study findings suggest that, controlling for sociodemographic background, sexual risk behavior, and coping strategy, HIV testing among adolescents with emotional and behavioral problems may be increased when adolescents learn about HIV/AIDS from personal sources such as their healthcare providers, family, and friends. PMID:25656380

  2. HIV-1 TAT and IMMUNE DYSREGULATION in AIDS PATHOGENESIS: a THERAPEUTIC TARGET.

    PubMed

    Chiozzini, Chiara; Toschi, Elena

    2016-01-01

    The HIV-1 transactivator Tat protein plays a key role in AIDS pathogenesis. Besides the Tat role as activator of HIV-1 transcription, it exerts several important functions on infected and uninfected cells. In fact, HIV-1 Tat is released by infected cells and is taken up by neighboring cells. In this way it regulates expression of viral and cellular genes and it modulates several cellular pathways leading to HIV-1 infection spreading and immune dysregulation. So far, Tat protein and the cellular pathways targeted by Tat may represent potential targets for new anti-HIV therapeutic approaches and vaccine development against AIDS. PMID:26302810

  3. HIV-1 gp120 as a therapeutic target: Navigating a moving labyrinth

    PubMed Central

    Acharya, Priyamvada; Lusvarghi, Sabrina; Bewley, Carole A.; Kwong, Peter D.

    2015-01-01

    Introduction The HIV-1 gp120 envelope (Env) glycoprotein mediates attachment of virus to human target cells that display requisite receptors, CD4 and co-receptor, generally CCR5. Despite high affinity interactions with host receptors and proof-of-principle by the drug maraviroc that interference with CCR5 provides therapeutic benefit, no licensed drug currently targets gp120. Areas covered An overview of the role of gp120 in HIV-1 entry and of sites of potential gp120 vulnerability to therapeutic inhibition is presented. Viral defenses that protect these sites and turn gp120 into a moving labyrinth are discussed together with strategies for circumventing these defenses to allow therapeutic targeting of gp120 sites of vulnerability. Expert opinion The gp120 envelope glycoprotein interacts with host proteins through multiple interfaces and has conserved structural features at these interaction sites. In spite of this, targeting gp120 for therapeutic purposes is challenging. Env mechanisms evolved to evade the humoral immune response also shield it from potential therapeutics. Nevertheless, substantial progress has been made in understanding HIV-1 gp120 structure and its interactions with host receptors, and in developing therapeutic leads that potently neutralize diverse HIV-1 strains. Synergies between advances in understanding, needs for therapeutics against novel viral targets, and characteristics of breadth and potency for a number of gp120-targetting lead molecules bodes well for gp120 as a HIV-1 therapeutic target. PMID:25724219

  4. High-Throughput Humanized Mouse Models for Evaluation of HIV-1 Therapeutics and Pathogenesis.

    PubMed

    Thomas, Tynisha; Seay, Kieran; Zheng, Jian Hua; Zhang, Cong; Ochsenbauer, Christina; Kappes, John C; Goldstein, Harris

    2016-01-01

    Mice cannot be used as a model to evaluate HIV-1 therapeutics because they do not become infected by HIV-1 due to structural differences between several human and mouse proteins required for HIV-1 replication. This has limited their use for in vivo assessment of anti-HIV-1 therapeutics and the mechanism by which cofactors, such as illicit drug use accelerate HIV-1 replication and disease course in substance abusers. Here, we describe the development and application of two in vivo humanized mouse models that are highly sensitive and useful models for the in vivo evaluation of candidate anti-HIV therapeutics. The first model, hu-spl-PBMC-NSG mice, uses NOD-SCID IL2rγ(-/-) (NSG) mice intrasplenically injected with human peripheral blood mononuclear cells (PBMC) which develop productive splenic HIV-1 infection after intrasplenic inoculation with a replication-competent HIV-1 expressing Renilla reniformis luciferase (HIV-LucR) and enables investigators to use bioluminescence to visualize and quantitate the temporal effects of therapeutics on HIV-1 infection. The second model, hCD4/R5/cT1 mice, consists of transgenic mice carrying human CD4, CCR5 and cyclin T1 genes, which enables murine CD4-expressing cells to support HIV-1 entry, Tat-mediated LTR transcription and consequently develop productive infection. The hCD4/R5/cT1 mice develop disseminated infection of tissues including the spleen, small intestine, lymph nodes and lungs after intravenous injection with HIV-1-LucR. Because these mice can be infected with HIV-LucR expressing transmitted/founder and clade A/E and C Envs, these mouse models can also be used to evaluate the in vivo efficacy of broadly neutralizing antibodies and antibodies induced by candidate HIV-1 vaccines. Furthermore, because hCD4/R5/cT1 mice can be infected by vaginal inoculation with replication-competent HIV-1 expressing NanoLuc (HIV-nLucR)-, this mouse model can be used to evaluate the mechanisms by which substance abuse and other factors enhance mucosal transmission of HIV-1. PMID:26714715

  5. [HIV/AIDS in The Netherlands: improved treatment possibilities necessitate HIV instead of AIDS surveillance].

    PubMed

    Termorshuizen, F; Houweling, H

    1997-10-01

    An abrupt decrease of the number of reported new AIDS cases took place in the first half of 1997 in the Netherlands. This decrease was most prominent in homosexual/bisexual men and intravenous drug users, and less conspicuous in heterosexual men and women. The number of heterosexual patients with a non-Dutch nationality even increased compared with the first half of 1996. The most probable explanation of these observations is the introduction of improved treatment possibilities for HIV-infected people starting July 1996, which lead to a longer incubation period. Owing to these developments monitoring the HIV/AIDS epidemic in the Netherlands will depend more and more on HIV status surveillance instead of on registration of new AIDS cases. PMID:9550740

  6. Understanding HIV infection for the design of a therapeutic vaccine. Part I: Epidemiology and pathogenesis of HIV infection.

    PubMed

    de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A

    2015-03-01

    HIV infection leads to a gradual loss CD4+ T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive life-long adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. PMID:25496723

  7. CARBOHYDRATE – BASED EXPERIMENTAL THERAPEUTICS FOR CANCER, HIV/AIDS AND OTHER DISEASES

    PubMed Central

    Oppenheimer, Steven B.; Alvarez, Maribel; Nnoli, Jennifer

    2008-01-01

    SUMMARY This review, primarily for general readers, briefly presents experimental approaches to therapeutics of cancer, HIV/AIDS and various other diseases based on advances in glycobiology and glycochemistry. Experimental cancer and HIV/AIDS vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate – rich surface antigens using carriers, adjuvants and novel carbohydrate antigen constructs. Current carbohydrate – based vaccines are used for typhus, pneumonia, meningitis and vaccines for anthrax, malaria and leishmaniasis are under development. The link between O– linked β-N-acetylglucosamine glycosylation and protein phosphorylation in diseases including diabetes and Alzheimer's disease is also explored. Carbohydrate – associated drugs that are in current use or under development such as heparan sulphate binders, lectins, acarbose, aminoglycosides, tamiflu, and heparin, and technologies using carbohydrate and lectin microarrays, that offer improved diagnostic and drug development possibilities, are described. Advances in carbohydrate synthesis, analysis, and manipulation through the emerging fields of glycochemistry and glycobiology, are providing new approaches to disease therapeutics. PMID:17963823

  8. Transglutaminase activity as a possible therapeutical target in neurodegenerative diseases.

    PubMed

    Iannaccone, Martina; Titta, Federica; Serretiello, Enrica; De Vivo, Giulia; Martin, Antonio; Gentile, Vittorio

    2013-12-01

    Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. For example, neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible molecular mechanisms responsible for such diseases and on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity. The article presents some promising patents on the transglutaminase activity. PMID:24286449

  9. Cerebral glucose transporter: the possible therapeutic target for ischemic stroke.

    PubMed

    Zhang, Shuai; Zuo, Wei; Guo, Xiao-Feng; He, Wen-Bin; Chen, Nai-Hong

    2014-05-01

    Hyperglycemia is considered to be associated with poor outcomes of ischemic stroke. However, it is controversial about the blood glucose-lowering therapy in patients with stroke. According to the current reports, hyperglycemia is an indicator of severe stroke and cannot increase cerebral glucose content but promotes further ischemia in brain. Consequently, cerebral glucose control is significant to maintain the energy homeostasis. Compared with blood glucose level, the cerebral glucose content, controlled by glucose transporters (GLUTs), is more directly and important to maintain the energy supply in brain, especially to the patients with ischemic stroke. Some active materials, such as Glucagon-like peptide-1, progesterone, tPA and N-acetylcysteine, have been found to ameliorate ischemic stroke by regulating GLUTs expression. Therefore, this review discusses the significance of cerebral glucose level and GLUTs. Additionally, cerebral GLUTs and their actions in ischemic stroke are detailed in order to promote research on GLUTs as a possible therapeutic target for ischemic stroke. PMID:24657444

  10. Pioglitazone and Endothelial Dysfunction: Pleiotropic Effects and Possible Therapeutic Implications.

    PubMed

    Radenković, Miroslav

    2014-12-01

    The vascular endothelium has a central role in the modulation of vascular tone with associated antioxidant, anti-inflammatory, pro-fibrinolytic, anti-adhesive, and anticoagulant effects. This is primarily accomplished by the timely release of endothelial autacoids. On the other hand, endothelial dysfunction (ED) provoked by insulin resistance has been linked with reduced nitric oxide bioavailability, increased production of reactive oxygen species, and alterations of endothelial regeneration. Pioglitazone is classified as an insulin-sensitizing, anti-hyperglycemic agent. The mechanism of action associated with pioglitazone includes the activation of peroxisome proliferator-activated receptor-gamma with stable improvement in glycemic control in diabetic patients. Today, it is known that apart from the beneficial effects on glucose homeostasis, pioglitazone exerts several pleiotropic effects, including the improvement of ED. Thus, the aim of this article was to summarize the current knowledge related to signaling mechanisms of the pioglitazone-induced improvement or reversal of ED. The relevant clinical studies and possible therapeutic implications connected to pioglitazone-related action on the endothelium were analyzed too. PMID:26171320

  11. Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation

    PubMed Central

    Chervyakov, Alexander V.; Chernyavsky, Andrey Yu.; Sinitsyn, Dmitry O.; Piradov, Michael A.

    2015-01-01

    Transcranial magnetic stimulation (TMS) is an effective method used to diagnose and treat many neurological disorders. Although repetitive TMS (rTMS) has been used to treat a variety of serious pathological conditions including stroke, depression, Parkinson’s disease, epilepsy, pain, and migraines, the pathophysiological mechanisms underlying the effects of long-term TMS remain unclear. In the present review, the effects of rTMS on neurotransmitters and synaptic plasticity are described, including the classic interpretations of TMS effects on synaptic plasticity via long-term potentiation and long-term depression. We also discuss the effects of rTMS on the genetic apparatus of neurons, glial cells, and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth and sprouting and neurotrophic factors are described, including change in brain-derived neurotrophic factor concentration under the influence of rTMS. Also, non-classical effects of TMS related to biophysical effects of magnetic fields are described, including the quantum effects, the magnetic spin effects, genetic magnetoreception, the macromolecular effects of TMS, and the electromagnetic theory of consciousness. Finally, we discuss possible interpretations of TMS effects according to dynamical systems theory. Evidence suggests that a rTMS-induced magnetic field should be considered a separate physical factor that can be impactful at the subatomic level and that rTMS is capable of significantly altering the reactivity of molecules (radicals). It is thought that these factors underlie the therapeutic benefits of therapy with TMS. Future research on these mechanisms will be instrumental to the development of more powerful and reliable TMS treatment protocols. PMID:26136672

  12. Evaluating the potential of IL-27 as a novel therapeutic agent in HIV-1 infection

    PubMed Central

    Swaminathan, Sanjay; Dai, Lue; Lane, H. Clifford; Imamichi, Tomozumi

    2013-01-01

    Interleukin 27 (IL-27) is an immunomodulatory cytokine with important roles in both the innate and adaptive immune systems. In the last five years, the addition of exogenous IL-27 to primary cell cultures has been demonstrated to decrease HIV-1 replication in a number of cell types including peripheral blood mononuclear cells (PBMCs), CD4+ T cells, macrophages and dendritic cells. These in-vitro findings suggest that IL-27 may have therapeutic value in the setting of HIV-1 infection. In this review, we describe the current knowledge of the biology of IL-27, its effects primarily on HIV-1 replication but also in other viral infections and explore its potential role as a therapeutic cytokine for the treatment of patients with HIV-1 infection. PMID:23962745

  13. Malignancies in HIV/AIDS: from epidemiology to therapeutic challenges.

    PubMed

    Rubinstein, Paul G; Aboulafia, David M; Zloza, Andrew

    2014-02-20

    The incidence of AIDS-defining cancers (ADCs) - Kaposi sarcoma, primary central nervous system lymphoma, non-Hodgkin lymphoma, and cervical cancer - although on the decline since shortly after the introduction of HAART, has continued to be greater even in treated HIV-infected persons than in the general population. Although the survival of newly infected people living with HIV/AIDS now rivals that of the general population, morbidity and mortality associated with non-AIDS-defining cancers (NADCs) such as lung, liver, anal, and melanoma are significant and also continue to rise. Increasing age (i.e. longevity) is the greatest risk factor for NADCs, but longevity alone is not sufficient to fully explain these trends in cancer epidemiology. In this review, we briefly review the epidemiology and etiology of cancers seen in HIV/AIDS, and in this context, discuss preclinical research and broad treatment considerations. Investigation of these considerations provides insight into why malignancies continue to be a major problem in the current era of HIV/AIDS care. PMID:24401642

  14. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions

    PubMed Central

    Graziani, Gina M; Angel, Jonathan B

    2015-01-01

    Introduction The development of an effective therapeutic HIV vaccine that induces immunologic control of viral replication, thereby eliminating or reducing the need for antiretroviral therapy (ART), would be of great value. Besides the obvious challenges of developing a therapeutic vaccine that would generate effective, sustained anti-HIV immunity in infected individuals is the issue of how to best assess the efficacy of vaccine candidates. Discussion This review discusses the various outcome measures assessed in therapeutic HIV vaccine clinical trials involving individuals receiving suppressive ART, with a particular focus on the role of analytical treatment interruption (ATI) as a way to assess the virologic control induced by an immunotherapy. This strategy is critical given that there are otherwise no readily available measures to determine the ability of a vaccine-induced immune response to effectively control HIV replication. The various outcome measures that have been used to assess vaccine efficacy in published therapeutic HIV vaccine clinical trials will also be discussed. Outcome measures have included the kinetics of viral rebound, the new viral set point and changes in the size of the viral reservoir. Clinically relevant outcomes such as the CD4 decline, the time to resume therapy or the time to meet the criterion to resume therapy, the proportion of participants who resume therapy and/or the development of clinical symptoms such as acute retroviral syndrome are also measures of vaccine efficacy. Conclusions Given the lack of consistency between therapeutic HIV vaccine trials in how efficacy is assessed, comparing vaccines has been difficult. It would, therefore, be beneficial to determine the most clinically relevant measure for use in future studies. Other recommendations for future clinical trials also include studying compartments in addition to blood and replacing ATIs with single-copy assays in situations in which the use of an ATI is not ideal. PMID:26561337

  15. Cell-penetrating peptides: Possible transduction mechanisms and therapeutic applications

    PubMed Central

    GUO, ZHENGRONG; PENG, HUANYAN; KANG, JIWEN; SUN, DIANXING

    2016-01-01

    Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse peptides with 5–30 amino acids. CPPs are divided into cationic, amphipathic and hydrophobic CPPs. They are able to carry small molecules, plasmid DNA, small interfering RNA, proteins, viruses, imaging agents and other various nanoparticles across the cellular membrane, resulting in internalization of the intact cargos. However, the mechanisms of CPP internalization remain to be elucidated. Recently, CPPs have received considerable attention due to their high transduction efficiency and low cytotoxicity. These peptides have a significant potential for diagnostic and therapeutic applications, such as delivery of fluorescent or radioactive compounds for imaging, delivery of peptides and proteins for therapeutic application, and delivery of molecules into induced pluripotent stem cells for directing differentiation. The present study reviews the classifications and transduction mechanisms of CPPs, as well as their potential applications. PMID:27123243

  16. Decelerating gastric emptying: therapeutic possibilities in type 2 diabetes.

    PubMed

    Phillips, W T; Schwartz, J G

    1996-09-01

    There is clear evidence of a positive correlation between carbohydrate absorption, plasma concentration of glucose, and the rate of gastric emptying. This suggests that clinical manipulation of gastric emptying rates may have therapeutic potential in glycaemic control. Cholecystokinin (CCK-8) has been shown to delay gastric emptying in individuals with Type 2 diabetes, but its potential as a therapy is limited by the need to administer it intravenously. The preferred routes of administration would be intramuscular injections, an intranasal spray or the use of orally ingested CCK analogues. Alternatively, the oral administration of an agent that enhances endogenous release of CCK could represent an important approach to the treatment of Type 2 diabetes. Agents such as POT II may have a therapeutic indication in patients with recently diagnosed Type 2 diabetes. PMID:8894471

  17. Therapeutic Approaches to Eradicate Latent HIV-1 in Resting CD4+ T Cells.

    PubMed

    Sluis-Cremer, Nicolas

    2016-01-01

    While combination antiretroviral therapy (cART) can drive HIV-1 RNA levels to < 50 copies/mL in patient plasma, most infected individuals continue to harbor low-level persistent viremia. Latently infected resting CD4+ T cells are thought to constitute the major reservoir of HIV-1 persistence. In this reservoir, the integrated provirus remains transcriptionally silent as long as the host cell is in a resting state. On discontinuation of cART, these viruses can reactivate and lead to waves of de novo infection events. The prevailing hypothesis in the field is that molecules that reactivate latent HIV-1 infection will purge this reservoir by inducing transcription of the latent provirus, thereby causing cells to undergo apoptosis. This review article summarizes the results of all therapeutic approaches that have been clinically evaluated for their potential to reverse HIV latency. PMID:26324046

  18. HBV and HIV co-infection: Impact on liver pathobiology and therapeutic approaches

    PubMed Central

    Parvez, Mohammad Khalid

    2015-01-01

    The consequences of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection on progression of severe liver diseases is a serious public health issue, worldwide. In the co-infection cases, about 90% of HIV-infected population is seropositive for HBV where approximately 5%-40% individuals are chronically infected. In HIV co-infected individuals, liver-related mortality is estimated over 17 times higher than those with HBV mono-infection. The spectrum of HIV-induced liver diseases includes hepatitis, steatohepatitis, endothelialitis, necrosis, granulomatosis, cirrhosis and carcinoma. Moreover, HIV co-infection significantly alters the natural history of hepatitis B, and therefore complicates the disease management. Though several studies have demonstrated impact of HIV proteins on hepatocyte biology, only a few data is available on interactions between HBV and HIV proteins. Thus, the clinical spectrum as well as the complexity of the co-infection offers challenging fronts to study the underlying molecular mechanisms, and to design effective therapeutic strategies. PMID:25625003

  19. Host Factors and HIV-1 Replication: Clinical Evidence and Potential Therapeutic Approaches

    PubMed Central

    Santa-Marta, Mariana; de Brito, Paula Matos; Godinho-Santos, Ana; Goncalves, Joao

    2013-01-01

    HIV and human defense mechanisms have co-evolved to counteract each other. In the process of infection, HIV takes advantage of cellular machinery and blocks the action of the host restriction factors (RF). A small subset of HIV+ individuals control HIV infection and progression to AIDS in the absence of treatment. These individuals known as long-term non-progressors (LNTPs) exhibit genetic and immunological characteristics that confer upon them an efficient resistance to infection and/or disease progression. The identification of some of these host factors led to the development of therapeutic approaches that attempted to mimic the natural control of HIV infection. Some of these approaches are currently being tested in clinical trials. While there are many genes which carry mutations and polymorphisms associated with non-progression, this review will be specifically focused on HIV host RF including both the main chemokine receptors and chemokines as well as intracellular RF including, APOBEC, TRIM, tetherin, and SAMHD1. The understanding of molecular profiles and mechanisms present in LTNPs should provide new insights to control HIV infection and contribute to the development of novel therapies against AIDS. PMID:24167505

  20. [Novel possibilities of development and therapeutical application of liposomes].

    PubMed

    Bozó, Tamás; Pál, Szilárd; Dévay, Attila

    2008-01-01

    Properties and possibilities of application of liposomal drug delivery systems are summarized in this review. Technological and biopharmeceutical criteria that have to be taken into consideration in the course of development of biocompatible liposomes are discussed. The manner and possibilities of active and passive targeting are shown according to the literary data and special liposome-based drug delivery systems responsible for pathologic or arteficial stimuli are introduced. PMID:18986087

  1. [Genetic determinant factors of resistance to HIV infection and of control of progression to AIDS: implications on pathogenesis and therapeutic approaches for the eradication of HIV. A review].

    PubMed

    Zúñiga, J; Vargas-Alarcón, G; Salgado, N; Flores, C; Martínez-Tripp, S; Miranda, A; Balbuena, A; Osnaya, N; Juárez, F; Granados, J; Reyes-Terán, G

    2000-01-01

    In this review, we describe and discuss the genetic factors that, up to some point, determine resistance to the infection and control the progression of the disease in HIV-infected individuals. Genetic factors may account for non-progression or slow progression of the disease in some of so called long-term non progressors HIV-infected individuals. In general, this group shows no symptoms for more than 10 years, while their circulating T CD4+ cells levels remain stable and they usually have a low virus load. Even though non-progression and rapid progression phenomenon are still not fully understood, there probability exists that some class I and class II MHC alleles are associated with a greater or smaller risk to develop AIDS. Class I HLA-B*35 and Cw*04 alleles are the ones commonly associated with the rapid transition of the infection into AIDS. In contrast, heterozygosity for class I HLA alleles and, particularly, the absence of HLA-B*35 and Cw*04 may contribute to non-progression. Studies which set forward other HLA alleles as possibly taking part of the pathogenic mechanism of non-progression are also described; although, relevant methodological problems can be noticed. Furthermore, this review explains and discusses allelic variations for some of the components of the chemokine receptors family, particularly the genes which codify for CCR5 and CCR2 and other genetic factors such as the SDF1-3'. A variant of the alpha SDF1 chemokine gene that have been associated with AIDS' slow progression or non-progression in HIV-infected individuals. As a whole, the factors described in this review are those that influence the natural history of the disease due to HIV and give an example of what genetic or multigenetic influence can have over the pattern of evolution of HIV infection. Finally, we mention the possible implications that the identification of the genetic markers has in the pathogenesis of HIV disease and in the development of the new therapeutic strategies to control or eliminate HIV. PMID:10953612

  2. Indian herbal medicines: possible potent therapeutic agents for rheumatoid arthritis.

    PubMed

    Rathore, Brijesh; Ali Mahdi, Abbas; Nath Paul, Bhola; Narayan Saxena, Prabhu; Kumar Das, Siddharth

    2007-07-01

    Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA. PMID:18392103

  3. Indian Herbal Medicines: Possible Potent Therapeutic Agents for Rheumatoid Arthritis

    PubMed Central

    Rathore, Brijesh; Ali Mahdi, Abbas; Nath Paul, Bhola; Narayan Saxena, Prabhu; Kumar Das, Siddharth

    2007-01-01

    Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology and is mainly characterized by the progressive erosion of cartilage leading to chronic polyarthritis and joint distortion. Although the exact pathogenesis of the disease has yet not been elucidated, however, studies suggest that cellular proliferation of synoviocytes result in pannus formation which damages the cartilage and bone. Recent reports also support the role of free radicals in its pathogenesis. Apart from the conventional treatment strategies using nonsteroidal anti-inflammatory drugs, disease modifying antirheumatic drugs and glucocorticoids, newer and safer drugs are continuously being searched, as long term usage of these drugs have resulted in adverse effects. Alternative medicine provides another approach for treatment of RA and currently a number of medicinal plants are under scientific evaluation to develop a novel drug. There is a dire need to investigate the complete therapeutic potential and adverse effects, if any, of these herbals for providing newer and safer treatment options with minimum side effects. In this review we have tried to explore various Indian ancient Ayurvedic, Unani and Tibbi, as also some Chinese and Korean, herbals for their potential to treat RA. PMID:18392103

  4. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets?

    PubMed

    Serafini, Gianluca; Hayley, Shawn; Pompili, Maurizio; Dwivedi, Yogesh; Brahmachari, Goutam; Girardi, Paolo; Amore, Mario

    2014-01-01

    Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis. Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel alternative antidepressant medications that target these systems is discussed in this review. PMID:25470403

  5. Past experiences, current realities and future possibilities for HIV nursing education and care in Canada

    PubMed Central

    Mill, Judy; Caine, Vera; Arneson, Cheryl; Maina, Geoffrey; De Padua, Anthony; Dykeman, Margaret

    2016-01-01

    Nurses may have inadequate basic education and opportunities for continuing education in relation to HIV care. As well nurses may perpetuate and impose stigma. We developed, implemented and evaluated an educational intervention to reduce stigma and discrimination among nurses providing HIV care. The intervention used a mentorship model that brought experienced nurses in HIV care and people living with HIV together with nurses who wanted to learn more about HIV nursing care. We examined our findings in relation to past experiences, current realities and future possibilities for HIV nursing education and care in Canada. Our findings demonstrated that many nurses were interested in improving their HIV care, yet few opportunities existed for them to do so. We found that HIV nursing education and expertise were significantly different among participants and across clinical sites. This difference was visible in basic education, services offered for HIV and AIDS care, the collaborative and inter-professional nature of care, and opportunities for continuing education. Mentorship education is an effective strategy to not only address a critical void in knowledge, but also to promote a fundamental shift in attitudes. With the recent call by the World Health Organization to place nurses in key positions to provide HIV care, treatment and prevention, it is imperative to prepare nurses at both the undergraduate and graduate level, as well as those in practice, to fulfill this call.

  6. HIV-infected People in Sudan Moving Toward Chronic Poverty: Possible Interventions.

    PubMed

    Ismail, Salwa Muddthir; Eisa, Ammar Abobakre; Ibrahim, Faisal

    2016-01-01

    We sought to identify the socioeconomic impact on people living with HIV (PLWH) in Sudan. Focus group discussions were used to collect data and identify the most outstanding domains of HIV impact on PLWH and the survival mechanisms that may be common to a group of diverse HIV-infected persons (n = 30). The findings indicated that the most striking financial and social impacts were due to stigma associated with HIV in the conservative Sudanese society, which led to loss of work with all its consequences (e.g., children's education and health care expenses were affected). The socioeconomic impacts of HIV on infected populations are discussed, and suggestions for possible interventions to mitigate harmful impacts and stigma within the society, the workplace, and health care settings are highlighted. We concluded that HIV has intensified the existing problems of infected people, contributing to their vulnerability to poverty. PMID:26190419

  7. Intracellular signals of lung cancer cells as possible therapeutic targets

    PubMed Central

    Tanaka, Kiyomichi; Kumano, Keiki; Ueno, Hiroo

    2015-01-01

    In recent years, several molecularly targeted therapies have been developed as part of lung cancer treatment; they have produced dramatically good results. However, among the many oncogenes that have been identified to be involved in the development of lung cancers, a number of oncogenes are not covered by these advanced therapies. For the treatment of lung cancers, which is a group of heterogeneous diseases, persistent effort in developing individual therapies based on the respective causal genes is important. In addition, for the development of a novel therapy, identification of the lung epithelial stem cells and the origin cells of lung cancer, and understanding about candidate cancer stem cells in lung cancer tissues, their intracellular signaling pathways, and the mechanism of dysregulation of the pathways in cancer cells are extremely important. However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well-known phenomenon. In this article, we discuss major causal genes of lung cancers and intracellular signaling pathways involving those genes, and review studies on origin and stem cells of lung cancers, as well as the possibility of developing molecularly targeted therapies based on these studies. PMID:25707772

  8. Cytokine production and dysregulation in HIV pathogenesis: Lessons for development of therapeutics and vaccines

    PubMed Central

    Reuter, Morgan A.; Pombo, Carolina; Betts, Michael R.

    2012-01-01

    Numerous studies have characterized the cytokine modulation observed in human immunodeficiency virus (HIV) infected individuals, from initial infection through chronic disease. Progressive and non-progressive HIV infection models show the cytokine milieu differs in terms of production and responsiveness in these two groups, suggesting an understanding of the role cytokines play during infection is necessary for directing the immune response toward viral control. This review will cover cytokine induction and dysfunction during HIV pathogenesis, with a focus on the interplay between cytokines and transcription factors, T cell activation, and exhaustion. We highlight cytokines that have either vaccine adjuvant or therapeutic potential and discuss the need to identify key factors required for prevention of progression, clearance of infection, or protection from acquisition. PMID:22743036

  9. Exploring the Potential of Monoclonal Antibody Therapeutics for HIV-1 Eradication

    PubMed Central

    Euler, Zelda

    2015-01-01

    Abstract The HIV field has seen an increased interest in novel cure strategies. In particular, new latency reversal agents are in development to reverse latency to flush the virus out of its hiding place. Combining these efforts with immunotherapeutic approaches may not only drive the virus out of latency, but allow for the rapid elimination of these infected cells in a “shock and kill” approach. Beyond cell-based approaches, growing interest lies in the potential use of functionally enhanced “killer” monoclonal therapeutics to purge the reservoir. Here we discuss prospects for a monoclonal therapeutic-based “shock and kill” strategy that may lead to the permanent elimination of replication-competent virus, making a functional cure a reality for all patients afflicted with HIV worldwide. PMID:25385703

  10. Hck inhibitors as potential therapeutic agents in cancer and HIV infection.

    PubMed

    Musumeci, F; Schenone, S; Brullo, C; Desogus, A; Botta, L; Tintori, C

    2015-01-01

    Hematopoietic cell kinase (Hck) is a member of the Src-family of non-receptor tyrosine kinases, which plays many roles in signalling pathways involved in the regulation of cell processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It participates in phagocytosis, adhesion, migration, regulation of protrusion formation on cell membrane, lysosome exocytosis, podosome formation and actin polymerization. More importantly from a medicinal chemistry point of view, high levels of Hck are involved in chronic myeloid leukemia and other hematologic tumors. Furthermore, Hck activity has been associated with virus infections including HIV-1. In particular, Hck is activated by the HIV-1 accessory protein Nef, a multifunctional HIV-1 protein that accelerates progression to AIDS and enhances the infectivity of progeny viruses. Nef binding to Hck leads to kinase activation which is important in AIDS pathogenesis. For these reasons, Hck represents a potentially good therapeutic target for the treatment of both specific cancers and HIV infection. This article summarizes Hck biological activities connected with malignancies and HIV infection, many of which have been only recently reported, and presents an overview of the compounds endowed with Hck inhibitory activity, especially focusing on the medicinal chemistry aspect. PMID:25666803

  11. CXCL8 as a Potential Therapeutic Target for HIV-Associated Neurocognitive Disorders.

    PubMed

    Mamik, Manmeet K; Ghorpade, Anuja

    2016-01-01

    Chemokine CXCL8 is a low molecular weight neutrophil chemoattractant implicated in various neurodegenerative disorders including Alzheimer's disease and stroke. Increased expression of CXCL8 has been reported in serum, plasma and brain of human immunodeficiency virus (HIV)-1 infected individuals with neurocognitive impairment, indicating its role in neuroinflammation associated with HIV-1 infection of the brain. Since chemokines are critical in eliciting immune responses in the central nervous system (CNS), CXCL8 is of particular importance for being one of the first chemokines described in the brain. Activation of astrocytes and microglia by HIV-1 and virus associated proteins results in production of this chemokine in the brain microenvironment. Consequently, CXCL8 exerts its effect on target cells via Gprotein coupled receptors CXCR1 and CXCR2. Neutrophils are the main target cells for CXCL8; however, microglia and neurons also express CXCR1/CXCR2 and therefore are important targets for CXCL8-mediated crosstalk. The objective of this review is to focus on CXCL8 production, signaling and regulation in neuronal and glial cells in response to HIV-1 infection. We highlight the role of HIV-1 secreted proteins such as trans-activator of transcription, envelope glycoprotein, negative regulatory factor and viral protein r in the regulation of CXCL8. We discuss dual role of CXCL8 in neurodegeneration as well as neuroprotection in the CNS. Thus, targeting CXCL8 through the development of CXCR1/CXCR2-based therapeutic strategies to either selectively agonize or antagonize receptors may be able to selectively promote neuroprotective and anti-inflammatory outcomes, leading to significant clinical applications in many neuroinflammatory CNS diseases, including HIV-associated neurocognitive disorders. PMID:26112047

  12. HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies

    PubMed Central

    Battistini, Angela; Sgarbanti, Marco

    2014-01-01

    The major obstacle towards HIV-1 eradication is the life-long persistence of the virus in reservoirs of latently infected cells. In these cells the proviral DNA is integrated in the host’s genome but it does not actively replicate, becoming invisible to the host immune system and unaffected by existing antiviral drugs. Rebound of viremia and recovery of systemic infection that follows interruption of therapy, necessitates life-long treatments with problems of compliance, toxicity, and untenable costs, especially in developing countries where the infection hits worst. Extensive research efforts have led to the proposal and preliminary testing of several anti-latency compounds, however, overall, eradication strategies have had, so far, limited clinical success while posing several risks for patients. This review will briefly summarize the more recent advances in the elucidation of mechanisms that regulates the establishment/maintenance of latency and therapeutic strategies currently under evaluation in order to eradicate HIV persistence. PMID:24736215

  13. Inhibition of the HIV Rev transactivator : a new target for therapeutic intervention.

    PubMed

    Heguy, A

    1997-01-01

    The viral transactivator Rev is essential for HIV replication, since it allows the nuclear export of unspliced and partially spliced viral mRNAs that encode the structural proteins. Rev is an RNA binding protein that interacts with a highly structured RNA element, the RRE, found within the envelope sequences. This viral protein also interacts with cellular proteins, termed nucleoporins, and acts as an adaptor between the viral mRNAs and the cellular nuclear export machinery. Both interactions are specific, and required for Rev function. Because of its crucial role in the HIV replication cycle, and its novel mechanism of action, Rev represents an ideal target for therapeutic intervention. This review describes the efforts towards Rev inhibition. Gene therapy approaches, including the expression of trans-dominant mutants and RNA decoys, as well as antisense therapies and small molecule inhibitors of Rev-RRE binding or Rev interaction with the cellular machinery will be discussed PMID:9206979

  14. Dose–response curve slope helps predict therapeutic potency and breadth of HIV broadly neutralizing antibodies

    PubMed Central

    Webb, Nicholas E.; Montefiori, David C.; Lee, Benhur

    2015-01-01

    A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose–response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120–gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations. PMID:26416571

  15. Epigenetic Modulations in Activated Cells Early after HIV-1 Infection and Their Possible Functional Consequences

    PubMed Central

    Maricato, Juliana T.; Furtado, Maria N.; Takenaka, Maisa C.; Nunes, Edsel R. M.; Fincatti, Patricia; Meliso, Fabiana M.; da Silva, Ismael D. C. G.; Jasiulionis, Miriam G.; Ceclia de Araripe Sucupira, Maria; Diaz, Ricardo Sobhie; Janini, Luiz M. R.

    2015-01-01

    Epigenetic modifications refer to a number of biological processes which alter the structure of chromatin and its transcriptional activity such as DNA methylation and histone post-translational processing. Studies have tried to elucidate how the viral genome and its products are affected by epigenetic modifications imposed by cell machinery and how it affects the ability of the virus to either, replicate and produce a viable progeny or be driven to latency. The purpose of this study was to evaluate epigenetic modifications in PBMCs and CD4+ cells after HIV-1 infection analyzing three approaches: (i) global DNA- methylation; (ii) qPCR array and (iii) western blot. HIV-1 infection led to methylation increases in the cellular DNA regardless the activation status of PBMCs. The analysis of H3K9me3 and H3K27me3 suggested a trend towards transcriptional repression in activated cells after HIV-1 infection. Using a qPCR array, we detected genes related to epigenetic processes highly modulated in activated HIV-1 infected cells. SETDB2 and RSK2 transcripts showed highest up-regulation levels. SETDB2 signaling is related to transcriptional silencing while RSK2 is related to either silencing or activation of gene expression depending on the signaling pathway triggered down-stream. In addition, activated cells infected by HIV-1 showed lower CD69 expression and a decrease of IL-2, IFN-? and metabolism-related factors transcripts indicating a possible functional consequence towards global transcriptional repression found in HIV-1 infected cells. Conversely, based on epigenetic markers studied here, non-stimulated cells infected by HIV-1, showed signs of global transcriptional activation. Our results suggest that HIV-1 infection exerts epigenetic modulations in activated cells that may lead these cells to transcriptional repression with important functional consequences. Moreover, non-stimulated cells seem to increase gene transcription after HIV-1 infection. Based on these observations, it is possible to speculate that the outcome of viral infections may be influenced by the cellular activation status at the moment of infection. PMID:25875202

  16. The highly specific carbohydrate-binding protein cyanovirin-N: structure, anti-HIV/Ebola activity and possibilities for therapy.

    PubMed

    Barrientos, Laura G; Gronenborn, Angela M

    2005-01-01

    Cyanovirin-N (CV-N), a cyanobacterial lectin, is a potent viral entry inhibitor currently under development as a microbicide against a broad spectrum of enveloped viruses. CV-N was originally identified as a highly active anti-HIV agent and later, as a virucidal agent against other unrelated enveloped viruses such as Ebola, and possibly other viruses. CV-N's antiviral activity appears to involve unique recognition of N-linked high-mannose oligosaccharides, Man-8 and Man-9, on the viral surface glycoproteins. Due to its distinct mode of action and opportunities for harnessing the associated interaction for therapeutic intervention, a substantial body of research on CV-N has accumulated since its discovery in 1997. In this review we focus in particular on structural studies on CV-N and their relationship to biological activity. PMID:15638789

  17. Role of fever in infection: has induced fever any therapeutic potential in HIV infection?

    PubMed Central

    Morton, R S; Rashid, S

    1997-01-01

    Ancient societies had no rational understanding of fever. The Greeks were the first to recognise that it may be part of nature's method of effecting cure in some diseases. How best to assist nature went through many trials and errors. Appreciation of the prognostic value of fever and how it may be controlled was slow to appear. That there was a place in the therapeutic arsenal for induced fever came only with the 20th century. Finding a suitable, safe, and satisfactory means came slowly. The curative power of well controlled and reproducible levels of fever was proved by the arrest of one deadly and incurable complication of a sexually transmitted disease in the first half of this century. The purpose of this review is to promote discussion and, hopefully, well ordered laboratory and clinical trials aimed at learning whether or not induced fevers have a place in the care of patients with HIV/AIDS. Images PMID:9306904

  18. Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: a randomised placebo-controlled study.

    PubMed

    Harrer, Thomas; Plettenberg, Andreas; Arastéh, Keikawus; Van Lunzen, Jan; Fätkenheuer, Gerd; Jaeger, Hans; Janssens, Michel; Burny, Wivine; Collard, Alix; Roman, François; Loeliger, Alfred; Koutsoukos, Marguerite; Bourguignon, Patricia; Lavreys, Ludo; Voss, Gerald

    2014-05-01

    The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination. Reactogenicity was clinically acceptable and no vaccine-related serious adverse events were reported. The frequency of HIV-1-specific CD4(+) T-cells 2 weeks post-dose 2 was significantly higher in the vaccine group than in the placebo group in both cohorts (p<0.05). Vaccine-induced HIV-1-specific CD4(+) T-cells exhibited a polyfunctional phenotype, expressing at least CD40L and IL-2. No increase in HIV-1-specific CD8(+) T-cells or change in CD8(+) T-cell activation marker expression profile was detected. Absolute CD4(+) T-cell counts were variable over time in both cohorts. Viral load remained suppressed in ART-experienced subjects. In ART-naïve subjects, a transient reduction in viral load from baseline was observed 2 weeks after the second F4/AS01 dose, which was concurrent with a higher frequency of HIV-1-specific CD4(+) T-cells expressing at least IL-2 in this cohort. In conclusion, F4/AS01 showed a clinically acceptable reactogenicity and safety profile, and induced polyfunctional HIV-1-specific CD4(+) T-cell responses in ART-experienced and ART-naïve subjects. These findings support further clinical investigation of F4/AS01 as a potential HIV-1 vaccine for therapeutic use in individuals with HIV-1 infection. PMID:24144472

  19. Amyloid β-interacting partners in Alzheimer's disease: From accomplices to possible therapeutic targets.

    PubMed

    Han, Sun-Ho; Park, Jong-Chan; Mook-Jung, Inhee

    2016-02-01

    Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases in modern society because of insurmountable difficulties in early diagnosis and lack of therapeutic treatments. AD pathogenesis is tightly linked to the abnormal accumulation and aggregation of amyloid β (Aβ), seemingly the main causative factor of AD; however, intensive research on Aβ has not yet explained the complexity of AD pathogenesis. Consequently, the role of other supportive partners of Aβ have been elucidated and evaluated in the etiology of AD, and their potential molecular mechanisms have emerged as possible therapeutic targets. In this review, we compile information regarding Aβ-interacting partners in normal conditions and AD pathology, and analyze their etiological roles in diverse areas. Furthermore, we integrate this information into suggestions for probable clinical applications for AD diagnosis and therapeutics. We include Aβ-interacting partners localized to the cell surface and intracellular and extracellular compartments of different cell types ranging from the central nervous system to peripheral regions. Additionally, we expand the range of Aβ-interacting partners by including not only proteins, but also inorganic substances like metals, expecting that one of these partners may yield a critical breakthrough in the field of AD diagnostics and therapeutic drug development. PMID:26721621

  20. The Role of Chemokines in Breast Cancer Pathology and Its Possible Use as Therapeutic Targets

    PubMed Central

    Palacios-Arreola, M. Isabel; Nava-Castro, Karen E.; Castro, Julieta I.; García-Zepeda, Eduardo; Carrero, Julio C.; Morales-Montor, Jorge

    2014-01-01

    Chemokines are small proteins that primarily regulate the traffic of leukocytes under homeostatic conditions and during specific immune responses. The chemokine-chemokine receptor system comprises almost 50 chemokines and approximately 20 chemokine receptors; thus, there is no unique ligand for each receptor and the binding of different chemokines to the same receptor might have disparate effects. Complicating the system further, these effects depend on the cellular milieu. In cancer, although chemokines are associated primarily with the generation of a protumoral microenvironment and organ-directed metastasis, they also mediate other phenomena related to disease progression, such as angiogenesis and even chemoresistance. Therefore, the chemokine system is becoming a target in cancer therapeutics. We review the emerging data and correlations between chemokines/chemokine receptors and breast cancer, their implications in cancer progression, and possible therapeutic strategies that exploit the chemokine system. PMID:25165728

  1. Cross-Learning: The Possibilities of a Learning Dialogue between the HIV and AIDS and Disability Movements

    ERIC Educational Resources Information Center

    Rule, Peter

    2011-01-01

    Sub-Saharan Africa is the region of the world most affected by HIV & AIDS, accounting for two-thirds of the global burden of the pandemic. People with disabilities are regarded as a high-risk group for HIV but have been largely neglected in programmes of education, treatment and support. This paper examines the possibilities for a learning

  2. Cross-Learning: The Possibilities of a Learning Dialogue between the HIV and AIDS and Disability Movements

    ERIC Educational Resources Information Center

    Rule, Peter

    2011-01-01

    Sub-Saharan Africa is the region of the world most affected by HIV & AIDS, accounting for two-thirds of the global burden of the pandemic. People with disabilities are regarded as a high-risk group for HIV but have been largely neglected in programmes of education, treatment and support. This paper examines the possibilities for a learning…

  3. The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization

    PubMed Central

    Frecska, Ede; Bokor, Petra; Winkelman, Michael

    2016-01-01

    Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor (Sig-1R) agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: (1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and (2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the Sig-1R which can explain its widespread therapeutic indications. PMID:26973523

  4. The Therapeutic Potentials of Ayahuasca: Possible Effects against Various Diseases of Civilization.

    PubMed

    Frecska, Ede; Bokor, Petra; Winkelman, Michael

    2016-01-01

    Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor (Sig-1R) agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: (1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and (2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the Sig-1R which can explain its widespread therapeutic indications. PMID:26973523

  5. Therapeutic doses of irradiation activate viral transcription and induce apoptosis in HIV-1 infected cells.

    PubMed

    Iordanskiy, Sergey; Van Duyne, Rachel; Sampey, Gavin C; Woodson, Caitlin M; Fry, Kelsi; Saifuddin, Mohammed; Guo, Jia; Wu, Yuntao; Romerio, Fabio; Kashanchi, Fatah

    2015-11-01

    The highly active antiretroviral therapy reduces HIV-1 RNA in plasma to undetectable levels. However, the virus continues to persist in the long-lived resting CD4(+) T cells, macrophages and astrocytes which form a viral reservoir in infected individuals. Reactivation of viral transcription is critical since the host immune response in combination with antiretroviral therapy may eradicate the virus. Using the chronically HIV-1 infected T lymphoblastoid and monocytic cell lines, primary quiescent CD4(+) T cells and humanized mice infected with dual-tropic HIV-1 89.6, we examined the effect of various X-ray irradiation (IR) doses (used for HIV-related lymphoma treatment and lower doses) on HIV-1 transcription and viability of infected cells. Treatment of both T cells and monocytes with IR, a well-defined stress signal, led to increase of HIV-1 transcription, as evidenced by the presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the HIV-1 promoter. This correlated with the increased GFP signal and elevated level of intracellular HIV-1 RNA in the IR-treated quiescent CD4(+) T cells infected with GFP-encoding HIV-1. Exposition of latently HIV-1infected monocytes treated with PKC agonist bryostatin 1 to IR enhanced transcription activation effect of this latency-reversing agent. Increased HIV-1 replication after IR correlated with higher cell death: the level of phosphorylated Ser46 in p53, responsible for apoptosis induction, was markedly higher in the HIV-1 infected cells following IR treatment. Exposure of HIV-1 infected humanized mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in plasma, lung and brain tissues. Collectively, these data point to the use of low to moderate dose of IR alone or in combination with HIV-1 transcription activators as a potential application for the "Shock and Kill" strategy for latently HIV-1 infected cells. PMID:26184775

  6. Cytotoxic and Cytolytic Cnidarian Venoms. A Review on Health Implications and Possible Therapeutic Applications

    PubMed Central

    Mariottini, Gian Luigi; Pane, Luigi

    2013-01-01

    The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested in order to evaluate some fundamental parameters, such as the activity on cell survival, functioning and metabolism, and to improve the knowledge about the mechanisms of action of these compounds. In agreement with the modern tendency aimed to avoid the utilization of living animals in the experiments and to substitute them with in vitro systems, established cell lines or primary cultures have been employed to test cnidarian extracts or derivatives. Several cnidarian venoms have been found to have cytotoxic properties and have been also shown to cause hemolytic effects. Some studied substances have been shown to affect tumour cells and microorganisms, so making cnidarian extracts particularly interesting for their possible therapeutic employment. The review aims to emphasize the up-to-date knowledge about this subject taking in consideration the importance of such venoms in human pathology, the health implications and the possible therapeutic application of these natural compounds. PMID:24379089

  7. Long-term follow-up: no effect of therapeutic vaccination with HIV-1 p17/p24:Ty virus-like particles on HIV-1 disease progression.

    PubMed

    Lindenburg, Catharina E A; Stolte, Ineke; Langendam, Miranda W; Miedema, Frank; Williams, Ian G; Colebunders, Robert; Weber, Jonathan N; Fisher, Martin; Coutinho, Roel A

    2002-05-22

    Long-term effects of therapeutic vaccination of human immunodeficiency virus (HIV)-1-infected subjects with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) on progression to AIDS, death, a CD4 cell count therapeutic vaccination with p24-VLP is not related to slower HIV-1 disease progression. PMID:12009290

  8. Implication of Green Tea as a Possible Therapeutic Approach for Parkinson Disease.

    PubMed

    Jurado-Coronel, Juan C; Ávila-Rodriguez, Marco; Echeverria, Valentina; Hidalgo, Oscar Alejandro; Gonzalez, Janneth; Aliev, Gjumrakch; Barreto, George E

    2016-01-01

    Green tea is a beverage consumed around the world that is believed to have substantial health benefits such as reducing the risk of cancer, cardiovascular diseases, diabetes and neurodegeneration. This beverage is prepared from the leaves (steamed and dried) of the Camellia sinesis plant and contains strong antioxidant and neuroprotective phenolic compounds from which the most important is (-)-Epigallocatechin-3-gallate. Parkinson's disease (PD) is the second more common neurodegenerative disorders, after Alzheimer's disease and is characterized by degeneration of dopaminergic neurons in the pars compact of the substantia nigra of the basal ganglia. It has been shown in pre-clinical and clinical studies that green tea may be able to prevent PD, but its optimal dose or a possible mechanism explaining its health benefit in PD has not been properly established. In this review, we discuss the potential role of green tea's phenolic compounds and their therapeutic effectin modulating key signaling pathways in the PD brain. PMID:26831259

  9. Mitochondrial abnormalities in Alzheimer’s disease: Possible targets for therapeutic intervention

    PubMed Central

    Silva, Diana F.; Selfridge, J. Eva; Lu, Jianghua; Lezi, E; Cardoso, Sandra M.; Swerdlow, Russell H.

    2013-01-01

    Mitochondria from persons with Alzheimer’s disease (AD) differ from those of age-matched, control subjects. Differences in mitochondrial morphology and function are well-documented, and are not brain-limited. Some of these differences are present during all stages of AD, and are even seen in individuals who are without AD symptoms and signs but who have an increased risk of developing AD. This chapter considers the status of mitochondria in AD subjects, the potential basis for AD subject mitochondrial perturbations, and the implications of these perturbations. Data from multiple lines of investigation, including epidemiologic, biochemical, molecular, and cytoplasmic hybrid studies are reviewed. The possibility that mitochondria could potentially constitute a reasonable AD therapeutic target is discussed, as are several potential mitochondrial medicine treatment strategies. PMID:22840745

  10. Immune and genetic mechanisms in COPD: possible targets for therapeutic interventions.

    PubMed

    Tzortzaki, Eleni G; Papi, Alberto; Neofytou, Eirini; Soulitzis, Nikolaos; Siafakas, Nikolaos M

    2013-02-01

    Genetic, immune and environmental interactions are key elements for the development of COPD. Cigarette smoking is considered the primary risk factor initiating inflammatory cascades in genetically susceptible individuals. The "danger signals" elicited by the injured cells of non-specific immunity induce the downstream activation of proinflammatory cascades and antigen-specific adaptive immune responses. The produced oxidative stress further damages the lung leading to acquired genetic changes (histone deacetylation, microsatellite DNA instability, DNA methylation, telomere shortening, miRNA alterations) due to an inefficient DNA repair machinery. On the other hand, augmented apoptosis, impaired efferocytosis and abnormal tissue remodeling contribute to the chronic inflammatory response and tissue destruction in COPD. This review focuses on the role of genetic, epigenetic and immune mechanisms in the development of COPD in order to put forward possible prognostic and therapeutic targets. PMID:23256714

  11. The Therapeutic Potential of Adenosine Triphosphate as an Immune Modulator in the Treatment of HIV/AIDS: A Combination Approach with HAART

    PubMed Central

    Wagner, Marc C.E.

    2011-01-01

    Extracellular adenosine triphosphate (eATP) is a potent molecule that has the capacity to modulate various aspects of cell functions including gene expression. This element of modulation is essential to the role of ATP as a therapeutic agent. The hypothesis presented is that ATP can have an important impact on the treatment of HIV infection. This is supported in part by published research, although a much greater role for ATP is suggested than prior authors ever thought possible. ATP has the ability to enhance the immune system and could thus improve the hosts own defense mechanisms to eradicate the virus-infected cells and restore normal immune function. This could provide effective therapy when used in conjunction with highly active antiretroviral therapies (HAART) to eliminate the latently infected cells. The key lies in applying ATP through the methodology described. This article presents a strategy for using ATP therapeutically along with background evidence to substantiate the importance of using ATP in the treatment of HIV infection. PMID:21675943

  12. Bacterial esophagitis associated with CD4+ T-lymphocytopenia without HIV infection. Possible role of corticosteroid treatment.

    PubMed

    Richert, S M; Orchard, J L

    1995-01-01

    Although infectious esophagitis is usually due to infection with Candida, herpes virus, or cytomegalovirus, bacterial esophagitis is occasionally observed. Recently, patients have been reported with CD4+ T-lymphocytopenia without HIV infection. Bacterial esophagitis per se has not been reported in these patients. We report the case of an 80-year-old patient admitted with a COPD exacerbation after being on chronic steroids. The patient developed esophageal symptoms and was found to have bacterial esophagitis by biopsy. Her CD4+ counts were found to be low, but she denied HIV risk factors and HIV testing was negative. Her CD4+ counts rose into the normal range as her steroids were tapered, and her esophagitis improved on antibiotics. This case is reported to alert physicians to the possible association of bacterial esophagitis with CD4+ T-lymphocytopenia without HIV infection and to discuss the possible etiological role of corticosteroid treatment. PMID:7821107

  13. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    SciTech Connect

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

  14. True User Involvement by People Living With HIV is Possible: Description of a User-driven HIV Clinic in Norway.

    PubMed

    Berg, Rigmor C; Gamst, Are; Said, Maryan; Aas, Kristin Bårdsen; Songe, Solveig Helene; Fangen, Kim; Rysstad, Ole

    2015-01-01

    The Greater Involvement of People Living with or Affected by HIV principle highlights the various contributions HIV-infected people can make in HIV program development and implementation. We present a unique example of how service users' involvement led to a complete organizational redesign of an outpatient HIV clinic in Southern Norway. We applied a user-driven, case study method, which showed that establishing a user board laid the foundation for the redesign process, as the board provided a clear infrastructure of user involvement and developed a set of user-defined targets for services. The main targets-optimal health, holistic care and treatment, and empowerment-were operationalized as a set of action points, such as establishing HIV nurse coordinators. While there is no single method for user involvement, we offer useful ideas that can help others develop an involvement project that is effective and sustainable. PMID:26255897

  15. Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma.

    PubMed

    Savoia, Paola; Deboli, Tommaso; Previgliano, Alberto; Broganelli, Paolo

    2015-01-01

    Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I-II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%-0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC. PMID:26426005

  16. [Rooming-in as a therapeutic possibility for a 6-year-old autistic girl].

    PubMed

    Wurst, E; Feyrer, R; Bartik, D

    1984-01-01

    The possibilities of rooming-in as a form of therapy for the psychic abnormal child are demonstrated on the basis of the example of a mother-child-therapy, which lasted six weeks and happened during the stay of mother and child on our station. The patient was a six year old, intellectually retarded girl with autistic behavior disturbances. The points of main effort in our therapeutical interventions were set on reaching a higher selfreliance of the patient as far as every day life-routine was concerned, further more on increasing the child's social and intellectual capabilities and on eliminating the girl's sleeping troubles. In order to reach these aims we started a training in behavior modification (operant conditioning, modeling) for mother and child. The remarkable developmental progresses of our patient are attributed most of all to the thorough efforts that were made in order to improve the abilities of the girl by modifying the contact between mother and child. Besides, the possibility of being able to use the whole day for therapy, to discuss and,--if necessary--to correct immediately the learning experiences that have been made, seems to be a great chance for reaching the appropriate forms of action and interaction in a quicker way. PMID:6504548

  17. Usefulness of Photodynamic Therapy as a Possible Therapeutic Alternative in the Treatment of Basal Cell Carcinoma

    PubMed Central

    Savoia, Paola; Deboli, Tommaso; Previgliano, Alberto; Broganelli, Paolo

    2015-01-01

    Basal cell carcinoma (BCC) is the most common cancer in individuals with fair skin type (I–II) and steadily increasing in incidence (70% of skin malignancy). It is locally invasive but metastasis is usually very rare, with an estimated incidence of 0.0028%–0.55%. Conventional therapy is surgery, especially for the H region of the face and infiltrative lesions; in case of inoperable tumors, radiotherapy is a valid option. Recently, topical photodynamic therapy (PDT) has become an effective treatment in the management of superficial and small nodular BCC. PDT is a minimally invasive procedure that involves the administration of a photo-sensibilizing agent followed by irradiation at a pre-defined wavelength; this determines the creation of reactive oxygen species that specifically destroy target cells. The only major side effect is pain, reported by some patients during the irradiation. The high cure rate and excellent cosmetic outcome requires considering this possibility for the management of patients with both sporadic and hereditary BCC. In this article, an extensive review of the recent literature was made, in order to clarify the role of PDT as a possible alternative therapeutic option in the treatment of BCC. PMID:26426005

  18. Aging and HIV/AIDS: pathogenetic role of therapeutic side effects

    PubMed Central

    Torres, Rebecca A; Lewis, William

    2014-01-01

    The intersection of aging and HIV/AIDS is a looming epidemic within an epidemic. This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active anti-retroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies. PMID:24336070

  19. An in silico approach for identification of novel inhibitors as a potential therapeutics targeting HIV-1 viral infectivity factor.

    PubMed

    Sinha, Chanda; Nischal, Anuradha; Bandaru, Srinivas; Kasera, Priyadarshani; Rajput, Ashish; Nayarisseri, Anuraj; Khattri, Sanjay

    2015-01-01

    Currently available antiviral drugs target the pol-encoded retroviral enzymes or integrases, in addition, inhibitors that target HIV-1 envelope-receptor interactions have also been recently approved. Recent understanding of the interactions between HIV-1 and host restriction factors has provided fresh avenues for development of novel antiviral drugs. For example, viral infectivity factor (Vif) now surfaced as an important therapeutic target in treatment of HIV infection. Vif suppresses A3G antiviral activity by targeting these proteins for polyubiquitination and proteasomal degradation. In the present study we analyzed the inhibitory potential of VEC5 and RN18 to inhibit the Vif-A3G interaction through protein- protein docking studies. Perusal of the study showed that, VEC5 and RN18 though inhibits the interaction however showed sub optimal potential. To overcome this set back, we identified 35 structural analogues of VEC5 and 18 analogues of RN18 through virtual screening approach. Analogue with PubCID 71624757 and 55358204 (AKOS006479723) -structurally akin to VEC5 and RN18 respectively showed much appreciable interaction than their respective parent compound. Evident from Vif-A3G; protein - protein docking studies, analogue PubCID 71624757 demonstrated 1.08 folds better inhibitory potential than its parent compound VEC5 while analogue PubCID 55358204 was 1.15 folds better than RN18. Further these analogues passed drug likeness filters and predicted to be non- toxic. We expect these analogues can be put to pharmacodynamic studies that can pave way the breakthrough in HIV therapeutics. PMID:25579575

  20. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    PubMed

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  1. Nanoparticle-conjugated animal venom-toxins and their possible therapeutic potential

    PubMed Central

    Biswas, Archita; Gomes, Aparna; Sengupta, Jayeeta; Datta, Poulami; Singha, Santiswarup; Dasgupta, Anjan Kr; Gomes, Antony

    2012-01-01

    Nano-medical approaches to develop drugs have attracted much attention in different arenas to design nanoparticle conjugates for better efficacy of the potential bio-molecules. A group of promising candidates of this category would be venom-toxins of animal origin of potential medicinal value. Traditional systems of medicine as well as folklores mention the use of venom-toxins for the treatment of various diseases. Research has led to scientific validation of medicinal applications of venoms-toxins and many active constituents derived from venoms-toxins are already in clinical use or under clinical trial. Nanomedicine is an emerging field of medicine where nanotechnology is used to develop molecules of nano-scale dimension, so that these molecules can be taken up by the cells more easily and have better efficacy, as compared to large molecules that may tend to get eliminated. This review will focus on some of the potential venoms and toxins along with nanoparticle conjugated venom-toxins of snakes, amphibians, scorpions and bees, etc., for possible therapeutic clues against emerging diseases. PMID:23236583

  2. Possible Therapeutic Effect of Stem Cell in Atherosclerosis in Albino Rats. A Histological and Immunohistochemical Study

    PubMed Central

    Abdel-Kawi, Samraa H; Hashem, Khalid S

    2015-01-01

    Background Atherosclerosis is the leading cause of death worldwide. there are no effective approaches to regressing atherosclerosis due to not fully understood mechanisms. Recently, stem cell-based therapies have held promises to various diseases, including vascular diseases. Aim The present study aimed at investigating the possible effect of cord blood mesenchymal stem cell (MSC) therapy on atherosclerosis. Material and Methods Eighty adult male albino rats were divided into control group (I), atherogenic group (II): subjected to high cholesterol fed diet (200~300 mg/kg body weight) for 12 weeks and 1.8 million units of vitamin D / kg of diet for 6 weeks. Stem cell therapy group (III): injected with stem cells in the tail vein following confirmation of atherosclerosis. Histological, Immunohistochemical and morphometric studies were performed were conducted. Results Atherogenic group (II) showed increased aortic thickness, intimal proliferation, smooth muscle proliferation and migration. Increased area % of collagen fibers, iNOS and vimentin immunoreactions were recorded and proved morphometrically. All findings regressed on stem cell therapy. Conclusion A definite therapeutic effect of mesenchymal stem cells was found on atherosclerosis. PMID:26634068

  3. Monocyte/macrophage inflammatory response pathways to combat Francisella infection: possible therapeutic targets?

    PubMed Central

    Gillette, Devyn D.; Tridandapani, Susheela; Butchar, Jonathan P.

    2014-01-01

    Francisella tularensis can bypass and suppress host immune responses, even to the point of manipulating immune cell phenotypes and intercellular inflammatory networks. Strengthening these responses such that immune cells more readily identify and destroy the bacteria is likely to become a viable (and perhaps necessary) strategy for combating infections with Francisella, especially given the likelihood of antibiotic resistance in the foreseeable future. Monocytes and macrophages offer a niche wherein Francisella can invade and replicate, resulting in substantially higher bacterial load that can overcome the host. As such, understanding their responses to Francisella may uncover potential avenues of therapy that could promote a lowering of bacterial burden and clearance of infection. These response pathways include Toll-like Receptor 2 (TLR2), the caspase-1 inflammasome, Interferons, NADPH oxidase, Phosphatidylinositide 3-kinase (PI3K), and the Ras pathway. In this review we summarize the literature pertaining to the roles of these pathways during Francisella infection, with an emphasis on monocyte/macrophage responses. The therapeutic targeting of one or more such pathways may ultimately become a valuable tool for the treatment of tularemia, and several possibilities are discussed. PMID:24600590

  4. Developmental, Ethnic, and Social Influences on Participation in Sexual Possibility Situations for Youth with HIV-Positive and HIV-Negative Mothers

    ERIC Educational Resources Information Center

    Lewis, Linwood J.; Mellins, Claude A.; Brackis-Cott, Elizabeth

    2006-01-01

    This cross-sectional study examined the relationship among maternal HIV, pubertal development, gender, ethnicity, and spirituality and adolescent participation in sexual possibility situations (SPSs) and in sexual activity. SPSs are social encounters with cross-gender peers that afford the opportunity to engage in sexual activity. Heterosexual…

  5. Possible HIV transmission modes among at-risk groups at an early epidemic stage in the Philippines.

    PubMed

    Telan, Elizabeth Freda O; Samonte, Genesis May J; Palaypayon, Noel; Abellanosa-Tac-An, Ilya P; Leaño, Prisca Susan A; Tsuneki, Akeno; Kageyama, Seiji

    2013-12-01

    A concentrated human immunodeficiency virus (HIV) epidemic might have started in the Philippines. A subsequent characterization of viruses was carried out to estimate HIV transmission modes. Most HIV strains from injecting drug users belonged to subtype-B. CRF-01 was a major subtype harbored by three other at-risk populations: male visa applicants who had sex with men, "men who have sex with men," and visa applicants. An HIV phylogeny suggested that two strain groups of injecting drug users and others circulated separately. In contrast, there was substantial genetic overlap between two strain groups from "men who have sex with men" and visa applicants. Mean nucleotide distance within strains was shorter among subtype-B strains harbored by the injecting drug users (0.010) than among CRF-01 strains of the other three populations: male visa applicants who had sex with men (0.034), "men who have sex with men" (0.023), and visa applicants (0.032). Closely related strains of hepatitis C virus were derived from not only HIV-positive but also -negative individuals. These results suggest that there is potential for transmission from visa applicants to "men who have sex with men," and that once HIV occurs in injecting drug users, it spreads rapidly among them. Close contacts of hepatitis C virus carriers composed of HIV-negative and -positive individuals indicated ongoing HIV spread via blood and possible intervention points. Large-scale analysis is needed to provide more precise information on the transmission directions and to help curb the growth of this HIV epidemic in the Philippines. PMID:23959846

  6. The Effect of Therapeutic HIV Vaccination With ALVAC-HIV With or Without Remune on the Size of the Viral Reservoir (A CTN 173 Substudy)

    PubMed Central

    Routy, Jean-Pierre; Graziani, Gina M.; Tremblay, Cécile L.

    2015-01-01

    Objectives: To assess whether therapeutic vaccination with ALVAC-HIV ± Remune affects viral reservoir size in antiretroviral therapy–treated individuals. Methods: Participants in CTN 173, a multicentre, randomized, 3-arm, placebo-controlled, double-blind study, were vaccinated with ALVAC-HIV ± Remune (groups 1 and 2, respectively) or with placebos (group 3) over 20 weeks and assessed for changes in the size of their viral reservoirs from weeks 0 to 24. Results: Sixteen participants completed the viral reservoir substudy. The median sizes (interquartile range) of the viral reservoir at baseline (week 0) were 0.07 (0.03–0.37), 0.04 (0.02–0.33), and 0.13 (0.06–0.99) infectious units per million peripheral blood mononuclear cells for groups 1, 2, and 3, respectively; these baseline viral reservoir sizes were not significantly different (P = 0.37). By week 24, the median sizes of the viral reservoirs were 0.04 (0.01–2.16), 0.04 (0.01–0.34), and 0.12 (0.01–0.44) infectious units per million peripheral blood mononuclear cells for groups 1, 2, and 3 respectively; these week 24 viral reservoir sizes were not significantly different (P = 0.91). Furthermore, there were no statistically significant differences between baseline and week 24 reservoir sizes for any of the 3 groups (P = 0.88, P = 1.00, and P = 0.44, respectively). Conclusions: Despite evidence that ALVAC-HIV ± Remune was associated with a trend toward a delay in viral rebound and a smaller decrease in CD4 T-cell counts following antiretroviral therapy interruption, ALVAC-HIV ± Remune did not influence the size of the viral reservoir. PMID:26375464

  7. Therapeutic strategies underpinning the development of novel techniques for the treatment of HIV infection

    PubMed Central

    Tan, Jian J.; Cong, Xiao J.; Hu, Li M.; Wang, Cun X.; Jia, Lee; Liang, Xing-Jie

    2010-01-01

    The HIV replication cycle offers multiple targets for chemotherapeutic intervention, including the viral exterior envelope glycoprotein, gp120; viral co-receptors CXCR4 and CCR5; transmembrane glycoprotein, gp41; integrase; reverse transcriptase; protease and so on. Most currently used anti-HIV drugs are reverse transcriptase inhibitors or protease inhibitors. The expanding application of simulation to drug design combined with experimental techniques have developed a large amount of novel inhibitors that interact specifically with targets besides transcriptase and protease. This review presents details of the anti-HIV inhibitors discovered with computer-aided approaches and provides an overview of the recent five-year achievements in the treatment of HIV infection and the application of computational methods to current drug design. PMID:20096804

  8. Two cases of possible transmitted drug-resistant HIV: likely HIV superinfection and unmasking of pre-existing resistance

    PubMed Central

    Lee, John; Thomson, Emma; Tarrant, Nick; Hale, Antony; Lacey, Charles J

    2016-01-01

    In the UK, patients undergo HIV viral load and genotype testing before they are prescribed antiretroviral therapy. The genotype test guides clinicians in prescribing antiretroviral therapy with maximum efficacy against the patient’s specific viral strain. HIV viral load escape under antiretroviral drug therapy, to which the virus was thought to be genotypically susceptible, is commonly observed in patients with poor adherence. We observed early viral escapes in two-newly diagnosed patients, during antiretroviral treatment, with different sequences compared to their original viral resistance test and who reported excellent adherence to and tolerance of their therapy. HIV superinfection with a new viral strain was identified in a patient with multiple risk factors and co-infections with sexually transmitted infections. The second patient was a case of the emergence of primary resistant virus under drug pressure. Both suppressed their virus promptly after treatment switch. PMID:25663247

  9. Two cases of possible transmitted drug-resistant HIV: likely HIV superinfection and unmasking of pre-existing resistance.

    PubMed

    Martin, Fabiola; Lee, John; Thomson, Emma; Tarrant, Nick; Hale, Antony; Lacey, Charles J

    2016-01-01

    In the UK, patients undergo HIV viral load and genotype testing before they are prescribed antiretroviral therapy. The genotype test guides clinicians in prescribing antiretroviral therapy with maximum efficacy against the patient's specific viral strain. HIV viral load escape under antiretroviral drug therapy, to which the virus was thought to be genotypically susceptible, is commonly observed in patients with poor adherence. We observed early viral escapes in two-newly diagnosed patients, during antiretroviral treatment, with different sequences compared to their original viral resistance test and who reported excellent adherence to and tolerance of their therapy. HIV superinfection with a new viral strain was identified in a patient with multiple risk factors and co-infections with sexually transmitted infections. The second patient was a case of the emergence of primary resistant virus under drug pressure. Both suppressed their virus promptly after treatment switch. PMID:25663247

  10. Human immunodeficiency virus-1 (HIV-1)-mediated apoptosis: new therapeutic targets.

    PubMed

    Mbita, Zukile; Hull, Rodney; Dlamini, Zodwa

    2014-08-01

    HIV has posed a significant challenge due to the ability of the virus to both impair and evade the host's immune system. One of the most important mechanisms it has employed to do so is the modulation of the host's native apoptotic pathways and mechanisms. Viral proteins alter normal apoptotic signaling resulting in increased viral load and the formation of viral reservoirs which ultimately increase infectivity. Both the host's pro- and anti-apoptotic responses are regulated by the interactions of viral proteins with cell surface receptors or apoptotic pathway components. This dynamic has led to the development of therapies aimed at altering the ability of the virus to modulate apoptotic pathways. These therapies are aimed at preventing or inhibiting viral infection, or treating viral associated pathologies. These drugs target both the viral proteins and the apoptotic pathways of the host. This review will examine the cell types targeted by HIV, the surface receptors exploited by the virus and the mechanisms whereby HIV encoded proteins influence the apoptotic pathways. The viral manipulation of the hosts' cell type to evade the immune system, establish viral reservoirs and enhance viral proliferation will be reviewed. The pathologies associated with the ability of HIV to alter apoptotic signaling and the drugs and therapies currently under development that target the ability of apoptotic signaling within HIV infection will also be discussed. PMID:25196285

  11. Human Immunodeficiency Virus-1 (HIV-1)-Mediated Apoptosis: New Therapeutic Targets

    PubMed Central

    Mbita, Zukile; Hull, Rodney; Dlamini, Zodwa

    2014-01-01

    HIV has posed a significant challenge due to the ability of the virus to both impair and evade the host’s immune system. One of the most important mechanisms it has employed to do so is the modulation of the host’s native apoptotic pathways and mechanisms. Viral proteins alter normal apoptotic signaling resulting in increased viral load and the formation of viral reservoirs which ultimately increase infectivity. Both the host’s pro- and anti-apoptotic responses are regulated by the interactions of viral proteins with cell surface receptors or apoptotic pathway components. This dynamic has led to the development of therapies aimed at altering the ability of the virus to modulate apoptotic pathways. These therapies are aimed at preventing or inhibiting viral infection, or treating viral associated pathologies. These drugs target both the viral proteins and the apoptotic pathways of the host. This review will examine the cell types targeted by HIV, the surface receptors exploited by the virus and the mechanisms whereby HIV encoded proteins influence the apoptotic pathways. The viral manipulation of the hosts’ cell type to evade the immune system, establish viral reservoirs and enhance viral proliferation will be reviewed. The pathologies associated with the ability of HIV to alter apoptotic signaling and the drugs and therapies currently under development that target the ability of apoptotic signaling within HIV infection will also be discussed. PMID:25196285

  12. Recall of intestinal helminthiasis by HIV-infected South Africans and avoidance of possible misinterpretation of egg excretion in worm/HIV co-infection analyses

    PubMed Central

    Adams, Vera J; Markus, Miles B; Kwitshana, Zilungile L; Dhansay, Muhammad A; van der Merwe, Lize; Walzl, Gerhard; Fincham, John E

    2006-01-01

    Background Ascariasis and HIV/AIDS are often co-endemic under conditions of poverty in South Africa; and discordant immune responses to the respective infections could theoretically be affecting the epidemic of HIV/AIDS in various ways. It is well-known that sensitisation to helminthic antigens can aggravate or ameliorate several non-helminthic diseases and impair immunisation against cholera, tetanus and tuberculosis. The human genotype can influence immune responses to Ascaris strongly. With these factors in mind, we have started to document the extent of long-term exposure to Ascaris and other helminths in a community where HIV/AIDS is highly prevalent. In more advanced studies, objectives are to analyse relevant immunological variables (e.g. cytokine activity and immunoglobulin levels). We postulate that when Ascaris is hyperendemic, analysis of possible consequences of co-infection by HIV cannot be based primarily on excretion vs non-excretion of eggs. Methods Recall of worms seen in faeces was documented in relation to the age of adult volunteers who were either seropositive (n = 170) or seronegative (n = 65) for HIV. Reasons for HIV testing, deworming treatments used or not used, date and place of birth, and duration of residence in Cape Town, were recorded. Confidence intervals were calculated both for group percentages and the inter-group differences, and were used to make statistical comparisons. Results In both groups, more than 70% of participants were aware of having passed worms, often both when a child and as an adult. Most of the descriptions fitted Ascaris. Evidence for significantly prolonged exposure to helminthic infection in HIV-positives was supported by more recall of deworming treatment in this group (p < 0.05). Over 90% of the participants had moved to the city from rural areas. Conclusion There was a long-term history of ascariasis (and probably other helminthic infections) in both of the groups that were studied. In women in the same community, and in children living where housing and sanitation are better, Ascaris sero-prevalence exceeded egg-prevalence by two- and three-fold, respectively. For ongoing and future analyses of possible consequences of co-infection by Ascaris (and/or other helminths) and HIV/AIDS (and/or other bystander conditions), comparisons must be based mainly on disease-related immunological variables. Especially in adults, comparisons cannot be based only on the presence or absence of eggs in excreta. PMID:16725057

  13. THERAPEUTIC DRUG MONITORING OF PROTEASE INHIBITORS AND EFAVIRENZ IN HIV-INFECTED INDIVIDUALS WITH ACTIVE SUBSTANCE RELATED DISORDERS

    PubMed Central

    Ma, Qing; Zingman, Barry S.; Luque, Amneris; Fischl, Margaret A.; Gripshover, Barbara; Venuto, Charles; DiFrancesco, Robin; Forrest, Alan; Morse, Gene D.

    2011-01-01

    Background Achieving targeted antiretroviral (ART) plasma concentrations during long-term treatment in HIV-infected patients with substance related disorders (SRD) may be challenging due to a number of factors including medication adherence, co-infection with hepatitis B or C virus, medication intolerance and drug interactions. One approach to investigate these factors is to conduct therapeutic drug monitoring (TDM) to measure ART exposure during treatment. The objective of this study was to utilize TDM to compare efavirenz and protease inhibitor pharmacokinetics in patients with and without SRDs. Methods This was a multi-center, cross-sectional open-label study in patients with HIV-1 infection receiving ART, with active (n=129) or without (n=146) SRD according to National Institute on Drug Abuse criteria. 275 subjects who were receiving either protease inhibitor- or efavirenz-based ART regimens for more than 6 months were enrolled at four HIV treatment centers with an equal distribution of SRD and non-SRD at each site. Patients were instructed during enrollment visits with regard to the importance of adherence prior to and after study visits. Demographics and routine clinical laboratory tests were recorded. Results Among the 275 patients, 47% had SRD with at least one substance. There were no significant differences between SRD and non-SRD groups for race, gender, age, or CD4 count at entry. A significantly higher proportion of patients with SRD had an entry HIV RNA plasma concentration > 75 copies/ml compared to patients without SRD (40% vs. 28%, p=0.044). Logistic regression modeling revealed an association between HIV RNA plasma concentration and African-American race (p=0.017). A significantly higher proportion of SRDs also had an efavirenz or protease inhibitor trough concentration below the desired range (23% vs. 9%, p=0.048). Significantly lower trough concentrations were noted in patients with SRDs receiving atazanavir (0.290 vs. 0.976 µg/mL) or lopinavir (3.75 vs. 5.30 µg/mL). Conclusions The pharmacokinetic data indicate differences between HIV-infected patients with and without SRD that may influence viral load suppression during long-term ARV treatment. These findings require additional investigation in a randomized design with more intensive pharmacokinetic assessment to identify individual factors that are contributing to suboptimal ARV exposure in patients with SRDs. PMID:21544014

  14. Towards novel therapeutics for HIV through fragment-based screening and drug design.

    PubMed

    Tiefendbrunn, Theresa; Stout, C David

    2014-01-01

    Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins. PMID:25455312

  15. Demographical, Viro-Immunological, Clinical and Therapeutical Characteristics of HIV-Infected Patients in an “Epidemiologically Unexplored” Region of Italy (Calabria Region): the CalabrHIV Cohort

    PubMed Central

    Postorino, Maria Concetta; Luciani, Filippo; Mangano, Carmelo; Carpentieri, Maria Stella; Scerbo, Paolo; Priamo, Armando; Berardelli, Giuseppina; Marino, Roberto; Vallone, Alfredo; Serrao, Nicola; Pisani, Vincenzo; Costa, Chiara; Terremoto, Albano; Foti, Giuseppe; Cosco, Lucio; Calderazzo, Massimo; Corigliano, Domenico; Scordo, Preziosa; Strazzulla, Alessio; Torti, Carlo

    2015-01-01

    Background and Objectives HIV epidemics may differ among epidemiological contexts. We aimed at constructing an HIV clinical cohort whose main epidemiological, clinical and therapeutical characteristics are described (the CalabrHIV cohort, Calabria Region, Southern Italy). Methods The CalabrHIV Cohort includes all HIV patients on active follow-up in all infectious disease centers in the Calabria Region as at October 2014. All information was recorded in a common electronic database. Not-infectious co-morbidities (such as cardiovascular diseases, bone fractures, diabetes, renal failure and hypertension) were also studied. Results 548 patients (68% males; 59% aged <50 years) were included in the CalabrHIV cohort. Major risk factors were: sexual transmission (49%) and intravenous drug use (34%). 39% patients had HCV and/or HBV co-infection. Amongst 404 patients who had a complete clinical history, 34% were AIDS presenters and 49.3% had CD4 count ≤350/mm3 at HIV diagnosis. 83% patients on HAART had undetectable HIV-RNA. Hypertension was the most frequent co-morbidity (21.5%). Multimorbidity was more frequent in >50 years old patients than in <50 years old ones (30% vs. 6%; p<0.0001). Co-morbidity was more frequent in HCV and/or HBV co-infected than in HIV mono-infected patients (46.6% vs. 31.7%: p=0.0006). Conclusion This cohort presentation study sheds light, for the first time, on HIV patients’ characteristics in the Calabria Region. We showed that HIV-infected patients with chronic hepatitis were affected by concomitant not-infectious co-morbidities more than the HIV mono-infected individuals. New HCV treatments are therefore to be implemented in the co-infected population. PMID:26543523

  16. Exploring the Possibilities and Limitations of Service-Learning: A Critical Analysis of College Student Narratives about HIV/AIDS

    ERIC Educational Resources Information Center

    Jones, Susan Robb; LePeau, Lucy A.; Robbins, Claire K.

    2013-01-01

    This article reports the results of a study that explored the possibilities and limitations of service-learning by deconstructing the narratives about HIV/AIDS that emerged from five college students who participated in an alternative spring break program. Employing a critical (Rhoads, 1997) and anti-foundational (Butin, 2010) approach to inquiry,…

  17. Glucagon-like Peptide-1 (GLP-1) Analogs: Recent Advances, New Possibilities, and Therapeutic Implications

    PubMed Central

    2015-01-01

    Glucagon-like peptide-1 (GLP-1) is an incretin that plays important physiological roles in glucose homeostasis. Produced from intestine upon food intake, it stimulates insulin secretion and keeps pancreatic β-cells healthy and proliferating. Because of these beneficial effects, it has attracted a great deal of attention in the past decade, and an entirely new line of diabetic therapeutics has emerged based on the peptide. In addition to the therapeutic applications, GLP-1 analogs have demonstrated a potential in molecular imaging of pancreatic β-cells; this may be useful in early detection of the disease and evaluation of therapeutic interventions, including islet transplantation. In this Perspective, we focus on GLP-1 analogs for their studies on improvement of biological activities, enhancement of metabolic stability, investigation of receptor interaction, and visualization of the pancreatic islets. PMID:25349901

  18. A Future of Possibilities: Educating Children Living in HIV Impacted Households

    ERIC Educational Resources Information Center

    Kagotho, Njeri

    2012-01-01

    Close to one and a half million Kenyans reportedly live with HIV/AIDS. Using qualitative in-depth interviews this study explores the ways in which parents living with HIV/AIDS navigate their social and economic environment to provide educational opportunities for their children. Barriers identified include the economic costs of a free primary…

  19. A Future of Possibilities: Educating Children Living in HIV Impacted Households

    ERIC Educational Resources Information Center

    Kagotho, Njeri

    2012-01-01

    Close to one and a half million Kenyans reportedly live with HIV/AIDS. Using qualitative in-depth interviews this study explores the ways in which parents living with HIV/AIDS navigate their social and economic environment to provide educational opportunities for their children. Barriers identified include the economic costs of a free primary

  20. Modelling the long-term impacts on affected children of adult HIV: benefits, challenges and a possible approach.

    PubMed

    Desmond, Christopher; Bruce, Faikah; Tomlinson, M; Marlow, Marguerite B; Aber, J Lawrence; Ouifki, Rachid; Welte, Alex

    2014-07-01

    We outline the benefits, challenges and possible approaches to developing mathematical models that could be used to estimate the magnitude of negative consequences of adult HIV infection for children. Adult HIV infection can lead to numerous negative consequences for dependent children, including depression, anxiety, withdrawal from school and early sexual debut, among others. For advocacy and planning purposes, it is important to highlight and consider as many of these as possible. A focus solely on orphan numbers, which is the typical summary measure for children affected by HIV and AIDS, can be misleading. The complexity of child development that is characterized by the interaction of a multitude of proximal and distal factors, coupled with a significant lack of data on child development in the context of adult HIV infection make the development of models a challenging task. Although it may not be possible in the first attempt to develop a population-based model capable of examining family dynamics, the negative consequences together with the impact of interventions, steps in that direction can be taken. We propose approaches and assumptions that we believe will allow the development of a useful first set of models. We conclude with a brief discussion of the type of data that, if collected, would facilitate refinement and development of these models. PMID:24991900

  1. The hippocampo-prefrontal pathway: a possible therapeutic target for negative and cognitive symptoms of schizophrenia

    PubMed Central

    Ghoshal, Ayan; Conn, P Jeffrey

    2015-01-01

    The hippocampo-prefrontal (H-PFC) pathway has been linked to cognitive and emotional disturbances in several psychiatric disorders including schizophrenia. Preclinical evidence from the NMDA receptor antagonism rodent model of schizophrenia shows severe pathology selective to the H-PFC pathway. It is speculated that there is an increased excitatory drive from the hippocampus to the prefrontal cortex due to dysfunctions in the H-PFC plasticity, which may serve as the basis for the behavioral consequences observed in this rodent model. Thus, the H-PFC pathway is currently emerging as a promising therapeutic target for the negative and cognitive symptom clusters of schizophrenia. Here, we have reviewed the physiological, pharmacological and functional characteristics of the H-PFC pathway and we propose that allosteric activation of glutamatergic and cholinergic neurotransmission can serve as a plausible therapeutic approach. PMID:25825588

  2. Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities

    PubMed Central

    Pirooznia, Sheila K.; Elefant, Felice

    2013-01-01

    Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HAT) activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC) inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and HATs in neurodegenerative diseases and the future promising prospects of using specific HAT based therapeutic approaches. PMID:23543406

  3. Targeting specific HATs for neurodegenerative disease treatment: translating basic biology to therapeutic possibilities.

    PubMed

    Pirooznia, Sheila K; Elefant, Felice

    2013-01-01

    Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. While defects within the neural epigenome have traditionally been studied in the context of early developmental and heritable cognitive disorders, recent studies point to aberrant histone acetylation status as a key mechanism underlying acquired inappropriate alterations of genome structure and function in post-mitotic neurons during the aging process. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the lifetime of neurons through mechanisms related to loss of function of histone acetyltransferase (HAT) activity. Several HATs have been shown to participate in vital neuronal functions such as regulation of neuronal plasticity and memory formation. As such, dysregulation of such HATs has been implicated in the pathogenesis associated with age-associated neurodegenerative diseases and cognitive decline. In order to counteract the loss of HAT function in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules called histone deacetylase (HDAC) inhibitors that antagonize HDAC activity and thus enhance acetylation levels. Although this strategy has displayed promising therapeutic effects, currently used HDAC inhibitors lack target specificity, raising concerns about their applicability. With rapidly evolving literature on HATs and their respective functions in mediating neuronal survival and higher order brain function such as learning and memory, modulating the function of specific HATs holds new promises as a therapeutic tool in neurodegenerative diseases. In this review, we focus on the recent progress in research regarding epigenetic histone acetylation mechanisms underlying neuronal activity and cognitive function. We discuss the current understanding of specific HDACs and HATs in neurodegenerative diseases and the future promising prospects of using specific HAT based therapeutic approaches. PMID:23543406

  4. Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions.

    PubMed

    Geisbert, Thomas W; Hensley, Lisa E

    2004-09-21

    Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicized isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection. PMID:15383160

  5. The HIV epidemic in Southern Africa - Is an AIDS-free generation possible?

    PubMed

    Delva, Wim; Abdool Karim, Quarraisha

    2014-06-01

    Southern Africa, home to about 20 % of the global burden of infection continues to experience high rates of new HIV infection despite substantial programmatic scale-up of treatment and prevention interventions. While several countries in the region have had substantial reductions in HIV infection, almost half a million new infections occurred in this region in 2012. Sexual transmission remains the dominant mode of transmission. A recent national household survey in Swaziland revealed an HIV prevalence of 14.3 % among 18-19 year old girls, compared to 0.8 % among their male peers. Expanded ART programmes in Southern Africa have resulted in dramatically decreased HIV incidence and HIV mortality rates. In South Africa alone, it is estimated that more than 2.1 million of the 6.1 million HIV-positive people were receiving ART by the end of 2012, and that this resulted in more than 2.7 million life-years saved, and hundreds of thousands of HIV infections averted. Biological, behavioural and structural factors all contribute to the ongoing high rates of new HIV infection; however, as the epidemic matures and mortality is reduced from increased ART coverage, epidemiological trends become hard to quantify. What is clear is that a key driver of the Southern African epidemic is the high incidence rate of infection in young women, a vulnerable population with limited prevention options. Moreover, whilst ongoing trials of combination prevention, microbicides and behavioural economics hold promise for further epidemic control, an AIDS-free generation will not be realised unless incident infections in key populations are reduced. PMID:24676559

  6. A Phase I Randomized Therapeutic MVA-B Vaccination Improves the Magnitude and Quality of the T Cell Immune Responses in HIV-1-Infected Subjects on HAART

    PubMed Central

    Gómez, Carmen Elena; Perdiguero, Beatriz; García-Arriaza, Juan; Cepeda, Victoria; Sánchez-Sorzano, Carlos Óscar; Mothe, Beatriz; Jiménez, José Luis; Muñoz-Fernández, María Ángeles; Gatell, Jose M.; López Bernaldo de Quirós, Juan Carlos; Brander, Christian; García, Felipe; Esteban, Mariano

    2015-01-01

    Trial Design Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART. Methods The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination. Results MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1-specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses. Conclusion MVA-B vaccination represents a feasible strategy to improve T cell responses in individuals with pre-existing HIV-1-specific immunity. Trial Registration ClinicalTrials.gov NCT01571466 PMID:26544853

  7. School age children with HIV/AIDS: possible discrimination and attitudes against.

    PubMed

    Kurpas, Donata; Mroczek, Bozena; Sochocka, Lucyna; Church, Joseph

    2013-12-01

    Survey-based study what purpose was to analyse respondents' opinions about contacts with HIV/AIDS-affected people. It was performed using a paper-pencil method during visits of respondents at primary care centres and on-line through a link to the questionnaire distributed among patients of primary care physicians. The study involved 302 respondents, 80% of whom were women; the average age was 34.48 years. The majority of respondents did not know anyone with HIV/AIDS (89.6%). About 83.3% claimed that they would not decrease contacts with HIV/AIDS-affected people. According to 64.1% of respondents, children with HIV/AIDS should go to kindergarten/public or non-public school. We selected a group of respondents, who previously were not but now are inclined to limit such contacts. These respondents can be a potential target group for HIV/AIDS educational programmes. Most respondents think that there is insufficient information about the HIV/AIDS in the mass media. PMID:24626355

  8. Polymorphonuclear neutrophils in periodontitis and their possible modulation as a therapeutic approach.

    PubMed

    Nicu, Elena A; Loos, Bruno G

    2016-06-01

    The main focus of this review is polymorphonuclear neutrophilic granulocytes. Polymorphonuclear neutrophils play a pivotal role in normal host resistance to subgingival dental-plaque biofilm. Both hyper- and hypo-responsiveness of the immune system toward the microbial challenge in periodontitis have been described. We review polymorphonuclear neutrophil physiology with emphasis on the role of neutrophil functions and dysfunctions in periodontitis. Text boxes are given at the end of each subsection, which present the current knowledge on neutrophil-modulating agents as a potential therapeutic approach in periodontitis. PMID:27045435

  9. Warfarin therapy in the HIV medical home model: low rates of therapeutic anticoagulation despite adherence and differences in dosing based on specific antiretrovirals.

    PubMed

    Anderson, Albert M; Chane, Tanea; Patel, Manish; Chen, Shuo; Xue, Wenqiong; Easley, Kirk A

    2012-08-01

    To determine the indications for, rates of therapeutic anticoagulation during, and complications of warfarin therapy in HIV-infected individuals, in whom long-term anticoagulation is frequently indicated. To identify risk factors for nonoptimal anticoagulation and to determine if warfarin dosing is differentially affected by specific antiretroviral agents. Retrospective study of a dedicated anticoagulation program at one of the largest clinics for HIV-infected individuals in the United States. Seventy-three HIV-infected individuals on warfarin were followed for a total of 911 visits. The rate of therapeutic internation normalized ratio (INR) levels was 34.5% when including only visits at which patients were assessed to be adherent with warfarin. In multivariable analysis, injection drug use at baseline was an independent risk factor for subtherapeutic INR (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.3-4.7, p=0.01). Additionally, warfarin adherence was protective of both subtherapeutic (OR 0.4, 95% CI 0.2-0.6, p<0.0001) and supratherapeutic (OR 0.5, 95% CI 0.3-0.9, p=0.02) INR status. Efavirenz-based antiretroviral regimens were associated with lower weekly warfarin doses (46 mg) to maintain therapeutic INR compared to lopinavir/ritonavir-based regimens (68 mg; p=0.01) and atazanavir/ritonavir-based regimens (71 mg; p=0.007). Consistently therapeutic warfarin therapy is difficult to achieve in HIV-infected individuals, even with a dedicated anticoagulation program. Adherence to warfarin therapy is important but rates of therapeutic INR levels are nonetheless low. Lower warfarin dosing was required for efavirenz compared to two commonly used protease inhibitor-based regimens. Because of these factors, the emergence of new oral anticoagulants is an important development for HIV-infected individuals who require long term anticoagulation therapy. PMID:22742455

  10. Phosphorylation regulates transcriptional activity of PAX3/FKHR and reveals novel therapeutic possibilities.

    PubMed

    Amstutz, Ralf; Wachtel, Marco; Troxler, Heinz; Kleinert, Peter; Ebauer, Margret; Haneke, Torsten; Oehler-Jnne, Christoph; Fabbro, Doriano; Niggli, Felix K; Schfer, Beat W

    2008-05-15

    Inhibition of constitutive active signaling pathways, which are a characteristic phenomenon for many tumors, can be an effective therapeutic strategy. In contrast, oncogenic transcription factors, often activated by mutational events, are in general less amenable to small-molecule inhibition despite their obvious importance as therapeutic targets. One example of this is alveolar rhabdomyosarcoma (aRMS), in which specific translocations lead to the formation of the chimeric transcription factor PAX3/FKHR. Here, we found unexpectedly that the transcriptional activity of PAX3/FKHR can be inhibited by the kinase inhibitor PKC412. This occurs via specific phosphorylation sites in the PAX3 domain, phosphorylation of which is required for efficient DNA-binding and subsequent transcriptional activity. Consequently, we show that PKC412 exerts a potent antitumorigenic potential for aRMS treatment both in vitro and in vivo. Our study suggests that posttranscriptional modifications of oncogenic transcription factors can be explored as a promising avenue for targeted cancer therapy. PMID:18483260

  11. Oxidative stress and post-stroke depression: possible therapeutic role of polyphenols?

    PubMed

    Nabavi, Seyed Fazel; Dean, Olivia M; Turner, Alyna; Sureda, Antoni; Daglia, Maria; Nabavi, Seyed Mohammad

    2015-01-01

    Post-stroke depression is a common neuropsychiatric affective disorder that may develop after a stroke event. In addition to abnormalities in the biogenic amine neurotransmitters and cytokine expression induced by stroke we will focus on the role of oxidative stress and hypothesize that polyphenols may be useful as therapeutics targets for the treatment of post-stroke depression. In this paper, we discuss the hypothesis that increased oxidative stress in cerebral tissues during ischemia is implicated in the pathogenesis of depressive-like symptoms following stroke. There is substantive evidence regarding the role of oxidative stress in the pathogenesis of both stroke and depression, which provides support to this hypothesis. Reactive oxygen species, generated during stroke, cause oxidative stress, lipid peroxidation, protein oxidation, and DNA damage in neural tissues. The resultant pathophysiological processes in the neural tissues could be considered a leading mechanism in the induction of post-stroke depression. Antioxidants including polyphenols therefore, may play an important role in the outcomes of ischemia and stroke, due to their ability to protect neurons against oxidative stress, to mitigate ischemic damage via inhibition of lipid peroxidation and ability to interact with the generation of nitric oxide from the vascular endothelium, and also to decrease inflammation. These data suggest that polyphenols may therefore be a useful new therapeutic target for the treatment of post-stroke depression. PMID:25386821

  12. [HIV glycoprotein 120: possible etiological agent of AIDS-associated dementia].

    PubMed

    Galicia, Oscar; Sánchez-Alavez, Manuel; Méndez Díaz, Mónica; Navarro, Luz; Prospero-García, Oscar

    2002-01-01

    The AIDS or HIV associated dementia is a cognitive-motor disease, characterized by a strong deficit of several cognitive processes such as attention, memory, sensory perception, motor control among others. The HIV associated dementia affects 30% of adult to 50% of infant HIV positive subjects. Since neurons are not infected by HIV, its principal target in the brain is microglia. The pathophysiology of this syndrome, therefore, remains to be disclosed. Several hypothesis have been proposed, one of them suggests that opportunistic infections can affect the brain. Another hypothesis suggests that microglia secretes toxic products as a result of HIV infection and those are the ones causing the damage and finally, the hypothesis, suggesting that the brain is damaged as a result of the insult caused by HIV-derived proteins. In vitro studies suggest that the HIVgp120, a viral surface protein, is highly neurotoxic. For example HIVgp120 increases cytoplasmic Ca+2 by two ways: facilitating glutamate neurotransmission increasing Ca+2 conductance, and activating the IP3 pathway, facilitating Ca+2 release from the smooth endoplasmic reticulum. This Ca+2 in turn, activates several internal signaling pathways such as the MAPK pathway. We use an animal model to test the HIVgp120 effect on neurophysiological signals and behavior as well as several pharmacological approaches to prevent the HIVgp120 neurotoxic effects. This review updates with the most recent literature discussing the potential mechanisms implicated in the pathophysiology of the AIDS dementia complex. We, in addition, hope the reader will be able to correlate the clinical symptoms observed in the HIV infected subjects and the HIVgp120-induced behavioral changes observed in animal models. Likewise, we discuss the new drugs we are testing, in order to offer a new pharmacological treatment to the patient. PMID:12587419

  13. [Local administration of vaginal therapeutic drugs and their possible side effects].

    PubMed

    Spitzbart, H; Thust, U; Naumann, J

    1988-01-01

    We have proved with screening-electron-microscopic examinations that different chemical substances bend to formation of cristals on the vaginal skin. Different size of the cristals depends from different quantities of the drugs. Cytotoxic appearances are possible. PMID:3407352

  14. Bullous Lesions After Use of a Commercial Therapeutic Hypothermia Temperature Management System: A Possible Burn Injury?

    PubMed Central

    Wells, James M.; Rizk, Dana V.

    2013-01-01

    Therapeutic hypothermia (TH) is a novel technique for improving the likelihood of survival with good neurologic outcome after cardiopulmonary arrest. While commercial temperature management systems (TMS) are intended to facilitate cooling of the body during TH, their operation also involves body exposure to heat. We describe the case of a 72-year-old female postarrest patient who underwent TH using a commercial water-circulating TMS and concurrent continuous renal replacement therapy. The patient developed bullous lesions on the thigh and torso suspected to constitute a scald burn injury from the TMS. Clinicians must be aware of this important adverse event when providing TH, especially in the setting of concurrent hemodialysis therapy. PMID:24066269

  15. The possible therapeutic benefits of utilizing motion gaming systems on pediatric patients presenting autism.

    PubMed

    Crowder, Stephen A; Merritte, Kristin

    2013-09-01

    Autism is a pervasive developmental disorder that affects a growing number of children in the United States each year. It is characterized by substantive differences in brain structure and function that lead to long-term cognitive and social deficits. These differences, combined with the increasing prevalence of autism in children, warrant the need for development of innovative, cost-effective and widely available alternative and complementary therapies. Motion gaming has the potential to be highly efficacious as a therapeutic technique to aid in developing memory, facial recognition, motor skills and social integration in the pediatric autistic population. This paper outlines the major deficits in the brains of individuals with autism and describes how the use of motion gaming could capitalize on the individual strengths of each patient, leading to improvements in a variety of deficits. PMID:24027887

  16. mTORC1 signaling and IL-17 expression: Defining pathways and possible therapeutic targets.

    PubMed

    Ren, Wenkai; Yin, Jie; Duan, Jielin; Liu, Gang; Tan, Bie; Yang, Guan; Wu, Guoyao; Bazer, Fuller W; Peng, Yuanyi; Yin, Yulong

    2016-02-01

    IL-17 mediates immune responses against extracellular pathogens, and it is associated with the development and pathogenesis of various autoimmune diseases. The expression of IL-17 is regulated by various intracellular signaling cascades. Recently, it has been shown that mechanistic target of rapamycin (mTOR) signaling, comprised mainly of mTORC1 signaling, plays a critical role in IL-17 expression. Here, we review the current knowledge regarding mechanisms by which mTORC1 regulates IL-17 expression. mTORC1 positively modulates IL-17 expression through several pathways, i.e. STAT3, -HIF-1α, -S6K1, and -S6K2. Amino acids (AAs) also regulate IL-17 expression by being the energy source for Th17 cells, and by activating mTORC1 signaling. Altogether, the AA-mTORC1-IL-17 axis has broad therapeutic implications for IL-17-associated diseases, such as EAE, allergies, and colitis. PMID:26558536

  17. Why are some HIV/AIDS patients reluctant to receive antiviral therapy as soon as possible in China?

    PubMed

    Sun, Yang; Lu, Hongzhou

    2014-06-01

    In more than 20 years of medical practice, a surprising phenomenon has often occurred: some patients with acquired immunodeficiency syndrome (AIDS) decide not to go to the hospital and they do not let others know that they are suffering from the disease unless they believe that they are dieing. Zhang Shan (a pseudonym) is one such patient with human immunodeficiency virus (HIV)/AIDS who was reluctant to receive antiviral therapy as soon as possible, and this paper shares Zhang's story as he related it. Clearly, there are numerous views as to why patients in China behave as Zhang did. Presented here are several reasons, including society, history, morality and ideology, family, and education. Although all of these reasons do play a role, the patient's mindset and behavior is the most significant reason for a patient's reluctance to seek treatment or disclose his/her status. If the individual patient's mindset and behavior are not dealt with effectively, then HIV/AIDS can continue to spread and threaten additional lives and even the fabric of society. This paper analyzes the reasons why patients are hesitant to receive antiviral therapy, but this paper also suggests steps healthcare personnel can take to encourage patients to seek treatment. Such steps can save the lives of current patients with HIV/AIDS. In addition, sound public health measures and a rational approach to treatment are important to helping potential patients with HIV/AIDS. PMID:25030855

  18. Serious Non-AIDS Events: Therapeutic Targets of Immune Activation and Chronic Inflammation in HIV Infection.

    PubMed

    Hsu, Denise C; Sereti, Irini

    2016-04-01

    In the antiretroviral therapy (ART) era, serious non-AIDS events (SNAEs) have become the major causes of morbidity and mortality in HIV-infected persons. Early ART initiation has the strongest evidence for reducing SNAEs and mortality. Biomarkers of immune activation, inflammation and coagulopathy do not fully normalize despite virologic suppression and persistent immune activation is an important contributor to SNAEs. A number of strategies aimed to reduce persistent immune activation including ART intensification to reduce residual viremia; treatment of co-infections to reduce chronic antigen stimulation; the use of anti-inflammatory agents, reducing microbial translocation as well as interventions to improve immune recovery through cytokine administration and reducing lymphoid tissue fibrosis, have been investigated. To date, there is little conclusive evidence on which strategies beyond treatment of hepatitis B and C co-infections and reducing cardiovascular risk factors will result in clinical benefits in patients already on ART with viral suppression. The use of statins seems to show early promise and larger clinical trials are underway to confirm their efficacy. At this stage, clinical care of HIV-infected patients should therefore focus on early diagnosis and prompt ART initiation, treatment of active co-infections and the aggressive management of co-morbidities until further data are available. PMID:26915027

  19. Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets?

    PubMed

    Rochette, Luc; Lorin, Julie; Zeller, Marianne; Guilland, Jean-Claude; Lorgis, Luc; Cottin, Yves; Vergely, Catherine

    2013-12-01

    Nitric oxide (NO) is synthetized enzymatically from l-arginine (l-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of l-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein degradation in cells. Many disease states, including cardiovascular diseases and diabetes, are associated with increased plasma levels of ADMA. The N-terminal catalytic domain of these NOS isoforms binds the heme prosthetic group as well as the redox cofactor, tetrahydrobiopterin (BH(4)) associated with a regulatory protein, calmodulin (CaM). The enzymatic activity of NOS depends on substrate and cofactor availability. The importance of BH(4) as a critical regulator of eNOS function suggests that BH(4) may be a rational therapeutic target in vascular disease states. BH(4) oxidation appears to be a major contributor to vascular dysfunction associated with hypertension, ischemia/reperfusion injury, diabetes and other cardiovascular diseases as it leads to the increased formation of oxygen-derived radicals due to NOS uncoupling rather than NO. Accordingly, abnormalities in vascular NO production and transport result in endothelial dysfunction leading to various cardiovascular disorders. However, some disorders including a wide range of functions in the neuronal, immune and cardiovascular system were associated with the over-production of NO. Inhibition of the enzyme should be a useful approach to treat these pathologies. Therefore, it appears that both a lack and excess of NO production in diseases can have various important pathological implications. In this context, NOS modulators (exogenous and endogenous) and their therapeutic effects are discussed. PMID:23859953

  20. Melatonin and Its Agonist Ramelteon in Alzheimer's Disease: Possible Therapeutic Value

    PubMed Central

    Srinivasan, Venkatramanujam; Kaur, Charanjit; Pandi-Perumal, Seithikurippu; Brown, Gregory M.; Cardinali, Daniel P.

    2011-01-01

    Alzheimer's disease (AD) is an age-associated neurodegenerative disease characterized by the progressive loss of cognitive function, loss of memory and insomnia, and abnormal behavioral signs and symptoms. Among the various theories that have been put forth to explain the pathophysiology of AD, the oxidative stress induced by amyloid ?-protein (A?) deposition has received great attention. Studies undertaken on postmortem brain samples of AD patients have consistently shown extensive lipid, protein, and DNA oxidation. Presence of abnormal tau protein, mitochondrial dysfunction, and protein hyperphosphorylation all have been demonstrated in neural tissues of AD patients. Moreover, AD patients exhibit severe sleep/wake disturbances and insomnia and these are associated with more rapid cognitive decline and memory impairment. On this basis, the successful management of AD patients requires an ideal drug that besides antagonizing A?-induced neurotoxicity could also correct the disturbed sleep-wake rhythm and improve sleep quality. Melatonin is an effective chronobiotic agent and has significant neuroprotective properties preventing A?-induced neurotoxic effects in a number of animal experimental models. Since melatonin levels in AD patients are greatly reduced, melatonin replacement has the potential value to be used as a therapeutic agent for treating AD, particularly at the early phases of the disease and especially in those in whom the relevant melatonin receptors are intact. As sleep deprivation has been shown to produce oxidative damage, impaired mitochondrial function, neurodegenerative inflammation, and altered proteosomal processing with abnormal activation of enzymes, treatment of sleep disturbances may be a priority for arresting the progression of AD. In this context the newly introduced melatonin agonist ramelteon can be of much therapeutic value because of its highly selective action on melatonin MT1/MT2 receptors in promoting sleep. PMID:21197086

  1. Compromised redox homeostasis, altered nitroso–redox balance, and therapeutic possibilities in atrial fibrillation

    PubMed Central

    Simon, Jillian N.; Ziberna, Klemen; Casadei, Barbara

    2016-01-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso–redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF. PMID:26786158

  2. Possible new therapeutic approach for obesity-related diseases: Role of adiponectin receptor agonists.

    PubMed

    Lee, Chien-Hsing; Hung, Yi-Jen

    2015-05-01

    Adiponectin is a major adipokine that seems to have a crucial role in the protection from many metabolic abnormalities. There have been several reports that suggest a strong inverse relationship between plasma levels of adiponectin and the severity of obesity and its comorbidities, such as insulin resistance, type 2 diabetes and cardiovascular disease. Restoring adiponectin levels has salient benefits in many of the obesity-related diseases, which provides a strong rationale for adiponectin-based therapeutics for treating metabolic abnormalities. A Japanese team of researchers has screened and identified an orally active compound that binds to and activates the adiponectin receptor1 (AdipoR1) and AdipoR2 receptors that are named AdipRon. This molecule ameliorates insulin resistance and glucose intolerance in obese animal models, and also extends the shortened lifespan of diabetic obese mice. If this work can be extended to humans, the improved safety and efficacy of these orally active adiponectin agonists could offer a promising new approach to treating obesity-related diseases. PMID:25969709

  3. Association of Oxidative Stress to the Genesis of Anxiety: Implications for Possible Therapeutic Interventions

    PubMed Central

    Hassan, Waseem; Silva, Carlos Eduardo Barroso; Mohammadzai, Imdad Ullah; da Rocha, Joao Batista Teixeira; Landeira-Fernandez, J.

    2014-01-01

    Oxidative stress caused by reactive species, including reactive oxygen species, reactive nitrogen species, and unbound, adventitious metal ions (e.g., iron [Fe] and copper [Cu]), is an underlying cause of various neurodegenerative diseases. These reactive species are an inevitable by-product of cellular respiration or other metabolic processes that may cause the oxidation of lipids, nucleic acids, and proteins. Oxidative stress has recently been implicated in depression and anxiety-related disorders. Furthermore, the manifestation of anxiety in numerous psychiatric disorders, such as generalized anxiety disorder, depressive disorder, panic disorder, phobia, obsessive-compulsive disorder, and posttraumatic stress disorder, highlights the importance of studying the underlying biology of these disorders to gain a better understanding of the disease and to identify common biomarkers for these disorders. Most recently, the expression of glutathione reductase 1 and glyoxalase 1, which are genes involved in antioxidative metabolism, were reported to be correlated with anxiety-related phenotypes. This review focuses on direct and indirect evidence of the potential involvement of oxidative stress in the genesis of anxiety and discusses different opinions that exist in this field. Antioxidant therapeutic strategies are also discussed, highlighting the importance of oxidative stress in the etiology, incidence, progression, and prevention of psychiatric disorders. PMID:24669207

  4. Compromised redox homeostasis, altered nitroso-redox balance, and therapeutic possibilities in atrial fibrillation.

    PubMed

    Simon, Jillian N; Ziberna, Klemen; Casadei, Barbara

    2016-04-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso-redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF. PMID:26786158

  5. JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals

    PubMed Central

    Williams, Dionna W.; Anastos, Kathryn; Morgello, Susan; Berman, Joan W.

    2015-01-01

    Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40–70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14+CD16+ and CD14lowCD16+ monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14+CD16+ monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14+CD16+ monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14+CD16+ monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs. PMID:25420915

  6. JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals.

    PubMed

    Williams, Dionna W; Anastos, Kathryn; Morgello, Susan; Berman, Joan W

    2015-02-01

    Monocyte transmigration across the BBB is a critical step in the development of cognitive deficits termed HAND that affect 40-70% of HIV-infected individuals, even with successful antiretroviral therapy. The monocyte subsets that enter the CNS during HIV infection are not fully characterized. We examined PBMC from HIV-positive individuals from 2 distinct cohorts and enumerated monocyte populations, characterized their transmigration properties across an in vitro human BBB model, and identified surface proteins critical for the entry of these cells into the CNS. We demonstrated that the frequency of peripheral blood CD14(+)CD16(+) and CD14(low)CD16(+) monocytes was increased in HIV-seropositive compared with -seronegative individuals, despite virologic control. We showed that CD14(+)CD16(+) monocytes selectively transmigrated across our BBB model as a result of their increased JAM-A and ALCAM expression. Antibody blocking of these proteins inhibited diapedesis of CD14(+)CD16(+) monocytes but not of T cells from the same HIV-infected people across the BBB. Our data indicate that JAM-A and ALCAM are therapeutic targets to decrease the entry of CD14(+)CD16(+) monocytes into the CNS of HIV-seropositive individuals, contributing to the eradication of neuroinflammation, HAND, and CNS viral reservoirs. PMID:25420915

  7. Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities

    PubMed Central

    Fujita, Wakako; Gomes, Ivone; Devi, Lakshmi A

    2015-01-01

    Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24571499

  8. [Extending therapeutic possibilities in relapsing-remitting multiple sclerosis: dimethyl fumarate].

    PubMed

    Matolcsi, Judit; Rózsa, Csilla

    2015-01-30

    Dimethyl fumarate (DMF) is a novel oral therapy that has recently been approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Dimethyl fumarate shows anti-inflammatory and cytoprotective properties that are thought to be mediated primarily via activation of the nuclear factor (erythroid-derived 2)-like 2- Nrf2 transcriptional pathway, which up-regulates the genes involved in the cellular response to oxidative stress. The drug was evaluated in 2 large, randomized, double-blind, multicentric, multinational, 2-year, phase III clinical trials. The DEFINE and CONFIRM trials, conducted with over 2600 adult patients suffering from RRMS, unequivocally confirmed the efficacy of DMF (2 x 240 mg daily) in reducing the annualized relapse rate (ARR) and reducing the proportion of patients with MS relapse at 2 years. Significantly reduced sustained disability progression was observed with the drug versus placebo in DEFINE, while the same tendency was seen in CONFIRM. The MRI results of the studies were also convincing: DMF significantly reduced the number of new/enlarging T2-hyperintense lesions and the number of Gd-enhancing lesions compared to placebo. Dimethyl fumarate was generally well tolerated and no safety concern has been raised. Adverse events that occurred most frequently included flushing and gastrointestinal events. The long-term efficacy and tolerability of dimethyl fumarate is currently being investigated in the ENDORSE trial, with interim results demonstrating the same results as the two previous studies. In conclusion, although further, mostly comparative data are needed to fully establish the relative efficacy and tolerability of dimethyl fumarate compared with other therapies, dimethyl-fumarate is a valuable addition to the therapeutic options available for RRMS. PMID:25842911

  9. Troubling the Numbers: Is Teacher Demand Projections Possible within the Context of HIV/AIDS

    ERIC Educational Resources Information Center

    Ramrathan, P.

    2003-01-01

    This article explores two ways of knowing about teacher demand within the context of HIV/AIDS. It argues that by privileging particular variables that one wants to conceptualise, interrogate and understand, projections on teacher demands may vary. Which variables then needs to be conceptualised and what projections on teacher demand are reasonable…

  10. Influence of IFNgamma co-expression on the safety and antiviral efficacy of recombinant fowlpox virus HIV therapeutic vaccines following interruption of antiretroviral therapy.

    PubMed

    Emery, S; Kelleher, A D; Workman, C; Puls, R L; Bloch, M; Baker, D; Anderson, J; Hoy, J; Ip, S; Nalliah, K; Ward, L D; Law, M G; Cooper, D A

    2007-01-01

    Therapeutic immunization to stimulate host immune responses and control human immunodeficiency virus (HIV-1) replication is being investigated as a supplementary treatment for the management of HIV infection. On completion of an earlier study involving three vaccinations while taking combination antiretroviral therapy (CART), twenty-five subjects with plasma viral load (pVL) <50 copies/mL received a booster vaccination with either placebo (n = 7); fowl pox vaccine (rFPV) expressing HIV-1 Gag/Pol; [partial construct- PC (n = 8)] or rFPV coexpressing HIV-1 Gag/Pol and human interferon gamma[full construct - FC (n = 10)]. One week after the booster vaccination, participants stopped ART and were monitored for safety, pVL and immunological parameters for < or =20 weeks. The time weighted mean change (SD) from baseline plasma HIV RNA was 1.80 (0.72), 1.78 (0.91) and 0.96 (0.91) log(10) copies/mL for placebo, PC and FC recipients respectively (p = 0.06; mean differences between placebo and FC). Laboratory evaluations did not reveal differences in anti-HIV specific immune responses between study arms. No difference between treatment arms for host genetic factors known to affect pVL was demonstrated. In conclusion, vaccination with FC was associated with a trend toward lower rates of HIV replication following cessation of ART relative to placebo or PC. The promising antiretrovirological effect supports further study of FC in a larger trial with a broader population of patients with HIV disease. PMID:18340117

  11. [Sense of humour in schizophrenia--ability of humour reception and possibilities of its application in therapeutic interventions].

    PubMed

    Parnowska, Dorota; Braniecka, Anna; Radomska, Anna

    2013-01-01

    The existing research on sense of humour in schizophrenia is focused on two main areas, mainly, assessment of patients' abilities to understand and appreciate humour and denoting the possibilities of its application in therapeutic programs concentrating on the improvement of patients' functionality and preventing illness relapses. The vast majority of the conclusions from the above mentioned research corroborate the opinion on the usefulness of developing and reinforcing sense of humour in schizophrenia, emphasizing its beneficial effect on the patients' quality of life, above all, in terms of reducing aggression, anxiety and depression as well as improving general life satisfaction and social functioning. At the same time numerous research indicate low reception of humour in schizophrenia which can negatively influence its effective usage in therapeutic interventions. Further constraint with regard to the therapy can constitute an intensified fear for being laughed at, which has been confirmed in numerous empirical reports. Therefore, it seems that addressing humorous therapeutic interventions to the above mentioned group of patients requires especially careful planning taking into consideration its cognitive and affective limitations in the perception of humour and intensified fear for being laughed at. PMID:25011239

  12. The role of cytoskeleton and adhesion proteins in the resistance to photodynamic therapy. Possible therapeutic interventions.

    PubMed

    Di Venosa, Gabriela; Perotti, Christian; Batlle, Alcira; Casas, Adriana

    2015-08-01

    It is known that Photodynamic Therapy (PDT) induces changes in the cytoskeleton, the cell shape, and the adhesion properties of tumour cells. In addition, these targets have also been demonstrated to be involved in the development of PDT resistance. The reversal of PDT resistance by manipulating the cell adhesion process to substrata has been out of reach. Even though the existence of cell adhesion-mediated PDT resistance has not been reported so far, it cannot be ruled out. In addition to its impact on the apoptotic response to photodamage, the cytoskeleton alterations are thought to be associated with the processes of metastasis and invasion after PDT. In this review, we will address the impact of photodamage on the microfilament and microtubule cytoskeleton components and its regulators on PDT-treated cells as well as on cell adhesion. We will also summarise the impact of PDT on the surviving and resistant cells and their metastatic potential. Possible strategies aimed at taking advantage of the changes induced by PDT on actin, tubulin and cell adhesion proteins by targeting these molecules will also be discussed. PMID:25832889

  13. Possible therapeutic vaccines for canine myasthenia gravis: implications for the human disease and associated fatigue.

    PubMed

    Galin, F Shawn; Chrisman, Cheryl L; Cook, James R; Xu, Likang; Jackson, Patricia L; Noerager, Brett D; Weathington, Nathaniel M; Blalock, J Edwin

    2007-03-01

    Myasthenia gravis (MG) is caused by T cell-dependent antibodies reactive with acetylcholine receptors. These autoreactive antibodies cause muscle weakness by interfering with neuromuscular transmission via removal of acetylcholine receptors from the neuromuscular junction as well as changing the architecture of the junction itself. Consequently, muscle fatigue is a debilitating aspect of MG often leading to more general feelings of tiredness not directly due to muscle weakness. We have previously described two peptides that are mimetics of antigen receptors on certain autoreactive T and B cells that are involved in MG. When used as vaccines in the rat model of MG, these peptides prevented and ameliorated disease and muscle fatigue by blunting acetylcholine receptor antibody responses. Such disease protection resulted from vaccine-induced anergizing antibodies against acetylcholine receptor-specific T and B cell antigen receptors. The present study prospectively evaluated the efficacy of these two vaccines in spontaneous acquired MG in pet dogs. When compared to historical controls that were prospectively studied, the vaccines increased the proportion of remitted dogs from 17 to 75%. In comparison to retrospectively studied historical controls that spontaneously remitted from MG, the vaccines accelerated the rate of decline in acetylcholine receptor antibody titers which resulted in a 3-fold decrease in the mean time to remission. These results are suggestive of a new type of targeted therapy that can drive autoimmune responses into long-term remission and possibly afford a means of determining whether correction of a physical cause of muscle weakness also corrects the perception of chronic, generalized fatigue. PMID:17113748

  14. [Trajectory of a research on the HIV/AIDS theme: limits and (im) possibilities].

    PubMed

    Motta, Maria da Graça Corso; Pedro, Eva Neri Rubim; Coelho, Débora Fernandes; Wachholz, Neiva Isabel Raffo; Greff, Aramita Prates

    2009-06-01

    The article presents the trajectory of a research group upon the development of the project funded by the Health Ministry, through the National HIV/AIDS/DST Program, named "Impact of adhesion to the anti-retroviral among children and adolescents under the perspective of the family, the child and the adolescent in the municipalities of Porto Alegre andSanta Maria, RS". With the objective of presenting the stages of the research, from its planning up to the phase of data collection, the study was carried out in two municipalities simultaneously, counting on 20 participants comprising researchers and scholarship students. The stages developed until the data collection were: inclusion of care and teaching professionals in the research nucleus; selection and training of scholarship students; elaboration of the instrument; elaboration of a manual team habilitation; application of the pilot test. PMID:20027969

  15. The current status and challenges in the development of fusion inhibitors as therapeutics for HIV-1 infection.

    PubMed

    Tan, Jian Jun; Ma, Xue Ting; Liu, Chang; Zhang, Xiao Yi; Wang, Cun Xin

    2013-01-01

    HIV-1 membrane fusion as a part of the process of viral entry in the target cells is facilitated by gp41 and gp120, which are encoded by Env gene of HIV-1. Based on the structure and the mechanism researches, new treatment options targeting HIV-1 entry process have been proposed. Enfuvirtide, which mimics amino acid sequences of viral envelope glycoprotein gp41, is the first HIV-1 fusion inhibitor approved by FDA. Although it fulfills vital functions by binding to gp41 and abolishing the membrane fusion reaction when used in combination, it could induce drug resistant virus variants. Currently, a number of design and modification schemes have been presented, a large number of prospective fusion peptides have emerged. For these fusion inhibitors, multiple mutations in gp41 have been associated with the loss of susceptibility to agents. This review reported the current developments and innovative designs of HIV-1 membrane fusion inhibitors. PMID:23092283

  16. VS411 Reduced Immune Activation and HIV-1 RNA Levels in 28 Days: Randomized Proof-of-Concept Study for AntiViral-HyperActivation Limiting Therapeutics

    PubMed Central

    Lori, Franco; De Forni, Davide; Katabira, Elly; Baev, Denis; Maserati, Renato; Calarota, Sandra A.; Cahn, Pedro; Testori, Marco; Rakhmanova, Aza; Stevens, Michael R.

    2012-01-01

    Background A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4+ T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. Methods Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. Results VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4+ T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: −1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3) and fewest adverse events. Conclusions VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. Trial Registration ITEudraCT 2007-002460-98 PMID:23094055

  17. Induced adaptive resistance to oxidative stress in the CNS: a discussion on possible mechanisms and their therapeutic potential.

    PubMed

    Bishop, Amy; Cashman, Neil R

    2003-04-01

    The free radical, nitric oxide (NO), is synthesized by mammalian cells and is utilized for normal cellular functions. High levels of NO are released during disease, injury and inflammation. NO at high concentrations more readily combines with other oxidants to form reactive nitrogenous species (RNS), which can wreak havoc on the cell by damaging a variety of cellular targets, such as DNA and proteins, ultimately leading to apoptosis, mutagenesis or carcinogenesis. Cells have natural resistance mechanisms to nitrooxidative stress that are either defective (as can occur in disease), or overwhelmed (as can occur in injury and inflammation). It has been found recently in the CNS that resistance to normally toxic levels of NO can be induced by nontoxic levels of NO and that this induction is correlated with and dependent upon increased levels and activity of the heme-metabolizing enzyme, heme oxygenase-1 (HO-1). HO1-mediated metabolism of heme groups released from NO-damaged proteins leads to a change in the levels of redox-active iron and a release of carbon monoxide (CO) and bilirubin, all of which have been implicated in cellular resistance to oxidative stress. Perhaps one or more of the products of HO1 heme metabolism is involved in induced adaptive resistance or perhaps a heme-independent mechanism is involved. In fact, a variety of possible mechanisms may be involved in induced resistance to NO in the CNS. Ultimately elucidating these mechanisms will enable us to modulate them for therapeutic potential. PMID:12678694

  18. A multi-scale mathematical modeling framework to investigate anti-viral therapeutic opportunities in targeting HIV-1 accessory proteins.

    PubMed

    Suryawanshi, Gajendra W; Hoffmann, Alexander

    2015-12-01

    Human immunodeficiency virus-1 (HIV-1) employs accessory proteins to evade innate immune responses by neutralizing the anti-viral activity of host restriction factors. Apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G, A3G) and bone marrow stromal cell antigen 2 (BST2) are host resistance factors that potentially inhibit HIV-1 infection. BST2 reduces viral production by tethering budding HIV-1 particles to virus producing cells, while A3G inhibits the reverse transcription (RT) process and induces viral genome hypermutation through cytidine deamination, generating fewer replication competent progeny virus. Two HIV-1 proteins counter these cellular restriction factors: Vpu, which reduces surface BST2, and Vif, which degrades cellular A3G. The contest between these host and viral proteins influences whether HIV-1 infection is established and progresses towards AIDS. In this work, we present an age-structured multi-scale viral dynamics model of in vivo HIV-1 infection. We integrated the intracellular dynamics of anti-viral activity of the host factors and their neutralization by HIV-1 accessory proteins into the virus/cell population dynamics model. We calculate the basic reproductive ratio (Ro) as a function of host-viral protein interaction coefficients, and numerically simulated the multi-scale model to understand HIV-1 dynamics following host factor-induced perturbations. We found that reducing the influence of Vpu triggers a drop in Ro, revealing the impact of BST2 on viral infection control. Reducing Vif׳s effect reveals the restrictive efficacy of A3G in blocking RT and in inducing lethal hypermutations, however, neither of these factors alone is sufficient to fully restrict HIV-1 infection. Interestingly, our model further predicts that BST2 and A3G function synergistically, and delineates their relative contribution in limiting HIV-1 infection and disease progression. We provide a robust modeling framework for devising novel combination therapies that target HIV-1 accessory proteins and boost antiviral activity of host factors. PMID:26385832

  19. Dendritic cell-based therapeutic vaccine elicits polyfunctional HIV-specific T-cell immunity associated with control of viral load.

    PubMed

    Lvy, Yves; Thibaut, Rodolphe; Montes, Monica; Lacabaratz, Christine; Sloan, Louis; King, Bryan; Prusat, Sophie; Harrod, Carson; Cobb, Amanda; Roberts, Lee K; Surenaud, Mathieu; Boucherie, Cline; Zurawski, Sandra; Delaugerre, Constance; Richert, Laura; Chne, Genevive; Banchereau, Jacques; Palucka, Karolina

    2014-09-01

    Efforts aimed at restoring robust immune responses limiting human immunodeficiency virus (HIV)-1 replication therapeutically are warranted. We report that vaccination with dendritic cells generated ex vivo and loaded with HIV lipopeptides in patients (n = 19) on antiretroviral therapy was well tolerated and immunogenic. Vaccination increased: (i) the breadth of the immune response from 1 (1-3) to 4 (2-5) peptide-pool responses/patient (p = 0.009); (ii) the frequency of functional T cells (producing at least two cytokines among IFN-?, TNF-?, and IL-2) from 0.026 to 0.32% (p = 0.002) and from 0.26 to 0.35% (p = 0.005) for CD4(+) and CD8(+) T cells, respectively; and (iii) the breadth of cytokines secreted by PBMCs upon antigen exposure, including IL-2, IFN-?, IL-21, IL-17, and IL-13. Fifty percent of patients experienced a maximum of viral load (VL) 1 log10 lower than the other half following antiretroviral treatment interruption. An inverse correlation was found between the maximum of VL and the frequency of polyfunctional CD4(+) T cells (p = 0.007), production of IL-2 (p = 0.006), IFN-? (p = 0.01), IL-21 (p = 0.006), and IL-13 (p = 0.001). These results suggest an association between vaccine responses and a better control of viral replication. These findings will help in the development of strategies for a functional cure for HIV infection. PMID:25042008

  20. Possible Prognostic and Therapeutic Significance of c-Kit Expression, Mast Cell Count and Microvessel Density in Renal Cell Carcinoma

    PubMed Central

    Marech, Ilaria; Gadaleta, Cosmo Damiano; Ranieri, Girolamo

    2014-01-01

    Renal cell carcinoma (RCC) is the most frequent renal tumor and its incidence is increasing worldwide. Tumor angiogenesis is known to play a crucial role in the etiopathogenesis of RCC and over the last few years an even deeper knowledge of its contribution in metastatic RCC development has led to the development of numerous molecular targeting agents (such as sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and dovitinib). The above agents are principally directed against vascular endothelial growth factor receptor (VEGFR) members and also against c-Kit receptor (c-KitR). The role of c-kitR inhibition on clear cell RCC (ccRCC), the main RCC subtype, is less well established. Whether c-kitR activation through its ligand, stem cell factor (SCF) contributes significantly to the effects of tyrosine kinase inhibitors (TKIs) treatment remains to be established. It is important to underscore that the c-KitR is expressed on mast cells (MCs) and cancer cells. After an examination of the c-KitR/SCF pathway, we review here the principal studies that have evaluated c-Kit expression in RCC. Moreover, we summarize some investigations that have observed the distribution of MCs in primary renal cancer and in adjacent normal tissue with appropriate histological immunohistochemical techniques. We also focus on few studies that have evaluated the correlation between RCC proliferation, MC count and microvessel density (MVD), as hallmarks of tumor angiogenesis. Thus, the aim of this review of the literature is to clarify if c-KitR expression, MC count and MVD could have prognostic significance and the possible predictive therapeutic implications in RCC. PMID:25056544

  1. HIV chemotherapy

    NASA Astrophysics Data System (ADS)

    Richman, Douglas D.

    2001-04-01

    The use of chemotherapy to suppress replication of the human immunodeficiency virus (HIV) has transformed the face of AIDS in the developed world. Pronounced reductions in illness and death have been achieved and healthcare utilization has diminished. HIV therapy has also provided many new insights into the pathogenesis and the viral and cellular dynamics of HIV infection. But challenges remain. Treatment does not suppress HIV replication in all patients, and the emergence of drug-resistant virus hinders subsequent treatment. Chronic therapy can also result in toxicity. These challenges prompt the search for new drugs and new therapeutic strategies to control chronic viral replication.

  2. Elevated Chemokine Concentrations in Sera of Human Immunodeficiency Virus (HIV)-Seropositive and HIV-Seronegative Patients with Tuberculosis: a Possible Role for Mycobacterial Lipoarabinomannan

    PubMed Central

    Juffermans, Nicole P.; Verbon, Annelies; van Deventer, Sander J. H.; van Deutekom, Henk; Belisle, John T.; Ellis, Michael E.; Speelman, Peter; van der Poll, Tom

    1999-01-01

    Levels of interleukin 8 (IL-8), gamma interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1β (MIP-1β) were elevated in patients with tuberculosis. IP-10 and MCP-1 levels were higher in human immunodeficiency virus (HIV)-seropositive patients than in HIV-seronegative patients with tuberculosis. Lipoarabinomannan induced IL-8, MCP-1, and MIP-1β in vitro, which was partly inhibited by anti-tumor necrosis factor antibody. PMID:10417209

  3. SupT1 Cell Infusion as a Possible Cell-Based Therapy for HIV: Results from a Pilot Study in Hu-PBMC BRGS Mice.

    PubMed

    Fior, Jonathan

    2016-01-01

    In a previous in vitro study, the SupT1 cell line was explored as a decoy target for HIV-1, proposing SupT1 cell infusion as a possible cell-based therapy for HIV. In the present work, the previous in vitro model was translated into an in vivo setting. Specifically, Hu-PBMC BRGS mice were infected with a high input of HIV-1 LAI (100,000 TCID50), and 40 million 30 Gy-irradiated SupT1 cells were infused weekly for 4 weeks as a therapy. Blood samples were taken to monitor CD4+ T cell count and viral load, and mice were monitored daily for signs of illness. At the earliest time point analyzed (Week 1), there was a significantly lower plasma viral load (~10-fold) in all animals treated with SupT1 cell infusion, associated with a higher CD4+ T cell count. At later time points, infection proceeded with robust viral replication and evident CD4+ T cell depletion, except in one mouse that showed complete suppression of viral replication and preservation of CD4+ T cell count. No morbidity or mortality was associated with SupT1 cell infusion. The interesting tendencies observed in the generated data suggest that this approach should be further investigated as a possible cell-based HIV therapy. PMID:27128948

  4. Possible therapeutic benefits of adenosine-potentiating drugs in reducing age-related degenerative disease in dogs and cats.

    PubMed

    Scaramuzzi, R J; Baker, D J

    2003-10-01

    Adenosine is a ubiquitous, biologically important molecule that is a precursor of other biologically active molecules. It also is a component of some co-factors and has distinct physiological actions in its own right. Levels are maintained by synthesis from dietary precursors and re-cycling. The daily turnover of adenosine is very high. Adenosine can act either as a hormone by binding to adenosine receptors, four adenosine receptor subtypes have been identified, and as an intracellular modulator, after transport into the cell by membrane transporter proteins. One of the principal intracellular actions of adenosine is inhibition of the enzyme phosphodiesterase. Extracellular adenosine also has specific neuromodulatory actions on dopamine and glutamate. Selective and nonselective agonists and antagonists of adenosine are available. The tasks of developing, evaluating and exploiting the therapeutic potential of these compounds is still in its infancy. Adenosine has actions in the central nervous system (CNS), heart and vascular system, skeletal muscle and the immune system and the presence of receptors suggests potential actions in the gonads and other organs. Adenosine agonists improve tissue perfusion through actions on vascular smooth muscle and erythrocyte fluidity and they can be used to improve the quality of life in aged dogs. This article reviews the therapeutic potential of adenosine-potentiating drugs in the treatment of age-related conditions in companion animals, some of which may be exacerbated by castration or spaying at an early age. PMID:14633184

  5. Therapeutic Roles of Heme Oxygenase-1 in Metabolic Diseases: Curcumin and Resveratrol Analogues as Possible Inducers of Heme Oxygenase-1

    PubMed Central

    Son, Yong; Lee, Ju Hwan; Chung, Hun-Taeg

    2013-01-01

    Metabolic diseases, such as insulin resistance, type II diabetes, and obesity, are associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of metabolic diseases, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of metabolic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce inflammatory stress, oxidative stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of metabolic diseases. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in metabolic diseases and present some emerging therapeutic options for HO-1 expression in treating metabolic diseases, together with the therapeutic potential of curcumin and resveratrol analogues that have their ability to induce HO-1 expression. PMID:24101950

  6. Enteric pathogens, immune status and therapeutic response in diarrhea in HIV/AIDS adult subjects from north India.

    PubMed

    Jha, Arun Kumar; Uppal, Beena; Chadha, Sanjim; Aggarwal, Prabhav; Ghosh, Roumi; Dewan, Richa

    2013-06-01

    Intestinal infection causing diarrheal disease is a dominant contributor to high morbidity and mortality in developing countries. This intervention study aimed to assess the response of specific anti-microbial and anti-retroviral therapy (ART) on enteropathogens identified in HIV/AIDS adult subjects from northern India. Seventy five ART naive (group 1) and seventy five ART adherent (group 2) HIV/AIDS adult subjects with diarrhea were enrolled. Stool samples from all subjects were examined for enteropathogens by wet mount, staining methods, culture and ELISA. Subjects with enteropathogens were started on specific therapy as per National AIDS Control Organisation, Government of India's guidelines. Follow-up stool samples were examined after 2-4 weeks of completion of therapy for persistence/clearing of enteropathogens. CD4+ T lymphocyte count was done for all subjects. At enrollment, group 1 had 26.13% bacterial, 57.66% parasitic & 16.22% fungal pathogens while group 2 had 11.9%, 69.05% & 19.05% pathogens, respectively. Parasitic diarrhea was more common than bacterial diarrhea. The coccidian parasites (Cryptosporidium spp. & Isospora belli) were the common parasites identified. Clearance of enteric pathogens was significant after specific anti-microbial therapy (p = 0.0001). Persistence of enteropathogens was seen primarily for coccidian parasites. Clearance of enteropathogens after specific therapy and the diagnostic yield of stool specimens were influenced by the CD4+ counts. Immune competence coupled with specific anti-microbial therapy displays the best response against enteric pathogens. PMID:23968293

  7. HIV and the Gut Microbiota, Partners in Crime: Breaking the Vicious Cycle to Unearth New Therapeutic Targets

    PubMed Central

    Jenabian, Mohammad-Ali

    2015-01-01

    The gut microbiota plays a key role in health and immune system education and surveillance. The delicate balance between microbial growth and containment is controlled by the immune system. However, this balance is disrupted in cases of chronic viral infections such as HIV. This virus is capable of drastically altering the immune system and gastrointestinal environment leading to significant changes to the gut microbiota and mucosal permeability resulting in microbial translocation from the gut into the peripheral blood. The changes made locally in the gut have far-reaching consequences on the other organs of the body starting in the liver, where microbes and their products are normally filtered out, and extending to the blood and even brain. Microbial translocation and their downstream effects such as increased indolamine 2,3-dioxygenase (IDO) enzyme expression and activity create a self-sustaining feedback loop which enhances HIV disease progression and constitute a vicious cycle of inflammation and immune activation combining viral and bacterial factors. Understanding this self-perpetuating cycle could be a key element in developing new therapies aimed at the gut microbiota and its fallout after infection. PMID:25759844

  8. Lessons Learned from HIV Vaccine Clinical Efficacy Trials

    PubMed Central

    Day, Tracey A.; Kublin, James G.

    2014-01-01

    The past few years have witnessed many promising advances in HIV prevention strategies involving pre-exposure prophylaxis approaches. Some may now wonder whether an HIV vaccine is still needed, and whether developing one is even possible. The partial efficacy reported in the RV144 trial and the encouraging results of the accompanying immune correlates analysis suggest that an effective HIV vaccine is achievable. These successes have provided a large impetus and guidance for conducting more HIV vaccine trials. A key lesson learned from RV144 is that assessment of HIV acquisition is now a feasible and valuable primary objective for HIV preventive vaccine trials. In this article we review how RV144 and other HIV vaccine efficacy trials have instructed the field and highlight some of the HIV vaccine concepts in clinical development. After a long and significant investment, HIV vaccine clinical research is paying off in the form of valuable lessons that, if applied effectively, will accelerate the path toward a safe and effective vaccine. Together with other HIV prevention approaches, preventive and therapeutic HIV vaccines will be invaluable tools in bringing the epidemic to an end. PMID:24033299

  9. An Essential Role for Coagulase in Staphylococcus aureus Biofilm Development Reveals New Therapeutic Possibilities for Device-Related Infections.

    PubMed

    Zapotoczna, Marta; McCarthy, Hannah; Rudkin, Justine K; O'Gara, James P; O'Neill, Eoghan

    2015-12-15

    High-level resistance to antimicrobial drugs is a major factor in the pathogenesis of chronic Staphylococcus aureus biofilm-associated, medical device-related infections. Antimicrobial susceptibility analysis revealed that biofilms grown for ≤ 24 hours on biomaterials conditioned with human plasma under venous shear in iron-free cell culture medium were significantly more susceptible to antistaphylococcal antibiotics. Biofilms formed under these physiologically relevant conditions were regulated by SaeRS and dependent on coagulase-catalyzed conversion of fibrinogen into fibrin. In contrast, SarA-regulated biofilms formed on uncoated polystyrene in nutrient-rich bacteriological medium were mediated by the previously characterized biofilm factors poly-N-acetyl glucosamine, fibronectin-binding proteins, or autolytic activity and were antibiotic resistant. Coagulase-mediated biofilms exhibited increased antimicrobial resistance over time (>48 hours) but were always susceptible to dispersal by the fibrinolytic enzymes plasmin or nattokinase. Biofilms recovered from infected central venous catheters in a rat model of device-related infection were dispersed by nattokinase, supporting the important role of the biofilm phenotype and identifying a potentially new therapeutic approach with antimicrobials and fibrinolytic drugs, particularly during the early stages of device-related infection. PMID:26044292

  10. Is it possible to diagnose the therapeutic adherence of patients with COPD in clinical practice? A cohort study

    PubMed Central

    2011-01-01

    Background Therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is poor. It is therefore necessary to determine the magnitude of non-adherence to develop strategies to correct this behaviour. The purpose of this study was to analyse the diagnostic validity of indirect adherence methods. Methods Sample: 195 COPD patients undergoing scheduled inhaled treatment attending 5 Primary Care Centres of Malaga, Spain. Variables: Sociodemographic profile, illness data, spirometry, quality of life (St. George Respiratory Questionnaire: SGRQ), and inhaled medication counting (count of dose/pill or electronic monitoring) were collected. The patient's knowledge of COPD (Batalla test:BT),their attitude towards treatment (Morisky-Green test: MGT) and their self-reported therapeutic adherence (Haynes-Sackett test: HST) were used as methods of evaluating adherence. The follow-up consisted four visits over one year (the recruitment visit: V0; and after 1 month:V1; 6 months:V2; and 1 year:V3). Results The mean age was 69.59 (95% CI, 68.29-70.89) years old and 93.8% were male. Other findings included: 85.4% had a low educational level, 23.6% were smokers, 71.5% mild-moderate COPD stage with a FEV1 = 56.86 (SD = 18.85); exacerbations per year = 1.41(95% CI, 1-1.8). The total SGRQ score was 44.96 (95% CI, 42.46-47.46), showing a mild self-perceived impairment in health. The prevalence of adherence (dose/pill count) was 68.1% (95% CI, 60.9-75.3) at V1, 80% (95% CI, 73-87) at V2 and 84% (95% CI, 77.9) at V3. The MGT showed a specificity of 67.34% at V1, 76.19% at V2 and 69.62% at V3. The sensitivity was 53.33% at V1, 66.66% at V2 and 33.33% at V3.The BT showed a specificity of 55.1% at V1, 70.23% at V2 and 67.09% at V3. The sensitivity was 68.88% at V1, 71.43% at V2 and 46.66% at V3. Considering both tests together, the specificity was 86.73% at V1, 94.04% at V2 and 92.49% at V3 and the sensitivity was 37.77% at V1, 47.62% at V2 and 13.3% at V3. Conclusions The prevalence of treatment adherence changes over time. Indirect methods (dose/pill count and self-reported) can be useful to detect non-adherence in COPD patients. The combination of MGT and BT is the best approach to test self-reported adherence. PMID:21261951

  11. Changes in key constituents of clonally propagated Artemisia annua L. during preparation of compressed leaf tablets for possible therapeutic use

    PubMed Central

    Weathers, Pamela J.; Towler, Melissa J.

    2014-01-01

    Artemisia annua L., long used as a tea infusion in traditional Chinese medicine, produces artemisinin. Although artemisinin is currently used as artemisinin-based combination therapy (ACT) against malaria, oral consumption of dried leaves from the plant showed efficacy and will be less costly than ACT. Many compounds in the plant have some antimalarial activity. Unknown, however, is how these plant components change as leaves are processed into tablets for oral consumption. Here we compared extracts from fresh and dried leaf biomass with compressed leaf tablets of A. annua. Using GC-MS, nineteen endogenous compounds, including artemisinin and several of its pathway metabolites, nine flavonoids, three monoterpenes, a coumarin, and two phenolic acids, were identified and quantified from solvent extracts to determine how levels of these compounds changed during processing. Results showed that compared to dried leaves, artemisinin, arteannuin B, artemisinic acid, chlorogenic acid, scopoletin, chrysoplenetin, and quercetin increased or remained stable with powdering and compression into tablets. Dihydroartemisinic acid, monoterpenes, and chrysoplenol-D decreased with tablet formation. Five target compounds were not detectable in any of the extracts of this cultivar. In contrast to the individually measured aglycone flavonoids, using the AlCl3 method, total flavonoids increased nearly fivefold during the tablet formation. To our knowledge this is the first study documenting changes that occurred in processing dried leaves of A. annua into tablets. These results will improve our understanding of the potential use of not only this medicinal herb, but also others to afford better quality control of intact plant material for therapeutic use. PMID:25228784

  12. Changes in key constituents of clonally propagated Artemisia annua L. during preparation of compressed leaf tablets for possible therapeutic use.

    PubMed

    Weathers, Pamela J; Towler, Melissa J

    2014-12-01

    Artemisia annua L., long used as a tea infusion in traditional Chinese medicine, produces artemisinin. Although artemisinin is currently used as artemisinin-based combination therapy (ACT) against malaria, oral consumption of dried leaves from the plant showed efficacy and will be less costly than ACT. Many compounds in the plant have some antimalarial activity. Unknown, however, is how these plant components change as leaves are processed into tablets for oral consumption. Here we compared extracts from fresh and dried leaf biomass with compressed leaf tablets of A. annua. Using GC-MS, nineteen endogenous compounds, including artemisinin and several of its pathway metabolites, nine flavonoids, three monoterpenes, a coumarin, and two phenolic acids, were identified and quantified from solvent extracts to determine how levels of these compounds changed during processing. Results showed that compared to dried leaves, artemisinin, arteannuin B, artemisinic acid, chlorogenic acid, scopoletin, chrysoplenetin, and quercetin increased or remained stable with powdering and compression into tablets. Dihydroartemisinic acid, monoterpenes, and chrysoplenol-D decreased with tablet formation. Five target compounds were not detectable in any of the extracts of this cultivar. In contrast to the individually measured aglycone flavonoids, using the AlCl3 method, total flavonoids increased nearly fivefold during the tablet formation. To our knowledge this is the first study documenting changes that occurred in processing dried leaves of A. annua into tablets. These results will improve our understanding of the potential use of not only this medicinal herb, but also others to afford better quality control of intact plant material for therapeutic use. PMID:25228784

  13. Phosphodiesterase-4 modulation as a potential therapeutic for cognitive loss in pathological and non-pathological aging: possibilities and pitfalls.

    PubMed

    Hansen, Rolf T; Zhang, Han-Ting

    2015-01-01

    Phosphodiesterases (PDEs) are a super family of 11 enzyme families responsible for the hydrolysis of the intracellular secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). PDE4, in particular, is highly expressed in brain regions involved with regulation of memory, anxiety, and depression, including the hippocampus, amygdala, and nucleus accumbens. Senescence has been shown to result in extreme dysregulation of the cAMP pathway in various brain regions. Thus, as a critical controller of intracellular cAMP levels, PDE4 may be a potential target for the treatment of senescence-related cognitive disorders, which could be pathological and/or non-pathological in origin. While there is great potential in the development of novel PDE4 inhibitors for treatment of senescent-cognition impairment, there are also currently many pitfalls that need to be overcome. PDE4 has four subfamilies (PDE4A, B, C, and D) that are differentially expressed throughout the brain and body, as well as at least 25 splice variants derived from alternative splicing and multiple promoter sites. PDE4 subtypes have been shown to have differential effects on behavior, and cAMP itself has also been shown to play a contrasting role in behavior in different brain regions. This review will focus on what is currently understood about PDE4 in aging, the potential for PDE4 modulation as a cognitive therapy, and current pitfalls and limitations that need to be overcome in the PDE4 field. Overall, furthering our understanding of this incredibly complex pathway may one day assist with the development of novel therapeutics for both pathological and non-pathological cognitive disorders associated with senescence. PMID:25159075

  14. Schizotypy and leadership: a contrasting model for deficit symptoms, and a possible therapeutic role for sex hormones.

    PubMed

    Alias, A G

    2000-04-01

    Associational loosening, slow and faulty information processing, poor gating of irrelevant stimuli, poor ability to shift attention, poor working memory, passivity, ambivalence, anhedonia, and impaired motor coordination are cardinal features of schizophrenia but, unlike delusions and hallucinations, they are related more to negative/deficit symptoms. As summarized by Bass, numerous studies have correlated leadership with 'ambition, initiative and persistence' (opposite of passivity), 'speed and accuracy of thought', 'finality of decision,' or decisiveness (the opposite of ambivalence), 'mood control, optimism and sense of humor' (opposite of anhedonia), etc. Andreasen et al postulate that a disruption in the circuitry among nodes located in the prefrontal regions, the thalamic nuclei, and the cerebellum produces 'cognitive dysmetria', meaning difficulty in prioritizing, coordinating, and responding to information, and that it can account for the broad diversity of symptoms of schizophrenia. A relationship between cognitive processes and cerebellar and basal ganglia functions, and a role of neocerebellum in rapidly shifting attention, have been demonstrated. The cognitive styles, including a proficiency to quickly shift attention, of several famous leaders are used as examples of this contrasting model. Julius Caesar and Napoleon, for instance, could dictate to up to six secretaries simultaneously, using their exceptional working memories, and proficiency in quickly and effortlessly shifting attention while flawlessly gating irrelevant external and internal stimuli. It is suggested that specific brain imaging studies could illustrate this contrast. Gray et al noted positive correlations between 'dominance', an important leadership trait, and serum levels of dehydroepiandrosterone (DHEA) and testosterone (T), but not of more potent dihydrotestosterone (DHT), in over 1700 older men. Though not scientifically rigorous, the author noted positive correlations (P = 0.0162) between the self-rated ratings of voice depth (promoted by T) and of leadership, but none between those of body hair (DHT dependent) and of leadership in 47 male US National Academy of Sciences members. And 43 male US Senators had deeper voices than 36 male House members (P<0.01) who, in turn, had deeper voices than either of two groups (numbers 102 and 72) of male scientists (P<0.01). Therapeutically, before chlorpromazine, DHEA had been used in young schizophrenics with modest success in improving deficit symptoms. DHEA, or other sex hormones, or some of their natural and synthetic derivatives may prove to be valuable to treat deficit symptoms of schizophrenia in both sexes. PMID:10859637

  15. Structural and electronic properties of new fullerene derivatives and their possible application as HIV-1 protease inhibitors

    NASA Astrophysics Data System (ADS)

    Ibrahim, Medhat; Saleh, Noha A.; Hameed, Ali Jameel; Elshemey, Wael M.; Elsayed, Anwar A.

    2010-02-01

    Density functional theory (DFT) calculations have been carried out at the hybrid Becke 3-Lee-Yang-Parr; B3LYP/3-21G** level of theory to study two series of hydroxy-chalca-acetic acid-(4-pyrrolidin-1-yl-phenyl) ester [C 60-C 2H 4N-(4-XCOCH 2OH)C 6H 4] and hydroxy-chalcoacetic acid-[2-(2-hydroxy-acetylchalcanyl)-4-pyrrolidin-1-yl-phenyl] ester[C 60-C 2H 4N-(3,4-XCOCH 2OH)C 6H 4]. The X atom is O, S or Se for the two series. The vibrational spectra, physical, chemical, thermodynamics and Quantitative Structure Activity Relationship (QSAR) properties of the studied molecules are calculated and discussed. We have evaluated these molecules as HIV-1 protease inhibitors based on the hydrogenation interaction between the hydroxymethylcarbonyl (HMC) groups and the two aspartic acid of the HIV-1 protease active site. Results show that some of the investigated fullerene-based derivatives can be considered promising as HIV-1 protease inhibitors.

  16. Nanoformulated Antiretroviral Combinations Extend Drug Release and Antiretroviral Responses in HIV-1 Infected Macrophages: Implications for NeuroAIDS Therapeutics

    PubMed Central

    Nowacek, Ari S.; McMillan, JoEllyn; Miller, Reagan; Anderson, Alec; Rabinow, Barrett; Gendelman, Howard E.

    2012-01-01

    We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus-type one infected people can be achieved through developments in nanoformulations. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies. This resulted in improved drug uptake, release and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated drug release from 15 to > 20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus-type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people. PMID:20237859

  17. Ultrasound-induced apoptosis in the presence of Sonazoid and associated alterations in gene expression levels: a possible therapeutic application.

    PubMed

    Furusawa, Yukihiro; Zhao, Qing-Li; Hassan, Mariame Ali; Tabuchi, Yoshiaki; Takasaki, Ichiro; Wada, Shigehito; Kondo, Takashi

    2010-02-01

    Ultrasound (US) has been shown to induce apoptosis and cell lysis in cancer cells. In this study, we report on the potential of using Sonazoid, a new echo-contrast agent, that is chemically more stable and US-resistant in combination with US in cancer therapy. The biological effects and their mechanisms in the presence or absence of ultrasonic exposure in vitro were investigated. In addition, the impact of the agent on the expression levels of genes responsive to US was studied using global-scale microarrays and computational gene expression analysis tools. Our results show that the combination led to enhanced cell killing in the presence of 1 MHz acoustic field. The apoptosis induction was shown to be mediated by the mitochondrial pathway. The occurrence of US-induced DNA damage was also observed. Despite these findings, the agent at concentrations similar to those clinically used can be considered as well tolerated. Furthermore, Sonazoid enhanced expression of genes that related to apoptosis and are responsive to US, although it alone had almost no effect. These results indicate the potential of Sonazoid for US contrast enhancement as well as the possibility of its use in US-aided therapies. PMID:19646810

  18. Increasing Obesity in Treated Female HIV Patients from Sub-Saharan Africa: Potential Causes and Possible Targets for Intervention

    PubMed Central

    McCormick, Claire L.; Francis, Arianne M.; Iliffe, Kim; Webb, Helen; Douch, Catherine J.; Pakianathan, Mark; Macallan, Derek C.

    2014-01-01

    Objectives: To investigate changing nutritional demographics of treated HIV-1-infected patients and explore causes of obesity, particularly in women of African origin. Methods: We prospectively reviewed nutritional demographics of clinic attenders at an urban European HIV clinic during four one-month periods at three-yearly intervals (2001, 2004, 2007, and 2010) and in two consecutive whole-year reviews (2010–2011 and 2011–2012). Risk-factors for obesity were assessed by multiple linear regression. A sub-study of 50 HIV-positive African female patients investigated body-size/shape perception using numerical, verbal, and pictorial cues. Results: We found a dramatic rise in the prevalence of obesity (BMI > 30 kg/m2), from 8.5 (2001) to 28% (2011–2012) for all clinic attenders, of whom 86% were on antiretroviral treatment. Women of African origin were most affected, 49% being obese, with a further 32% overweight (BMI 25–30 kg/m2) in 2012. Clinical factors strongly associated with obesity included female gender, black African ethnicity, non-smoking, age, and CD4 count (all P < 0.001); greater duration of cART did not predict obesity. Individual weight-time trends mostly showed slow long-term progressive weight gain. Investigating body-weight perception, we found that weight and adiposity were underestimated by obese subjects, who showed a greater disparity between perceived and actual adiposity (P < 0.001). Obese subjects targeted more obese target “ideal” body shapes (P < 0.01), but were less satisfied with their body shape overall (P = 0.02). Conclusion: Seropositive African women on antiretroviral treatment are at heightened risk of obesity. Although multifactorial, body-weight perception represents a potential target for intervention. PMID:25431572

  19. HIV Type 1 Gag as a Target for Antiviral Therapy

    PubMed Central

    2012-01-01

    Abstract The Gag proteins of HIV-1 are central players in virus particle assembly, release, and maturation, and also function in the establishment of a productive infection. Despite their importance throughout the replication cycle, there are currently no approved antiretroviral therapies that target the Gag precursor protein or any of the mature Gag proteins. Recent progress in understanding the structural and cell biology of HIV-1 Gag function has revealed a number of potential Gag-related targets for possible therapeutic intervention. In this review, we summarize our current understanding of HIV-1 Gag and suggest some approaches for the development of novel antiretroviral agents that target Gag. PMID:21848364

  20. Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase-a comprehensive drug target database for Lymphatic filariasis

    PubMed Central

    Sharma, Om Prakash; Kumar, Muthuvel Suresh

    2016-01-01

    Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in. PMID:26806463

  1. Potentiation of cytotoxicity of paclitaxel in combination with Cl-IB-MECA in human C32 metastatic melanoma cells: A new possible therapeutic strategy for melanoma.

    PubMed

    Soares, Ana S; Costa, Vera M; Diniz, Carmen; Fresco, Paula

    2013-10-01

    Metastatic melanoma monotherapies with drugs such as dacarbazine, cisplatin or paclitaxel (PXT) are associated with significant toxicity and low efficacy rates. These facts reinforce the need for development of novel agents or combinatory strategies. Cl-IB-MECA is a small molecule, orally bioavailable, well tolerated and currently under clinical trials as an anticancer agent. Our aim was to investigate a possible combinatory therapeutic strategy using PXT and Cl-IB-MECA on human C32 melanoma cells and its underlying mechanisms. Cytotoxicity was evaluated using MTT reduction, lactate dehydrogenase leakage and neutral red uptake assays, for different concentrations and combinations of both agents, at 24 and 48 h. Apoptosis was also assessed using fluorescence microscopy and through the evaluation of caspases 8, 9, and 3 activities. We demonstrated, for the first time, that combination of PXT and Cl-IB-MECA significantly increases cytotoxicity for clinically relevant concentrations. This combination seems to act synergistically in disrupting membrane integrity, but also causing lysosomal and mitochondrial dysfunction. When using the lowest PTX concentration (10 ng/mL), co-incubation with CI-IB-MECA (micromolar concentrations) potentiated overall cytotoxic effects and morphological signs of apoptosis. All combinations studied enhanced caspase 8, 9, and 3 activities, suggesting the involvement of both intrinsic and extrinsic apoptotic pathways. The possibility that cytotoxicity elicited by Cl-IB-MECA, alone or in combination with PXT, involves adenosine receptor activation was discarded and results confirmed that oxidative stress is only involved in cytotoxicity after treatment with PXT, alone. Being melanoma a very apoptosis-resistance cancer, this combination seems to hold promise as a new therapeutic strategy for melanoma. PMID:24035253

  2. Pin1 liberates the human immunodeficiency virus type-1 (HIV-1): Must we stop it?

    PubMed

    Hou, Hai; Wang, Jing-Zhang; Liu, Bao-Guo; Zhang, Ting

    2015-07-01

    Acquired immune deficiency syndrome (AIDS) is mainly caused by the human immunodeficiency virus type-1 (HIV-1). To our knowledge, this is the first review focusing on the vital role of Pin1 in the infection of HIV-1 and the development of AIDS. We and others have demonstrated that Pin1, the only known cis-to-trans isomerase recognizing the pThr/pSer-Pro motifs in proteins, plays striking roles in several human diseases. Interestingly, recent evidence gradually indicates that Pin1 regulates several key steps of the life cycle of HIV-1, including the uncoating of the HIV-1 core, the reverse transcription of the RNA genome of HIV-1, and the integration of the HIV-1 cDNA into human chromosomes. Whereas inhibiting Pin1 suppresses all of these key steps and attenuates the replication of HIV-1, at the same time different PIN1 gene variants are correlated with the susceptibility to HIV-1 infection. Furthermore, Pin1 potentially promotes HIV-1 infection by activating multiple oncogenes and inactivating multiple tumor suppressors, extending the life span of HIV-infected cells. These descriptions suggest Pin1 as a promising therapeutic target for the prevention of HIV-1 and highlight the possibility of blocking the development of AIDS by Pin1 inhibitors. PMID:25913034

  3. Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

    PubMed Central

    Brekke, Kristin; Lind, Andreas; Holm-Hansen, Carol; Haugen, Inger Lise; Sørensen, Birger; Sommerfelt, Maja; Kvale, Dag

    2014-01-01

    Background Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant. Methods Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β. Results Vacc-4x proliferative T cell responses increased only among the vaccinated (p≤0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = −0.82, p<0.001) and high regulation (r = 0.61, p = 0.010) at baseline. Conclusion Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation. Trial Registration ClinicalTrials.gov NCT01473810 PMID:25398137

  4. Damaging the Integrated HIV Proviral DNA with TALENs

    PubMed Central

    Strong, Christy L.; Guerra, Horacio P.; Mathew, Kiran R.; Roy, Nervik; Simpson, Lacy R.; Schiller, Martin R.

    2015-01-01

    HIV-1 integrates its proviral DNA genome into the host genome, presenting barriers for virus eradication. Several new gene-editing technologies have emerged that could potentially be used to damage integrated proviral DNA. In this study, we use transcription activator-like effector nucleases (TALENs) to target a highly conserved sequence in the transactivation response element (TAR) of the HIV-1 proviral DNA. We demonstrated that TALENs cleave a DNA template with the HIV-1 proviral target site in vitro. A GFP reporter, under control of HIV-1 TAR, was efficiently inactivated by mutations introduced by transfection of TALEN plasmids. When infected cells containing the full-length integrated HIV-1 proviral DNA were transfected with TALENs, the TAR region accumulated indels. When one of these mutants was tested, the mutated HIV-1 proviral DNA was incapable of producing detectable Gag expression. TALEN variants engineered for degenerate recognition of select nucleotide positions also cleaved proviral DNA in vitro and the full-length integrated proviral DNA genome in living cells. These results suggest a possible design strategy for the therapeutic considerations of incomplete target sequence conservation and acquired resistance mutations. We have established a new strategy for damaging integrated HIV proviral DNA that may have future potential for HIV-1 proviral DNA eradication. PMID:25946221

  5. Complications of HIV Disease and Antiretroviral Therapy

    PubMed Central

    Luetkemeyer, Anne F.; Havlir, Diane V.; Currier, Judith S.

    2011-01-01

    There is growing interest in the pathogenesis, treatment, and prevention of long-term complications of HIV disease and its therapies. Specifically, studies focused on cardiovascular, renal, bone, and fat abnormalities were prominent at the 17th Conference on Retroviruses and Opportunistic Infections. Although enthusiasm about the effectiveness of current antiretroviral therapy remains strong, collectively, the ongoing work in the area of HIV disease and treatment complications appears to reflect concerns that these clinical problems will continue to remain important and possibly increase over time in the current therapeutic era. This year’s conference also highlighted important data on prevention and optimal treatment of common coinfections that occur in HIV-infected individuals, including tuberculosis, influenza, and viral hepatitis. PMID:20516525

  6. HIV/AIDS: a minority health issue.

    PubMed

    Cargill, Victoria A; Stone, Valerie E

    2005-07-01

    HIV infection among racial and ethnic minorities is an ongoing health crisis. The disproportionate impact of HIV infection on racial and ethnic minorities has affected communities already struggling with many social and economic challenges, such as poverty, substance abuse, homelessness,unequal access to health care, and unequal treatment once in the health care system. Superimposed on these challenges is HIV infection, the transmission of which is facilitated by many of these factors. Although the epidemic is disproportionately affecting all racial and ethnic minorities, within these minority populations women are particularly affected. The care and management of racial and ethnic minorities who have HIV infection has been complicated by the unequal access to health care and the unequal treatment once enrolled in health care. Health insurance status, lack of concordance between the race of the patient and the provider, and satisfaction with the quality of their care all impact on treatment outcomes in this population. In addition, the provider must be aware of the many comorbid conditions that may affect the delivery of care to minority patients living with HIV infection: depression, substance and alcohol abuse, and posttraumatic stress disorders. The impact of these comorbid conditions on the therapeutic relationship, including treatment and adherence, warrants screening for these disorders and treating them when identified. Because the patient provider relationship has been repeatedly identified as a predictor of higher adherence, developing and maintaining a strong therapeutic alliance is critical. Participation of racial and ethnic minorities in HIV clinical trials, as in other disease states, has been very poor. Racial and ethnic minorities have been chronically underrepresented in HIV clinical trials, despite their overrepresentation in the HIV epidemiology. This underrepresentation seems to be the result of a combination of factors including (1) provider bias in referring to clinical trials, (2) mistrust of clinical research, (3) past poor experience with the health care system, and (4) the conspiracy theories of HIV disease. The paucity of minority health care professionals and minority investigators in HIV research further affects minority participation in clinical research. To improve racial and ethnic minority participation in clinical trials a sustained effort is necessary at multiple levels. Increased recruitment and retention is an ongoing need, and one that will not be satisfactorily addressed until there are better community-academic and research partner-ships, and the research questions posed also address issues of concern and significance to the affected community. Reduction in barriers to participation in clinical trials, especially given the many competing needs of racial and ethnic minority patients, is also needed. Multidisciplinary HIV care teams and research staff with training in cultural competency and cultural sensitivity may also be helpful. Prevention of HIV infection remains essential, especially among those seeking care for HIV infection. Despite several published recommendations for the inclusion of HIV prevention in the clinical care setting, studies have documented how few providers actually achieve this goal, especially those who care for disadvantaged patients. Although there are many barriers to discussing HIV risk behaviors and prevention strategies in an office visit,including time constraints and potential provider discomfort in discussing these matters, clinical visits represent an important opportunity to reinforce HIV prevention and possibly decrease further HIV transmission. PMID:15925655

  7. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: a double-blind, placebo-controlled, randomized trial.

    PubMed

    Emadi-Kouchak, Hamid; Mohammadinejad, Payam; Asadollahi-Amin, Ali; Rasoulinejad, Mehrnaz; Zeinoddini, Atefeh; Yalda, Alireza; Akhondzadeh, Shahin

    2016-01-01

    Patients with the HIV infection are at high risk for developing depression. The aim of this study was to investigate the safety and efficacy of antidepressant effects of minocycline on HIV patients with depression. Forty-six HIV patients, with mild-to-moderate depression and a Hamilton Depression Rating Scale (HDRS) up to 18, participated in a parallel, randomized, double-blind, placebo-controlled trial and underwent 6 weeks of treatment with either minocycline (100 mg twice daily) or placebo in the same manner. Patients were assessed using HDRS at baseline and at weeks 3 and 6. The primary outcome measure was to evaluate the efficacy of minocycline in improving depressive symptoms. General linear model repeated measures showed significant effect for time × treatment interaction on the HDRS score during the trial course [F(2, 88)=7.50, P=0.001]. There was no significant difference between the two groups regarding adverse events. No serious adverse event was reported. The administration of 100 mg minocycline twice daily seems to be safe and effective in improving depressive symptoms in HIV/AIDS patients with mild-to-moderate depression. PMID:26465919

  8. The same site on the integrase-binding domain of lens epitheliumderived growth factor is a therapeutic target for MLL leukemia and HIV

    PubMed Central

    Murai, Marcelo J.; Pollock, Jonathan; He, Shihan; Miao, Hongzhi; Purohit, Trupta; Yokom, Adam; Hess, Jay L.; Muntean, Andrew G.; Grembecka, Jolanta

    2014-01-01

    Lens epithelium-derived growth factor (LEDGF) is a chromatin-associated protein implicated in leukemia and HIV type 1 infection. LEDGF associates with mixed-lineage leukemia (MLL) fusion proteins and menin and is required for leukemic transformation. To better understand the molecular mechanism underlying the LEDGF integrase-binding domain (IBD) interaction with MLL fusion proteins in leukemia, we determined the solution structure of the MLL-IBD complex. We found a novel MLL motif, integrase domain binding motif 2 (IBM2), which binds to a well-defined site on IBD. Point mutations within IBM2 abolished leukemogenic transformation by MLL-AF9, validating that this newly identified motif is essential for the oncogenic activity of MLL fusion proteins. Interestingly, the IBM2 binding site on IBD overlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD from the menin-MLL complex. A short IBM2 peptide binds to IBD directly and inhibits both the IBD-MLL/menin and IBD-IN interactions. Our findings show that the same site on IBD is involved in binding to MLL and HIV-IN, revealing an attractive approach to simultaneously target LEDGF in leukemia and HIV. PMID:25305204

  9. A systematic review of the effects of different types of therapeutic exercise on physiologic and functional measurements in patients with HIV/AIDS

    PubMed Central

    Gomes-Neto, Mansueto; Conceição, Cristiano Sena; Carvalho, Vitor Oliveira; Brites, Carlos

    2013-01-01

    Several studies have reported the benefits of exercise training for adults with HIV, although there is no consensus regarding the most efficient modalities. The aim of this study was to determine the effects of different types of exercise on physiologic and functional measurements in patients with HIV using a systematic strategy for searching randomized controlled trials. The sources used in this review were the Cochrane Library, EMBASE, MEDLINE, and PEDro from 1950 to August 2012. We selected randomized controlled trials examining the effects of exercise on body composition, muscle strength, aerobic capacity, and/or quality of life in adults with HIV. Two independent reviewers screened the abstracts using the Cochrane Collaboration's protocol. The PEDro score was used to evaluate methodological quality. In total, 29 studies fulfilled the inclusion criteria. Individual studies suggested that exercise training contributed to improvement of physiologic and functional parameters, but that the gains were specific to the type of exercise performed. Resistance exercise training improved outcomes related to body composition and muscle strength, with little impact on quality of life. Aerobic exercise training improved body composition and aerobic capacity. Concurrent training produced significant gains in all outcomes evaluated, although moderate intensity and a long duration were necessary. We concluded that exercise training was shown to be a safe and beneficial intervention in the treatment of patients with HIV. PMID:24037014

  10. [Oral manifestations in HIV infection].

    PubMed

    Steinsvoll, Svein; Herlofson, Bente Brokstad

    2006-04-27

    In this review article, oral lesions in relation to HIV infection are presented and discussed. Lesions such as oral candidiasis, hairy leukoplakia and necrotising gingivitis or periodontitis may be the first sign of an HIV infection or of its progression. Almost all HIV-infected patients will contract oral diseases. Dentists and physicians play an essential role in early recognition of signs and symptoms of HIV disease or of its progression. Only through such recognition can appropriate definitive diagnostic testing be conducted and appropriate therapeutic intervention for the condition be considered. It is pivotal that both dentists and physicians are familiar with the most frequently occurring oral symptoms of HIV infection. PMID:16670745

  11. Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

    PubMed Central

    Armitage, Andrew E.; Deforche, Koen; Welch, John J.; Van Laethem, Kristel; Camacho, Ricardo; Rambaut, Andrew

    2014-01-01

    ABSTRACT Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plus-strand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined “footprints” of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. G-to-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. IMPORTANCE Collectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vif-specific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family. PMID:25165112

  12. Favorable therapeutic response with an antiretroviral salvage regimen in an HIV-1-positive subject infected with a CRF11-cpx virus.

    PubMed

    Tau, Pamela; Mancon, Alessandro; Mileto, Davide; Di Nardo Stuppino, Silvia; Bottani, Giulia; Gismondo, Maria Rita; Galli, Massimo; Micheli, Valeria; Rusconi, Stefano

    2014-05-01

    HIV drug resistance still represents a crucial problem in antiretroviral therapy. We report a case of a naive patient, harboring a CRF11-cpx virus, which showed drug resistance mutations in the reverse transcriptase. A drug resistance genotyping test was performed for the pol (protease, reverse transcriptase, and integrase) and V3 regions. The initial clinical parameter results showed a 4 log level of HIV-RNA (12,090 cp/ml) and a very low CD4(+) cell count (35 cells/μl). We designed an initial highly active antiretroviral therapy (HAART) regimen including lamivudine (3TC)+abacavir (ABC)+booster ritonavir (DRV/r). The virus was highly resistant to all nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) except for ABC, tenofovir (TDF), and efavirenz (EFV) and was susceptible to all protease inhibitors (PIs) and integrase inhibitors (INIs). A salvage regimen including raltegravir (RAL)+DRV/r was started. Ten months later, the immunovirological status shows CD4(+) 142/μl and HIV-RNA <37 cp/ml. Our results demonstrate the effectiveness of a treatment combination that includes RAL+DRV/r in a patient infected with a complex X4-tropic CRF11-cpx virus. PMID:24279648

  13. Therapeutic Drug Monitoring and Pharmacogenetic Study of HIV-Infected Ethnic Chinese Receiving Efavirenz-Containing Antiretroviral Therapy with or without Rifampicin-Based Anti-Tuberculous Therapy

    PubMed Central

    Lee, Kuan-Yeh; Lin, Shu-Wen; Sun, Hsin-Yun; Kuo, Ching-Hua; Tsai, Mao-Song; Wu, Bing-Ru; Tang, Sue-Yo; Liu, Wen-Chun; Chang, Sui-Yuan; Hung, Chien-Ching

    2014-01-01

    Objectives Plasma efavirenz concentrations in HIV-infected patients with tuberculosis (TB) may be affected by cytochrome P450 (CYP) 2B6 single-nucleotide polymorphisms and concurrent rifampicin use. We aimed to investigate the effects of CYP2B6 G516T polymorphisms and concomitant rifampicin use on the plasma efavirenz concentrations in HIV-infected Taiwanese. Methods HIV-infected patients with or without TB who had received combination antiretroviral therapy containing efavirenz (600 mg daily) for two weeks or greater were enrolled for determinations of CYP2B6 G516T polymorphism and plasma efavirenz concentrations with the use of polymerase-chain-reaction restriction fragment-length polymorphism and high-performance liquid chromatography, respectively. Results From October 2009 to August 2012, 171 HIV-infected patients, including 18 with TB, were enrolled 113 (66.1%) with CYP2B6 G516G, 55 (32.2%) GT, and 3 (1.8%) TT genotype. Patients receiving rifampicin had a significantly lower median plasma efavirenz concentration than the control group (2.16 vs 2.92 mg/L, P = 0.003); however, all patients achieved target plasma concentration (>1 mg/L). Patients with GT or TT genotype had a significantly higher plasma concentration than those with GG genotype (2.50 vs 3.47 mg/L for GT genotype and 8.78 mg/L for TT genotype, P<0.001). Plasma efavirenz concentration >4 mg/L was noted in 38 (22.2%) patients, which was associated with a lower weight (per 10-kg increase, odds ratio, 0.52; 95% confidence interval, 0.33–0.83) and GT or TT genotype (odds ratio, 4.35; 95% confidence interval, 1.97–9.59) in multivariate analysis. Conclusions Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB who receive efavirenz 600 mg daily. Carriage of CYP2B6 516 GT and TT genotypes and a lower weight are associated with higher plasma efavirenz concentrations. PMID:24551111

  14. HIV-1 Proteins, Tat and gp120, Target the Developing Dopamine System

    PubMed Central

    Fitting, Sylvia; Booze, Rosemarie M.; Mactutus, Charles F.

    2015-01-01

    In 2014, 3.2 million children (< 15 years of age) were estimated to be living with HIV and AIDS worldwide, with the 240,000 newly infected children in the past year, i.e., another child infected approximately every two minutes [1]. The primary mode of HIV infection is through mother-to-child transmission (MTCT), occurring either in utero, intrapartum, or during breastfeeding. The effects of HIV-1 on the central nervous system (CNS) are putatively accepted to be mediated, in part, via viral proteins, such as Tat and gp120. The current review focuses on the targets of HIV-1 proteins during the development of the dopamine (DA) system, which appears to be specifically susceptible in HIV-1-infected children. Collectively, the data suggest that the DA system is a clinically relevant target in chronic HIV-1 infection, is one of the major targets in pediatric HIV-1 CNS infection, and may be specifically susceptible during development. The present review discusses the development of the DA system, follows the possible targets of the HIV-1 proteins during the development of the DA system, and suggests potential therapeutic approaches. By coupling our growing understanding of the development of the CNS with the pronounced age-related differences in disease progression, new light may be shed on the neurological and neurocognitive deficits that follow HIV-1 infection. PMID:25613135

  15. HIV control in vivo: Dynamical analysis

    NASA Astrophysics Data System (ADS)

    Gumel, A. B.; Moghadas, S. M.

    2004-10-01

    A deterministic model for the immunological and therapeutic control of human immunodeficiency virus (HIV) in vivo is studied qualitatively. In addition to analyzing the local stability of the equilibria, the global stability of the infection-free equilibrium is established. The optimal efficacy level of anti-retroviral therapy needed to eradicate HIV from the body of an HIV-infected individual is obtained.

  16. Prison Therapeutic Community Treatment for Female Offenders: Profiles and Preliminary Findings for Mental Health and Other Variables (Crime, Substance Use and HIV Risk)

    ERIC Educational Resources Information Center

    Sacks, Joann Y.; Sacks, Stanley; Mckendrick, Karen; Banks, Steven; Schoeneberger, Marlies; Hamilton, Zachary; Stommel, Joseph; Shoemaker, Joanie

    2008-01-01

    This random assignment study compared women in a prison Therapeutic Community (TC) program with those in a cognitive-behavioral intervention. Over two thirds of study subjects received a lifetime diagnosis of severe mental disorder, nearly one-half received a diagnosis of PTSD, and virtually all reported exposure to trauma. Preliminary analysis (n…

  17. Are major reductions in new HIV infections possible with people who inject drugs? The case for low dead-space syringes in highly affected countries.

    PubMed

    Zule, William A; Cross, Harry E; Stover, John; Pretorius, Carel

    2013-01-01

    Circumstantial evidence from laboratory studies, mathematical models, ecological studies and bio behavioural surveys, suggests that injection-related HIV epidemics may be averted or reversed if people who inject drugs (PWID) switch from using high dead-space to using low dead-space syringes. In laboratory experiments that simulated the injection process and rinsing with water, low dead space syringes retained 1000 times less blood than high dead space syringes. In mathematical models, switching PWID from high dead space to low dead space syringes prevents or reverses injection-related HIV epidemics. No one knows if such an intervention is feasible or what effect it would have on HIV transmission among PWID. Feasibility studies and randomized controlled trials (RCTs) will be needed to answer these questions definitively, but these studies will be very expensive and take years to complete. Rather than waiting for them to be completed, we argue for an approach similar to that used with needle and syringe programs (NSP), which were promoted and implemented before being tested more rigorously. Before implementation, rapid assessments that involve PWID will need to be conducted to ensure buy-in from PWID and other local stakeholders. This commentary summarizes the existing evidence regarding the protective effects of low dead space syringes and estimates potential impacts on HIV transmission; it describes potential barriers to transitioning PWID from high dead space to low dead space needles and syringes; and it presents strategies for overcoming these barriers. PMID:22884539

  18. The change in cerebral glucose metabolism after electroacupuncture: a possible marker to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa

    PubMed Central

    Liu, Tao-Tao; Hong, Qing-Xiong; Xiang, Hong-Bing

    2015-01-01

    Some reports have demonstrated that deep brain stimulation (DBS) is a promising treatment for patients who suffer from intractable anorexia nervosa. However, the nature of DBS may not be viewed as a standard clinical treatment option for anorexia nervosa because of the unpredictable outcome before DBS. Just like DBS in the brain, electroacupuncture at acupoints is also efficient in treating refractory anorexia nervosa. Some neuroimaging studies using functional magnetic resonance imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) had revealed that both DBS and electroacupuncture at acupoints with electrical stimulation are related to the changes in cerebral glucose metabolism. Therefore, we hypothesize that the changes in cerebral glucose metabolism after electroacupuncture might be useful to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa. PMID:26770596

  19. Cross-Reactivity, Epitope Spreading, and De Novo Immune Stimulation Are Possible Mechanisms of Cross-Protection of Nonvaccine Human Papillomavirus (HPV) Types in Recipients of HPV Therapeutic Vaccines.

    PubMed

    Nakagawa, Mayumi; Greenfield, William; Moerman-Herzog, Andrea; Coleman, Hannah N

    2015-07-01

    Numerous versions of human papillomavirus (HPV) therapeutic vaccines designed to treat individuals with established HPV infection, including those with cervical intraepithelial neoplasia (CIN), are in development because approved prophylactic vaccines are not effective once HPV infection is established. As human papillomavirus 16 (HPV-16) is the most commonly detected type worldwide, all versions of HPV therapeutic vaccines contain HPV-16, and some also contain HPV-18. While these two HPV types are responsible for approximately 70% of cervical cancer cases, there are other high-risk HPV types known to cause malignancy. Therefore, it would be of interest to assess whether these HPV therapeutic vaccines may confer cross-protection against other high-risk HPV types. Data available from a few clinical trials that enrolled subjects with CINs regardless of the HPV type(s) present demonstrated clinical responses, as measured by CIN regression, in subjects with both vaccine-matched and nonvaccine HPV types. The currently available evidence demonstrating cross-reactivity, epitope spreading, and de novo immune stimulation as possible mechanisms of cross-protection conferred by investigational HPV therapeutic vaccines is discussed. PMID:25947147

  20. Cross-Reactivity, Epitope Spreading, and De Novo Immune Stimulation Are Possible Mechanisms of Cross-Protection of Nonvaccine Human Papillomavirus (HPV) Types in Recipients of HPV Therapeutic Vaccines

    PubMed Central

    Greenfield, William; Moerman-Herzog, Andrea; Coleman, Hannah N.

    2015-01-01

    Numerous versions of human papillomavirus (HPV) therapeutic vaccines designed to treat individuals with established HPV infection, including those with cervical intraepithelial neoplasia (CIN), are in development because approved prophylactic vaccines are not effective once HPV infection is established. As human papillomavirus 16 (HPV-16) is the most commonly detected type worldwide, all versions of HPV therapeutic vaccines contain HPV-16, and some also contain HPV-18. While these two HPV types are responsible for approximately 70% of cervical cancer cases, there are other high-risk HPV types known to cause malignancy. Therefore, it would be of interest to assess whether these HPV therapeutic vaccines may confer cross-protection against other high-risk HPV types. Data available from a few clinical trials that enrolled subjects with CINs regardless of the HPV type(s) present demonstrated clinical responses, as measured by CIN regression, in subjects with both vaccine-matched and nonvaccine HPV types. The currently available evidence demonstrating cross-reactivity, epitope spreading, and de novo immune stimulation as possible mechanisms of cross-protection conferred by investigational HPV therapeutic vaccines is discussed. PMID:25947147

  1. Updating the use of synthetic peptides as inhibitors of HIV-1 entry.

    PubMed

    Gómara, María José; Haro, Isabel

    2014-04-01

    The use of synthetic peptides as HIV-1 inhibitors has been the object of research over recent years. A large number of peptides that affect different stages of the HIV-1 life cycle have been and continue to be studied due to their possible clinical application in the fight against HIV-1 infection. The main advantages of synthetic peptides as therapeutic agents are their low systemic toxicity, the fact that structural modifications can be made to them and their resulting capacity to mimic certain substrates or epitopes. HIV-1-inhibiting peptides have been identified and/or developed using different methods. Some therapeutic peptides such as enfuvirtide-already approved for clinical use-are derived from HIV-1 itself. Others are natural peptides such as chemokines, defensins or the "virus inhibitory peptide"; while still others have been designed and synthesized based on crystallographic data on HIV-1 proteins or from peptide libraries. Initial attempts at therapeutic applications focused on HIV-coded enzymes (reverse transcriptase, protease and, more recently, integrase). However, structural HIV proteins and, more specifically, the mechanisms that involve the virus in cell infection and replication are now also considered therapeutic targets. Several chemical strategies to improve both the stability of peptides and their pharmacokinetics, including prolonging their half-life, have recently been described in the literature. There is growing an interest in inhibitors that prevent HIV entry into the host cell (fusion inhibitors) which could lead to the development of new antiviral agents. Knowledge of the mechanism of action of fusion inhibitors is essential not only for the development of future generations of entry inhibitors, but also to gain an understanding of the form and kinetics of membrane fusion induced by the virus. The physico-chemical processes involved at the interface between the lipid surface of cells and enveloped viruses (such as HIV-1) are essential to the action of peptides that prevent HIV-1 entry into the host cell. The interaction of these peptides with biological membranes may be related to their inhibition efficiency and to their mechanism of action, as the HIV-1 gp41 glycoprotein is bound and confined between the cellular membrane and the viral envelope. PMID:23931277

  2. Participation in HIV cure-related research: a scoping review of the proxy literature and implications for future research

    PubMed Central

    Dubé, Karine; Ramirez, Catalina; Handibode, Jessica; Taylor, Jeffrey; Skinner, Asheley; Greene, Sandra; Tucker, Joseph D

    2016-01-01

    Objective To identify the main types of HIV cure-related strategies and examine possible risks (and benefits) associated with participating in HIV cure-related research studies. Methods We undertook a scoping review to first map out the landscape of HIV cure-related research and then examined the risks and potential benefits associated with participating in HIV cure research. Given the early stage of many HIV cure-related studies, we used proxy literatures from non-cure HIV research and cancer research in order to anticipate possible motivators and deterrents of participation in HIV cure-related studies. Results We discussed four main categories of HIV cure-related research: (1) early antiretroviral treatment (ART); (2) latency-reversing agents (LRAs); (3) therapeutic vaccinations and immune-based therapies (IBT); and (4) stem-cell transplantation and gene therapy. At this juncture, these categories of HIV cure-related research have substantial individual risks and negligible individual and clinical benefits. Non-cure HIV research (including HIV prevention and treatment) and cancer research have empirical similarities (and differences) to HIV cure research and may provide an opportunity to anticipate ethical and logistical challenges associated with HIV cure-related research participation and decision-making. Learning from the cancer field, a strong foundation of patient-participant and clinician-researcher trust will need to be established to facilitate recruitment of participants into HIV cure-related studies. Conclusion Further empirical social science and ethics research will be necessary to inform clinical HIV cure-related research. The study of participation in HIV cure-related research can gain insights from proxy fields by incorporating study elements to clearly explain motivators and deterrents to participation and to inform the implementation of HIV cure-related studies. Study-specific contexts from the reviewed literature further demonstrate the importance of various types of research to assess factors affecting participation in HIV cure-related research, including adequate formative and ethics research. PMID:26866059

  3. Intracerebroventricular administration of HIV-1 Tat induces brain cytokine and indoleamine 2,3-dioxygenase expression: a possible mechanism for AIDS comorbid depression.

    PubMed

    Lawson, Marcus A; Kelley, Keith W; Dantzer, Robert

    2011-11-01

    Human immunodeficiency virus (HIV) remains a major public health concern despite a large education effort during the past 25 years. A persistent problem with HIV infection is the high comorbity rate of clinical depression. We previously established that increasing proinflammatory cytokines within the brain of mice induces sickness that can culminate in depressive-like behavior. Here we investigated the role of the HIV transactivator of transcription (Tat) protein in activation of brain cytokine signaling and subsequent induction of depressive-like behavior in a murine model. Adult Balb/c mice were administered a single intracerebroventricular (ICV) injection of Tat (40 ng). Social investigation of a novel juvenile was measured at 2, 4, 8 and 24 h post-treatment. Mice treated with Tat did not display signs of sickness, as measured by either decreased social investigation or loss of body weight. At 24 h post-injection, mice were subjected to the forced swim test (FST). ICV administration of Tat to Balb/c mice increased immobility in the FST at 24 h post injection. A different strain of mice, C57BL/6J, responded similarly in the FST. Furthermore, adult C57BL/6J mice injected with Tat and tested in a two-bottle 1% sucrose preference test displayed reduced preference for sucrose during the 24 h post-injection period. Subsequently, brain tissues from Tat-treated and control C57BL/6J mice were collected at 4 and 24 h post injection. CNS tissue from Tat-treated mice had increased expression of IL-1?, TNF-?, IL-6, and IDO mRNAs at 4 h post injection. These data demonstrate that a single exposure to Tat in the brain is sufficient to induce brain cytokine signaling that culminates in depressive-like behavior. The results reveal a potential role for Tat in the development of comorbid depression in HIV-infected individuals. PMID:21620953

  4. YC-1 reduces placental sFlt-1 and soluble endoglin production and decreases endothelial dysfunction: A possible therapeutic for preeclampsia.

    PubMed

    Brownfoot, Fiona C; Tong, Stephen; Hannan, Natalie J; Hastie, Roxanne; Cannon, Ping; Tuohey, Laura; Kaitu'u-Lino, Tu'uhevaha J

    2015-09-15

    Preeclampsia is a serious complication of pregnancy with no medical treatment. It is caused by intermittent placental hypoxia and release of sFlt-1 and soluble endoglin, leading to wide spread maternal endothelial dysfunction and multisystem organ injury. YC-1 is a guanylyl cyclase activator and HIF1α inhibitor developed for use in hypertension and atherosclerosis. We examined whether YC-1 reduces sFlt-1 and sENG secretion and reverses endothelial dysfunction in primary human tissues. YC-1 significantly reduced sFlt-1 and sENG secretion from human umbilical vein endothelial cells, purified primary trophoblast cells and placental explants taken from patients with preterm preeclampsia. This was concordant with reduced HIF1α expression. YC-1 also reversed TNFα induced endothelial dysfunction, including reduced vascular cell adhesion molecule 1 expression and monocyte adhesion to primary endothelial cells. We conclude YC-1 decreases placental production of sFlt-1 and sENG and decreases endothelial dysfunction. It is a novel therapeutic candidate for preeclampsia. PMID:26159901

  5. Present status and future prospects for HIV therapies.

    PubMed

    Johnston, M I; Hoth, D F

    1993-05-28

    Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed. PMID:7684163

  6. HIV Symptoms

    MedlinePlus

    ... Submit Home > HIV/AIDS > What is HIV/AIDS? HIV/AIDS This information in Spanish ( en español ) HIV symptoms Photo courtesy of AIDS.gov More information ... and brain Return to top More information on HIV symptoms Explore other publications and websites Basic Information ...

  7. Potential Anti-HIV Agents from Marine Resources: An Overview

    PubMed Central

    Vo, Thanh-Sang; Kim, Se-Kwon

    2010-01-01

    Human immunodeficiency virus (HIV) infection causes acquired immune deficiency syndrome (AIDS) and is a global public health issue. Anti-HIV therapy involving chemical drugs has improved the life quality of HIV/AIDS patients. However, emergence of HIV drug resistance, side effects and the necessity for long-term anti-HIV treatment are the main reasons for failure of anti-HIV therapy. Therefore, it is essential to isolate novel anti-HIV therapeutics from natural resources. Recently, a great deal of interest has been expressed regarding marine-derived anti-HIV agents such as phlorotannins, sulfated chitooligosaccharides, sulfated polysaccharides, lectins and bioactive peptides. This contribution presents an overview of anti-HIV therapeutics derived from marine resources and their potential application in HIV therapy. PMID:21339954

  8. Therapeutic granulocyte and monocyte apheresis (GMA) for treatment refractory sarcoidosis: a pilot study of clinical effects and possible mechanisms of action

    PubMed Central

    Olsen, H H; Muratov, V; Cederlund, K; Lundahl, J; Eklund, A; Grunewald, J

    2014-01-01

    Sarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2–4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4+/FoxP3+ T cells. Furthermore, the decrease in BALF CD4+/FoxP3+ T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4+/CD27− T cells and a trend towards an initial increase in the percentage of CD4+/FoxP3+ T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit. PMID:24773420

  9. H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications?

    PubMed

    Gessi, Marco; Gielen, Gerrit H; Hammes, Jennifer; Dörner, Evelyn; Mühlen, Anja Zur; Waha, Andreas; Pietsch, Torsten

    2013-03-01

    Pediatric glioblastomas recently have been exon sequenced with evidence that approximately 30 % of cases harbour mutations of the histone H3.3 gene. Although studies to determinate their role in risk stratification are on-going, it remains to be determined whether H3.3 mutations could be found in other tumors such as pediatric primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) and whether the presence of H3.3 mutations in glioblastomas could be used as diagnostic tool in their differential diagnosis with CNS-PNETs. We performed a large mutational pyrosequencing-based screening on 123 pediatric glioblastomas and 33 CNS-PNET. The analysis revealed that 39/123 (31.7 %) glioblastomas carry H3.3 mutations. The K27M (AAG → ATG, lysine → methionine) mutation was found in 33 glioblastomas (26 %); the G34R (GGG → AGG, glycine → arginine) was observed in 6 glioblastomas (5.5 %). However, we also identified 4 of 33 cases (11 %) of CNS-PNETs harbouring a H3.3 G34R mutation. Multiplex ligation-dependent probe amplification analysis revealed PDGFR-alpha amplification and EGFR gain in two cases and N-Myc amplification in one case of H3.3 G34R mutated CNS-PNET. None of H3.3 mutated tumors presented a CDKN2A loss. In conclusion, because pediatric patients with glioblastoma and CNS-PNET are treated according to different therapeutic protocols, these findings may raise further concerns about the reliability of the histological diagnosis in the case of an undifferentiated brain tumor harbouring G34R H3.3 mutation. In this view, additional studies are needed to determine whether H3.3 G34 mutated CNS-PNET/glioblastomas may represent a defined tumor subtype. PMID:23354654

  10. Access denied? The status of co-receptor inhibition to counter HIV entry.

    PubMed

    Biswas, Priscilla; Tambussi, Giuseppe; Lazzarin, Adriano

    2007-05-01

    As resistance and long-term metabolic abnormalities hamper the efficacy of previous drugs against HIV-1, targeting of HIV co-receptors represents an exciting new frontier for antiretroviral therapeutics. CCR5 inhibitors are most likely to be the new available drugs within the class of entry inhibitors. This paper reviews the most recent clinical data available on the small-molecule compounds vicriviroc and maraviroc and on the antibodies PRO 140 and CCR5mAb004, as well as some novel genetic approaches. A thorough overview of the many challenges, past, present and future, that CCR5 inhibitors encounter during their development pathway is then presented. Possible immunologic consequences are also discussed. It could be foreseen that the benefit for HIV-infected individuals derived by the use of these potential novel drugs will outweigh the costs/risks intrinsically present in every new therapeutic approach. PMID:17472538

  11. Clinical evaluation of BioPlex 2200 HIV Ag-Ab, an automated screening method providing discrete detection of HIV-1 p24 antigen, HIV-1 antibody, and HIV-2 antibody.

    PubMed

    Salmona, Maud; Delarue, Severine; Delaugerre, Constance; Simon, François; Maylin, Sarah

    2014-01-01

    Early and accurate diagnosis is essential for optimal therapeutic outcomes in patients infected with HIV. Currently, none of the commercially available fourth-generation assays differentiate HIV-1 and HIV-2 antibodies (Ab) or the HIV-1 p24 antigen (Ag). The aim of this study was to evaluate the performance of a novel assay, the BioPlex 2200 HIV Ag-Ab. This assay uses a multiplex flow immunoassay design allowing the simultaneous detection and identification of antibodies to HIV-1 (groups M and O), HIV-2, and the HIV-1 p24 antigen, in addition to providing a traditional composite result. A total of 1,505 routine serum samples were prospectively tested. Results were compared with those from the Architect HIV Combo assay. The sensitivity of the BioPlex 2200 was 100%. The specificity assessed on repeated false-positive samples was 99.5%. In addition, 524 frozen specimens from patients known to be infected with HIV-1 or HIV-2 were tested. Of these specimens, 420 were infected with HIV-1, including 156 of known genotypes, 86 were infected with HIV-2, 7 were infected with HIV-1 and HIV-2, and 11 were from patients with acute HIV infection. Sensitivity was 100% for the HIV genotypes tested. The differentiation capabilities of the BioPlex 2200 HIV Ag-Ab assay for HIV-1, HIV-2, dual HIV-1/HIV-2, and early infections were 100%, 90.7%, 100%, and 90.9%, respectively. The BioPlex 2200 is a sensitive and specific assay that offers advantages over conventional HIV combo assays, also referred to as fourth-generation assays, to accurately differentiate and report HIV-1 p24 antigen and HIV-1 and HIV-2 antibodies. PMID:24153130

  12. Isoniazid-resistant Mycobacterium kansasii in an HIV-positive patient, and possible development of immune reconstitution inflammatory syndrome after initiation of highly active antiretroviral therapy: case report.

    PubMed

    Despotovic, A; Savic, B; Salemovic, D; Ranin, J; Jevtovic, Dj

    2016-01-01

    Non-tuberculous mycobacteria are rare but important causes of infection in HIV-positive individuals. A 28-year-old HIV-positive male presented with a high fever, non-productive cough, right subcostal pain, splenomegaly, a very low CD4 count, elevated C-reactive protein and erythrocyte sedimentation rate, and a normal white blood cell count. The suspicion of tuberculosis (TB) was very high, and sputum samples were positive for acid-fast bacilli. Standard quadruple anti-TB therapy was initiated, but once culture of the sample revealed Mycobacterium kansasii, pyrazinamide was withdrawn. Highly active antiretroviral therapy (HAART) was initiated soon after, consisting of abacavir/lamivudine and efavirenz. The patient's general condition deteriorated 2 weeks after HAART initiation, which could have been due to the development of immune reconstitution inflammatory syndrome (IRIS). The patient recovered and was discharged in good condition. However, the results of resistance testing of the isolated organism arrived after discharge, and showed isoniazid and streptomycin resistance. This is the first case report of M. kansasii infection from Serbia and shows the difficulties encountered during the course of treatment. PMID:26603644

  13. Oral health and HIV.

    PubMed

    Rosenstein, David I

    2004-01-01

    Most oral health problems can be found in people who are either HIV positive or negative. Yet there are some important differences. A few conditions are seen almost exclusively in people with HIV, while some that are found in both populations are more problematic for people with HIV, especially those with advanced disease. A diminished immune system can alter the course of oral disease and require more aggressive treatment to prevent minor troubles from escalating into major health problems. Over 30 different oral manifestations of HIV disease have been reported since the beginning of the AIDS epidemic. This article will address several of the most common of these oral health issues. As with any health condition faced by HIV positive people, early identification and treatment should be emphasized. In many cases, referral to a dentist should be made as soon as possible. PMID:15104067

  14. [Studies on maternal transmission of HIV-1].

    PubMed

    Tabei, Y; Sadamasu, K; Mori, K; Monma, K; Sekine, H; Kudoh, Y; Miyazawa, Y; Okada, K

    1995-08-01

    To investigate HIV-1 transmission from mother to child, samples taken from 3 HIV-1 sero-positive pregnant mothers, 3 children born by caesareans from their mothers and therapeutic abortion from 2 HIV-1 sero-positive mothers were tested for HIV-1 antibody by westernblot, p24 antigen by antigen captured ELISA, proviral DNA by Nested-PCR and isolation of HIV-1 virus from peripheral blood, cord blood, amniotic fluid and placenta. HIV-1 proviral DNA was detected in the peripheral blood of all mothers, but p24 antigen and virus isolation were not detected. None of the HIV-1 markers, except for antibody, was detected in the samples from their children and placenta. These facts strongly suggest that there was no HIV-1 transmission from mother to child. PMID:7594776

  15. Nanoformulated antiretroviral drug combinations extend drug release and antiretroviral responses in HIV-1-infected macrophages: implications for neuroAIDS therapeutics.

    PubMed

    Nowacek, Ari S; McMillan, JoEllyn; Miller, Reagan; Anderson, Alec; Rabinow, Barrett; Gendelman, Howard E

    2010-12-01

    We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated individual drug release from 15 to >20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people. PMID:20237859

  16. Liposomes for HIV prophylaxis

    PubMed Central

    Malavia, Nikita; Zurakowski, David; Schroeder, Avi; Princiotto, Amy; Laury, Anna Ray; Epstein-Barash, Hila; Sodroski, Joseph; Langer, Robert; Madani, Navid; Kohane, Daniel S.

    2012-01-01

    There are approximately 33.4 million adults living with HIV worldwide of which an estimated 15.7 million are women. Although there has been enormous progress in the therapy of HIV/AIDS, treatment is not curative. Prevention is therefore of paramount importance, but vaccine-based and microbicidal approaches are still in their infancy. Since women acquire the virus largely through sexual intercourse, we developed liposomal systems potentially suitable for intravaginal use to prevent HIV-1 infection. We formulated liposomes from a range of naturally-occurring and synthetic lipids with varying physicochemical properties, and tested their ability to inhibit infection of transformed cells that express receptors specific to the virus. We identified formulations with the most favorable balance between decreasing HIV infection and causing cytotoxicity (i.e. therapeutic index). The therapeutic index improved with increasing cardiolipin content, and degree of unsaturation. Tissue reaction to these formulations was benign after intravaginal instillation in an in vivo female mouse model. These results support the potential use of cardiolipin-based liposomes enriched with synthetic lipids as microbicides for the prevention of HIV infection in women. PMID:21862123

  17. Addressing Ebola-related Stigma: Lessons Learned from HIV/AIDS

    PubMed Central

    Davtyan, Mariam; Brown, Brandon; Folayan, Morenike Oluwatoyin

    2014-01-01

    Background HIV/AIDS and Ebola Virus Disease (EVD) are contemporary epidemics associated with significant social stigma in which communities affected suffer from social rejection, violence, and diminished quality of life. Objective To compare and contrast stigma related to HIV/AIDS and EVD, and strategically think how lessons learned from HIV stigma can be applied to the current EVD epidemic. Methods To identify relevant articles about HIV/AIDS and EVD-related stigma, we conducted an extensive literature review using multiple search engines. PubMed was used to search for relevant peer-reviewed journal articles and Google for online sources. We also consulted the websites of the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), and the National Institutes of Health to retrieve up-to-date information about EVD and HIV/AIDS. Results Many stigmatizing attitudes and behaviors directed towards those with EVD are strikingly similar to those with HIV/AIDS but there are significant differences worthy of discussion. Both diseases are life-threatening and there is no medical cure. Additionally misinformation about affected groups and modes of transmission runs rampant. Unlike in persons with EVD, historically criminalized and marginalized populations carry a disproportionately higher risk for HIV infection. Moreover, mortality due to EVD occurs within a shorter time span as compared to HIV/AIDS. Conclusions Stigma disrupts quality of life, whether it is associated with HIV infection or EVD. When addressing EVD, we must think beyond the immediate clinical therapeutic response, to possible HIV implications of serum treatment. There are emerging social concerns of stigma associated with EVD infection and double stigma associated with EVD and HIV infection. Drawing upon lessons learned from HIV, we must work to empower and mobilize prominent members of the community, those who recovered from the disease, and organizations working at the grassroots level to disseminate clear and accurate information about EVD transmission and prevention while promoting stigma reduction in the process. In the long run, education, prevention, and a therapeutic vaccine will be the optimal solutions for reducing the stigma associated with both EVD and HIV. PMID:25382685

  18. Apolipoprotein L1 (APOL1) Variants (Vs) a possible link between Heroin-associated Nephropathy (HAN) and HIV-associated Nephropathy (HIVAN).

    PubMed

    Lan, Xiqian; Rao, T K S; Chander, Praveen N; Skorecki, Karl; Singhal, Pravin C

    2015-01-01

    In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at four-fold higher rate compared to European Americans (EAs). Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy), risk a 50% (10-fold greater) chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral, and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s) which caused renal disease in susceptible AA patients. In the 80's, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street), the disease was masked or replaced HIV infected patients (especially in untreated subjects), by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients. PMID:26106375

  19. Apolipoprotein L1 (APOL1) Variants (Vs) a possible link between Heroin-associated Nephropathy (HAN) and HIV-associated Nephropathy (HIVAN)

    PubMed Central

    Lan, Xiqian; Rao, T. K. S.; Chander, Praveen N.; Skorecki, Karl; Singhal, Pravin C.

    2015-01-01

    In 1970s, Heroin-associated Nephropathy (HAN), one form of focal and segmental glomerulosclerosis (FSGS), was a predominant cause of End-stage Kidney Disease (ESKD) in African-Americans (AAs). In 1980s, with the surge of Acquired Immune Deficiency Syndrome (AIDS) in AAs, HAN more or less disappeared, and the incidence of Human Immunodeficiency Virus associated Nephropathy (HIVAN) markedly increased. Recent studies in AAs have identified APOL1 variants (Vs) as a major risk factor for the development and progression of non-diabetic kidney diseases including idiopathic FSGS and hypertension-attributed nephrosclerosis. These observations have also offered partial insights into the mechanisms of development, and higher rate of occurrence of both HAN and HIVAN in AAs. AAs with APOL1Vs develop idiopathic FSGS at four-fold higher rate compared to European Americans (EAs). Similarly, HIV infected AAs with APOL1Vs (if not on antiviral therapy), risk a 50% (10-fold greater) chance of developing HIVAN. It has been suggested that APOL1Vs expression may render podocytes more vulnerable to various types of injury: bacterial, viral, and others. However, in addition to genetic variants, additional factors such as persistence of a second hit may determine the nature and severity of glomerular disease. In patients with HAN, heroin or contaminants may have been the offending second insult(s) which caused renal disease in susceptible AA patients. In the 80's, since heroin-induced second hit was neither consistent nor sustained (depending on drug availability in the street), the disease was masked or replaced HIV infected patients (especially in untreated subjects), by an overwhelming second hit by the virus which was both intense as well as persistent. It appears that APOL1Vs may be one of the links between the disappearance of HAN and emergence of HIVAN in AA patients. PMID:26106375

  20. Bone alterations associated with HIV.

    PubMed

    Warriner, Amy H; Mugavero, Michael; Overton, E Turner

    2014-09-01

    HIV infection and initiation of antiretroviral therapy (ART) have been consistently associated with decreased bone mineral density (BMD), with growing evidence linking HIV to an increased risk of fracture. This is especially concerning with the expanding number of older persons living with HIV. Interestingly, recent data suggest that HIV-infected children and youth fail to achieve peak BMD, possibly increasing their lifetime risk of fracture. Elucidating the causes of the bone changes in HIV-positive persons is challenging because of the multifactorial nature of bone disease in HIV, including contribution of the virus, immunosuppression, ART toxicity, and traditional osteoporosis risk factors, such as age, lower weight, tobacco, and alcohol use. Thus, practitioners must recognize the risk of low BMD and fractures and appropriately screen patients for osteoporosis if risk factors exist. If fractures do occur or elevated fracture risk is detected through screening, treatment with bisphosphonate medications appears safe and effective in the HIV+population. PMID:25064454

  1. Update on HIV infection.

    PubMed

    von Overbeck, Jan

    2005-01-01

    In the third decade of the global epidemic, it is evident that human immunodeficiency virus (HIV) disease is quite different from the disease first recognized among a small number of homosexual men in 1981. The spread of HIV has been particularly alarming in developing countries, especially sub-Saharan Africa and Southeast Asia, and it continues to threaten other populations in Eastern Europe, Latin America and the Caribbean. HIV therapeutic advances have resulted in a marked decrease in acquired immunodeficiency syndrome (AIDS) incidence and death in the United States and Western Europe. With the introduction of "triple therapy," antiretroviral treatment has resulted in an extraordinary increase in the quality of life and life expectancy among HIV-infected persons. However, the rate of decline in AIDS incidence and deaths from the latter part of 1998 through 2000 has slowed for a number of reasons. Even with the stabilization of HIV in Western countries, it remains as important as ever to follow sound insurance principles to address HIV risk. The clinical success stories have yet to be translated into the insurance realm. A very strict analysis of the medical literature will be needed. PMID:16259210

  2. Plasmids encoding therapeutic agents

    DOEpatents

    Keener, William K.

    2007-08-07

    Plasmids encoding anti-HIV and anti-anthrax therapeutic agents are disclosed. Plasmid pWKK-500 encodes a fusion protein containing DP178 as a targeting moiety, the ricin A chain, an HIV protease cleavable linker, and a truncated ricin B chain. N-terminal extensions of the fusion protein include the maltose binding protein and a Factor Xa protease site. C-terminal extensions include a hydrophobic linker, an L domain motif peptide, a KDEL ER retention signal, another Factor Xa protease site, an out-of-frame buforin II coding sequence, the lacZ.alpha. peptide, and a polyhistidine tag. More than twenty derivatives of plasmid pWKK-500 are described. Plasmids pWKK-700 and pWKK-800 are similar to pWKK-500 wherein the DP178-encoding sequence is substituted by RANTES- and SDF-1-encoding sequences, respectively. Plasmid pWKK-900 is similar to pWKK-500 wherein the HIV protease cleavable linker is substituted by a lethal factor (LF) peptide-cleavable linker.

  3. HIV counselling in prisons.

    PubMed

    Curran, L; McHugh, M; Nooney, K

    1989-01-01

    HIV presents particular problem in penal establishments: the nature of the population; conditions in prison; media attention and misinformation; the possibility of transmission within and beyond the prison population; the extra issues that apply to female prisoners. These are discussed in the context of prison policy regarding HIV and the broad strategic approach which is being adopted to manage the problem of HIV within penal institutions. Counselling has a key role in the overall strategy. Pre- and post-test counselling with prisoners is described and the particular problems presented by inmates are discussed and illustrated by reference to case histories. Developments in counselling provision for inmates are outlined. PMID:2488575

  4. [Therapeutic possibilities of venolymphatic disorders using thalassotherapy].

    PubMed

    Mulot, J P

    1988-01-01

    Venolymphatic pathology of the lower extremities represents a major part of the recruiting of a specialized thalassotherapy center, such as "Les Cures Marines de Trouville". The various treatments are adjusted according to each clinical case. The main techniques which are prescribed, include alternatively: active rehabilitation in sea-water pool at 34 degrees C; underwater showers and manual massages of the connective tissue; shower sprays; microbubbles; algi baths. The temperature of the baths and showers ranges between 32 and 35 degrees C. An example of the treatments administered in Trouville consists in underwater lymphatic drainage, performed by the physical therapist in a large tank, at minimum pressure. It begins with a symmetrical drainage of the trunk (or basic protocol), then drainage of the lymphedema, always starting at the root of the limb. Hygiene-dietetic rules are discussed in detail during the consultation. A fitted elastic bandage is prescribed at the end of the treatment. PMID:3406101

  5. T CELL THERAPIES FOR HIV

    PubMed Central

    Lam, Sharon; Bollard, Catherine

    2013-01-01

    Anti-retroviral therapy (ART) has improved the quality of life for HIV+ individuals but efficacy requires strict adherence and treatment is not curative. Recently, the use of T cells as therapeutic agents have been in the spotlight in the settings of post-transplant opportunistic infections and cancer. Whether T cell therapy can be harnessed for treating HIV remains to be determined but there are a few studies that seek to answer that question. Infusion of ex vivo expanded HIV-specific T cells showed limited efficacy but no adverse events. Genetically modified T cells expressing CD4 chimeric antigen receptors (CAR) have recently been shown to have persistence that outperforms CARs used for cancers. Although the results have not yet been published for many clinical studies using T cells for HIV, preclinical studies and the clinical data that is available highlight the potential for T cell therapy to decrease or eliminate HIV patients’ dependency on ART. PMID:23557423

  6. Interview: HIV-1 proviral DNA excision using an evolved recombinase.

    PubMed

    Hauber, Joachim

    2008-01-01

    HIV-1 integrates into the host chromosome of infected cells and persists as a provirus flanked by long terminal repeats. Current treatment strategies primarily target virus enzymes or virus-cell fusion, suppressing the viral life cycle without eradicating the infection. Since the integrated provirus is not targeted by these approaches, new resistant strains of HIV-1 may emerge. Here, we report that the engineered recombinase Tre (see Molecular evolution of the Tre recombinase, Buchholz, F., Max Planck Institute for Cell Biology and Genetics, Dresden) efficiently excises integrated HIV-1 proviral DNA from the genome of infected cells. We produced loxLTR containing viral pseudotypes and infected HeLa cells to examine whether Tre recombinase can excise the provirus from the genome of HIV-1 infected human cells. A virus particle-releasing cell line was cloned and transfected with a plasmid expressing Tre or with a parental control vector. Recombinase activity and virus production were monitored. All assays demonstrated the efficient deletion of the provirus from infected cells without visible cytotoxic effects. These results serve as proof of principle that it is possible to evolve a recombinase to specifically target an HIV-1 LTR and that this recombinase is capable of excising the HIV-1 provirus from the genome of HIV-1-infected human cells. Before an engineered recombinase could enter the therapeutic arena, however, significant obstacles need to be overcome. Among the most critical issues, that we face, are an efficient and safe delivery to targeted cells and the absence of side effects. PMID:19066545

  7. Women and HIV

    MedlinePlus

    ... Consumer Information by Audience For Women Women and HIV Share Tweet Linkedin Pin it More sharing options ... HIV? What should pregnant women know about HIV? HIV Quick Facts What is HIV? HIV is the ...

  8. Cancellers - Exploring the Possibility of Receptor Decoy Traps As a Superior Anti-Retroviral Strategy.

    PubMed

    Jeremiah, Sundararaj Stanley; Ohba, Kenji; Yamamoto, Naoki

    2016-01-01

    The global Human Immunodeficiency Virus (HIV) pandemic is still spreading due to the lack of ideal anti-retroviral measures and their availability. Till date, all attempts to produce an efficient vaccine have ended with unsatisfactory results. The highly active anti-retroviral therapy (HAART) is the only effective weapon currently available and is widely being used for curtailing the HIV pandemic. However, the HAART is also expected to fail in the near future due to the emergence and dissemination of antiviral resistance. This review sheds light on the reasons for the failure of the conventional anti-viral measures against HIV and the novel anti-retroviral strategies currently being developed. The various principles to be considered for the success of a novel anti-retroviral strategy are elaborately emphasized and an innovative concept is proposed on these lines. The proposed concept intends to use receptor decoy traps (RDT) called cancellers which are erythrocytes expressing the HIV entry receptors on their surface. If successfully developed, the cancellers would be capable of active targeting of the free HIV particles leading to the trapping of the viruses within the canceller, resulting in the neutralization of infectivity of the trapped virus. The possible ways of translating this concept into reality and the probable hurdles that can be encountered in the process are subsequently discussed. Also, the scope of cancellers in therapeutic and/or preventive strategies against HIV infection is envisaged upon their successful development. PMID:25882216

  9. Stem cell transplantation for lymphoma patients with HIV infection.

    PubMed

    Michieli, Mariagrazia; Mazzucato, Mario; Tirelli, Umberto; De Paoli, Paolo

    2011-01-01

    The advent of Highly Active Antiretroviral Therapy (HAART) has radically changed incidence characteristics and prognosis of HIV-positive patients affected by lymphomas. At this time there is consensus in the literature that, in first line, HIV-positive patients should always be treated with curative intent preferentially following the same approach used in the HIV-negative counterpart. On the contrary, an approach of salvage therapy in HIV-positive lymphomas is still a matter of debate given that for a wide range of relapsed or resistant HIV-negative Hodgkin's disease (HD) and non-Hodgkin lymphoma (NHL) patients, autologous peripheral or allogeneic stem cell transplantation are among the established options. In the pre-HAART era, therapeutic options derived from pioneering experiences gave only anecdotal success, either when transplantation was used to cure lymphomas or to improve HIV infection itself. Concerns relating to the entity, quality, and kinetics of early and late immune reconstitutions and the possible worsening of underlying viroimmunological conditions were additional obstacles. Currently, around 100 relapsed or resistant HIV-positive lymphomas have been treated with an autologous peripheral stem cell transplantation (APSCT) in the HAART era. Published data compared favorably with any previous salvage attempt showing a percentage of complete remission ranging from 48% to 90%, and overall survival ranging from 36% to 85% at median follow-up approaching 3 years. However, experiences are still limited and have given somewhat confounding indications, especially concerning timing and patients' selection for APSCT and feasibility and outcome for allogeneic stem cell transplant. Moreover, little data exist on the kinetics of immunological reconstitution after APSCT or relevant to the outcome of HIV infection. The aim of this review is to discuss current knowledge of the role of allogeneic and autologous stem cell transplantation as a modality in the cure of HIV and hemopoietic cancer patients. Several topics dealing with practical aspects concerning the management of APSCT in HIV-positive patients, including patient selection, timing of transplant, conditioning regimen, and relapse or nonrelapse mortality, are discussed. Data relating to the effects of mobilization and transplantation on virological parameters and pre- and posttransplant immune reconstitution are reviewed. Finally, in this review, we examine several ethical and legal issues relative to banking infected or potentially infected peripheral blood stem cells and we describe our experience and strategies to protect positive and negative donors/recipients and the health of caretakers. PMID:20875226

  10. HIV Transmission

    MedlinePlus

    ... Reduction Tool (BETA). Can I get HIV from anal sex? Yes. In fact, having anal sex is the riskiest type of sex for ... may allow HIV to enter the body during anal sex, but the top is also at risk ...

  11. HIV and preconceptional counselling.

    PubMed

    Steele, S J

    1991-01-01

    This article provides a general discussion of a variety of different features of HIV infection and the not widely accepted concept of preconception counseling. The focus is on testing, counseling and counselors, infertility clinics, promotion of awareness, attitudes to HIV testing, education, parameters for counseling, the risk of coitus and the value of contraceptive usage in the presence of HIV, accurate and understandable information, attitudes of children, legal significance, and the effect of disaster on the family and relationships. The author is concerned with the need to provide testing facilities, and prepregnancy testing. The risk of HIV infection adds to the importance of planned pregnancy and counseling in family planning and selecting appropriate methods. Informed and responsible decisions require adequate consideration of all the issues and information currently available. Preconceptual counseling clinics tend to be small in number, but the health care professionals serving the population in need must be well educated in the knowledge of obstetrics and the behavior of HIV infection/AIDS. Infertility clinics are one potential source of contact with those at high risk of HIV. A national campaign to emphasize the need to seek advice on family planning for those at risk of HIV is necessary in countries where HIV is widespread. Preconception counseling is possible only after there is awareness of risk of HIV infection and the risks of pregnancy. Confounding policies for testing and counseling are attitudes of politicians and officials which may reflect the general welfare rather than individual welfare or public opinion and attitudes of pressure groups which may not reflect the general welfare. 2 issues are of concern: that risk by accurately assessed, and terms like safe sex avoided. The following understandable information needs to be provided; a woman's risk with an HIV positive husband, a woman's pregnancy risk, a father's risk with an HIV infected partner, the fetal risk (estimated at 30%), prognosis for an infected child, the effect on family of having an infected child, possible cures/effective treatment in the future, the effect of relationships and parents work/life, the possibility of an orphaned child or loss of a parent, adverse effects of factors on pregnancy, the relevance of any treatment, and children's welfare with harmful parent lifestyles. Counselors must be aware of the influence of race, religion, class, and the pressures in prostitution for unprotected sex. Legal issues may arise between parent and child, or in counselor negligence. Caring for a handicapped child and the nature of discrimination against those with AIDs must be approached openmindedly. An informed decision must be an available option. PMID:12284244

  12. HIV/AIDS and Pregnancy

    MedlinePlus

    If you have HIV/AIDS and find out you are pregnant or think you may be pregnant, you should let your health care provider know as soon as possible. Some HIV/AIDS medicines may harm your baby. Your health care ...

  13. HIV Molecular Immunology 2014

    SciTech Connect

    Yusim, Karina; Korber, Bette Tina Marie; Barouch, Dan; Koup, Richard; de Boer, Rob; Moore, John P.; Brander, Christian; Haynes, Barton F.; Walker, Bruce D.

    2015-02-03

    HIV Molecular Immunology is a companion volume to HIV Sequence Compendium. This publication, the 2014 edition, is the PDF version of the web-based HIV Immunology Database (http://www.hiv.lanl.gov/content/immunology/). The web interface for this relational database has many search options, as well as interactive tools to help immunologists design reagents and interpret their results. In the HIV Immunology Database, HIV-specific B-cell and T-cell responses are summarized and annotated. Immunological responses are divided into three parts, CTL, T helper, and antibody. Within these parts, defined epitopes are organized by protein and binding sites within each protein, moving from left to right through the coding regions spanning the HIV genome. We include human responses to natural HIV infections, as well as vaccine studies in a range of animal models and human trials. Responses that are not specifically defined, such as responses to whole proteins or monoclonal antibody responses to discontinuous epitopes, are summarized at the end of each protein section. Studies describing general HIV responses to the virus, but not to any specific protein, are included at the end of each part. The annotation includes information such as crossreactivity, escape mutations, antibody sequence, TCR usage, functional domains that overlap with an epitope, immune response associations with rates of progression and therapy, and how specific epitopes were experimentally defined. Basic information such as HLA specificities for T-cell epitopes, isotypes of monoclonal antibodies, and epitope sequences are included whenever possible. All studies that we can find that incorporate the use of a specific monoclonal antibody are included in the entry for that antibody. A single T-cell epitope can have multiple entries, generally one entry per study. Finally, maps of all defined linear epitopes relative to the HXB2 reference proteins are provided.

  14. [Laboratory diagnosis of HIV infection].

    PubMed

    Wagner, R; Mayer, J; Reischl, U

    1995-04-10

    Recent use of modern methods in the field of molecular biology has provided new insights into the genetic and structural nature of HIV, which are now increasingly being applied to the diagnostic work-up. For the reliable laboratory diagnosis of HIV infection, three different possibilities are available: detection of specific antibodies against viral proteins (anti HIV AB), detection of the virus itself (HIV antigen) and detection of viral nucleic acid using in vitro amplification techniques. In this overview, we compare clinical and diagnostic parameters of an HIV infection, and discuss the current state of the art of an HIV infection and the future prospects offered by new molecular biological methods such as the use of recombinant antigens or the polymerase chain reaction (PCR) for the detection of viral nucleic acid. PMID:7737620

  15. Reevaluation of possible outcomes of infections with human immunodeficiency virus.

    PubMed

    Tamalet, C; Colson, P; Decroly, E; Dhiver, C; Ravaux, I; Stein, A; Raoult, D

    2016-04-01

    Several lines of evidence indicate that HIV infection can result in several possible incomes, including a very small proportion of individuals whose HIV replication is controlled after treatment interruption (known as HIV posttreatment controllers) or spontaneously without any treatment (known as HIV elite controllers). Both types of individuals are HIV RNA negative but HIV DNA positive, with living virus which can be stimulated ex vivo. A review was conducted to assess the literature on yet rarer cases with detectable integrated HIV DNA without HIV infectious virus in HIV-seropositive or -negative individuals. Three categories of patients were identified: (a) HIV-seropositive individuals with apparent spontaneous cure from their HIV infection, (b) HIV-seronegative children born to HIV-infected mothers and (c) highly exposed seronegative adults. Validity criteria were proposed to assess the presence of integrated HIV DNA as possible or unquestionable in these three categories. Only three articles among the 22 ultimately selected fulfilled these criteria. Among the highly exposed seronegative subjects, some individuals were described as being without integrated HIV DNA, probably because these subjects were not investigated using relevant, highly sensitive methods. Finally, we propose a definition of spontaneous cure of HIV infection based on clinical, immunologic and virologic criteria. PMID:26794031

  16. HIV-1 cellular and tissue replication patterns in infected humanized mice

    PubMed Central

    Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y.; Gorantla, Santhi; Gendelman, Howard E.

    2016-01-01

    Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice. Cells were analyzed by flow cytometry and sorted from species mixtures defined as CD34+ lineage negative progenitor cells, CD14+CD16+ monocyte-macrophages and central, stem cell and effector memory T cells. The cell distribution and viral life cycle were found dependent on the tissue compartment and time of infection. Cell subsets contained HIV-1 total and integrated DNA as well as multi-spliced and unspliced RNA in divergent proportions. The data support the idea that humanized mice can provide a means to examine the multifaceted sites of HIV-1 replication including, but not limited to progenitor cells and monocyte-macrophages previously possible only in macaques and human. PMID:26996968

  17. HIV-1 cellular and tissue replication patterns in infected humanized mice.

    PubMed

    Araínga, Mariluz; Su, Hang; Poluektova, Larisa Y; Gorantla, Santhi; Gendelman, Howard E

    2016-01-01

    Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Cells were analyzed by flow cytometry and sorted from species mixtures defined as CD34+ lineage negative progenitor cells, CD14+CD16+ monocyte-macrophages and central, stem cell and effector memory T cells. The cell distribution and viral life cycle were found dependent on the tissue compartment and time of infection. Cell subsets contained HIV-1 total and integrated DNA as well as multi-spliced and unspliced RNA in divergent proportions. The data support the idea that humanized mice can provide a means to examine the multifaceted sites of HIV-1 replication including, but not limited to progenitor cells and monocyte-macrophages previously possible only in macaques and human. PMID:26996968

  18. The impact of unprotected T cells in RNAi-based gene therapy for HIV-AIDS.

    PubMed

    Herrera-Carrillo, Elena; Liu, Ying Poi; Berkhout, Ben

    2014-03-01

    RNA interference (RNAi) is highly effective in inhibiting human immunodeficiency virus type 1 (HIV-1) replication by the expression of antiviral short hairpin RNA (shRNA) in stably transduced T-cell lines. For the development of a durable gene therapy that prevents viral escape, we proposed to combine multiple shRNAs against highly conserved regions of the HIV-1 RNA genome. The future in vivo application of such a gene therapy protocol will reach only a fraction of the T cells, such that HIV-1 replication will continue in the unmodified T cells, thereby possibly frustrating the therapy by generation of HIV-1 variants that escape from the inhibition imposed by the protected cells. We studied virus inhibition and evolution in pure cultures of shRNA-expressing cells versus mixed cell cultures of protected and unprotected T cells. The addition of the unprotected T cells indeed seems to accelerate HIV-1 evolution and escape from a single shRNA inhibitor. However, expression of three antiviral shRNAs from a single lentiviral vector prevents virus escape even in the presence of unprotected cells. These results support the idea to validate the therapeutic potential of this anti-HIV approach in appropriate in vivo models. PMID:24336172

  19. Zinc-finger-nucleases mediate specific and efficient excision of HIV-1 proviral DNA from infected and latently infected human T cells

    PubMed Central

    Qu, Xiying; Wang, Pengfei; Ding, Donglin; Li, Lin; Wang, Haibo; Ma, Li; Zhou, Xin; Liu, Shaohui; Lin, Shiguan; Wang, Xiaohui; Zhang, Gongmin; Liu, Sijie; Liu, Lin; Wang, Jianhua; Zhang, Feng; Lu, Daru; Zhu, Huanzhang

    2013-01-01

    HIV-infected individuals currently cannot be completely cured because existing antiviral therapy regimens do not address HIV provirus DNA, flanked by long terminal repeats (LTRs), already integrated into host genome. Here, we present a possible alternative therapeutic approach to specifically and directly mediate deletion of the integrated full-length HIV provirus from infected and latently infected human T cell genomes by using specially designed zinc-finger nucleases (ZFNs) to target a sequence within the LTR that is well conserved across all clades. We designed and screened one pair of ZFN to target the highly conserved HIV-1 5′-LTR and 3′-LTR DNA sequences, named ZFN-LTR. We found that ZFN-LTR can specifically target and cleave the full-length HIV-1 proviral DNA in several infected and latently infected cell types and also HIV-1 infected human primary cells in vitro. We observed that the frequency of excision was 45.9% in infected human cell lines after treatment with ZFN-LTR, without significant host-cell genotoxicity. Taken together, our data demonstrate that a single ZFN-LTR pair can specifically and effectively cleave integrated full-length HIV-1 proviral DNA and mediate antiretroviral activity in infected and latently infected cells, suggesting that this strategy could offer a novel approach to eradicate the HIV-1 virus from the infected host in the future. PMID:23804764

  20. [Viral entry as therapeutic target. Current situation of entry inhibitors].

    PubMed

    Arenzana-Seisdedos, Fernando

    2008-10-01

    Viral entry is an early stage and specific of the infection in which different viral and cellular targets are accessible to therapeutic treatment. CXCR4 and CCR5 act in this process as coreceptor molecules of HIV for its entry into the host cell. The predominant role played by the CCR5 coreceptor in the transmission and spreading of HIV makes this molecule the target of choice for blocking this mechanism. In the last few years, different specific inhibitors of HIV coreceptors have been generated of which only one, Maraviroc, has been approved for clinical use. The synthetic inhibitors developed act as allosteric antagonists that induce a non-permissive state or configuration of the coreceptor for binding viral envelope-glycoproteins. The CCR5 antagonists act on a wide spectrum of viruses with affinity or tropism for this receptor (virus R5), are absorbed orally and have powerful antiviral activity. However, the optimistic perspective offered by these new molecules has to be moderated due to the possible and expected appearance of viral resistances, on the one hand, and the propagation of viral species with affinity or tropism for the CXCR4 receptor (virus X4). This situation is a reality verified in the first clinical trials with these drugs and they acutely and urgently show the need to have effective and non-toxic CXCR4 inhibitors available to block this alternative viral replication and escape route. PMID:19133215

  1. Two-Drug Treatment Approaches in HIV: Finally Getting Somewhere?

    PubMed

    Kelly, Sean G; Nyaku, Amesika N; Taiwo, Babafemi O

    2016-04-01

    The advent of combination antiretroviral therapy (ART) has significantly decreased AIDS-related morbidity and mortality. Nevertheless, the benefits of ART are only realized through adherence to lifelong treatment. Though contemporary antiretroviral (ARV) drugs have fewer adverse effects in comparison to older ARV drugs, many agents are associated with negative or unknown long-term effects. There is increasing evidence that two-drug (dual-therapy) regimens may be an effective alternative to the currently recommended three-drug (triple-therapy) regimens. In this review, we provide a comprehensive and critical review of recently completed and ongoing trials of dual-therapy regimens in treatment-naïve and treatment-experienced HIV-1-infected patients. We also review current HIV/AIDS society recommendations regarding dual therapy as well as future therapeutic possibilities. PMID:26886135

  2. HIV Treatment: The Basics

    MedlinePlus

    HIV Treatment HIV Treatment: The Basics (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points Antiretroviral therapy (ART) ... reduces the risk of HIV transmission . How do HIV medicines work? HIV attacks and destroys the infection- ...

  3. Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection.

    PubMed

    Tincati, Camilla; Douek, Daniel C; Marchetti, Giulia

    2016-01-01

    Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota. PMID:27073405

  4. MACROMOLECULAR THERAPEUTICS

    PubMed Central

    Yang, Jiyuan; Kopeček, Jindřich

    2014-01-01

    This review covers water-soluble polymer-drug conjugates and macromolecules that possess biological activity without attached low molecular weight drugs. The main design principles of traditional and backbone degradable polymer-drug conjugates as well as the development of a new paradigm in nanomedicines – (low molecular weight) drug-free macromolecular therapeutics are discussed. To address the biological features of cancer, macromolecular therapeutics directed to stem/progenitor cells and the tumor microenvironment are deliberated. Finally, the future perspectives of the field are briefly debated. PMID:24747162

  5. HIV-1 Envelope Glycan Moieties Modulate HIV-1 Transmission

    PubMed Central

    Raska, Milan; Bimczok, Diane; Novak, Jan

    2014-01-01

    ABSTRACT The HIV-1 envelope protein (Env) is heavily glycosylated, with approximately 50% of the Env molecular mass being contributed by N-glycans. HIV-1 Env N-glycans shield the protein backbone and have been shown to play key roles in determining Env structure, surface exposure, and, consequently, antigenicity, infectivity, antibody neutralization, and carbohydrate and receptor binding. Studies of HIV-1 glycosylation have focused mainly on the position of glycosylation, rather than the types of glycans. Also, the role of Env glycan moieties on HIV-1 transmission has not been systematically defined. Using viruses with modified Env glycan content and heterogeneity, we examined the effects of Env glycan moieties on the major events of HIV-1 transmission. Compared to viruses with less oligomannose and more complex Env glycans, viruses with more oligomannose and less complex glycans more efficiently (i) transcytosed across an epithelial cell monolayer, (ii) attached to monocyte-derived macrophages (MDMs), (iii) bound monocyte-derived dendritic cells (MoDCs), and (iv) trans-infected primary lymphocytes via MoDCs. However, viruses with more oligomannose and less complex glycans displayed impaired infectivity in TZMbl cells, MDMs, primary lymphocytes, and fresh human intestinal tissue. Thus, N-linked Env glycans display discordant effects on the major events of HIV-1 transmission, with mature oligosaccharide structures on Env playing a crucial role in HIV-1 infection. Env glycosylation should be taken into consideration in the development of vaccine strategies to interdict HIV-1 transmission. IMPORTANCE HIV-1 Env N-glycans shield the protein backbone and play key roles in determining Env structure and surface exposure, thereby impacting Env antigenicity, infectivity, antibody neutralization, and carbohydrate and receptor binding. Studies of HIV-1 glycosylation have focused mainly on the position of glycosylation, rather than the types of glycans. In the study described in this report, we investigated systematically the role of Env glycan moieties on HIV-1 transmission. We show that N-linked Env glycans display discordant effects on the major events of HIV-1 transmission. These data indicate that Env glycan moieties impact HIV-1 transmission and that modulation of Env glycan moieties offers a potential strategy for the development of therapeutic or prophylactic vaccines against HIV-1. PMID:25275130

  6. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen C.; Ruegsegger, Mark; Barnes, Philip D.; Smith, Bryan R.; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'etre of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multi-step work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  7. Therapeutic Nanodevices

    NASA Astrophysics Data System (ADS)

    Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro

    Therapeutic nanotechnology offers minimally invasive therapies with high densities of function concentrated in small volumes, features that may reduce patient morbidity and mortality. Unlike other areas of nanotechnology, novel physical properties associated with nanoscale dimensionality are not the raison d'être of therapeutic nanotechnology, whereas the aggregation of multiple biochemical (or comparably precise) functions into controlled nanoarchitectures is. Multifunctionality is a hallmark of emerging nanotherapeutic devices, and multifunctionality can allow nanotherapeutic devices to perform multistep work processes, with each functional component contributing to one or more nanodevice subroutine such that, in aggregate, subroutines sum to a cogent work process. Cannonical nanotherapeutic subroutines include tethering (targeting) to sites of disease, dispensing measured doses of drug (or bioactive compound), detection of residual disease after therapy and communication with an external clinician/operator. Emerging nanotherapeutics thus blur the boundaries between medical devices and traditional pharmaceuticals. Assembly of therapeutic nanodevices generally exploits either (bio)material self-assembly properties or chemoselective bioconjugation techniques, or both. Given the complexity, composition, and the necessity for their tight chemical and structural definition inherent in the nature of nanotherapeutics, their cost of goods (COGs) might exceed that of (already expensive) biologics. Early therapeutic nanodevices will likely be applied to disease states which exhibit significant unmet patient need (cancer and cardiovascular disease), while application to other disease states well-served by conventional therapy may await perfection of nanotherapeutic design and assembly protocols.

  8. Fighting with the enemy's weapons? the role of costimulatory molecules in HIV.

    PubMed

    De Keersmaecker, B; Thielemans, K; Aerts, J L

    2011-04-01

    HIV infection is characterized by a number of abnormalities in several components of the immune system. For example, during HIV infection, a massive decrease of CD4(+) T cells is observed, as well as a progressive depletion of naïve CD8(+) T cells. Furthermore, elevated numbers of apoptotic B and T cells are present in HIV-infected patients, and a systemic immune activation results in T-cell exhaustion. Finally, HIV infection is characterized by the presence of functionally impaired dendritic cells, with decreased expression of maturation markers, decreased secretion of cytokines and defects in antigen processing and presentation. All these characteristics result in the occurrence of non-functional cytotoxic T lymphocytes, that fail to control HIV-replication in most individuals during progressive disease. Costimulatory and co-inhibitory molecules are involved in the activation, differentiation and survival of several cell-types of the immune system. Each costimulatory receptor (generally expressed on effector cells) can conjugate with one or more specific ligands (expressed on antigen-presenting cells), which leads to an activation of intracellular signaling pathways inside the cells on which they are expressed. HIV infection is characterized by an aberrant expression of these molecules on cells of the immune system. Many of the immune deficiencies mentioned in the previous paragraph can be explained by abnormal expression of costimulatory molecules, and could consequently be overcome by interfering with their interactions. In this review, we give an overview of the functions and expression patterns of the receptor/ligand pairs of the tumor necrosis factor and the B7 super-families of costimulatory and co-inhibitory molecules in HIV-infected patients. We will also discuss possibilities for manipulating their signaling as a therapeutic anti-HIV tool. PMID:21375494

  9. HIV-associated neurological disorders: a guide to pharmacotherapy.

    PubMed

    Tan, Ik L; McArthur, Justin C

    2012-02-01

    In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorder (HAND) continues to be a common and significant morbidity among individuals infected with HIV. The term HAND encompasses a spectrum of progressively severe CNS involvement, ranging from asymptomatic neurocognitive impairment and minor neurocognitive disorder through to the most severe form of HIV-associated dementia (HAD). While the incidence of HAD has declined significantly with HAART, the milder forms of HAND persist. In addition, HAND now develops in individuals with less advanced immunosuppression. The reasons for the persistence of milder forms of HAND in individuals treated with HAART are not entirely known. There are several hypotheses to explain this phenomenon that include the legacy effect, a failure of antiretroviral agents to reverse neurological damage, poor access of antiretroviral agents to the CNS, chronic systemic immune activation associated with microbial translocation products, sustained CNS inflammation, the improved survival of HIV-seropositive individuals and the possible contribution from aging, amyloid deposition and other co-morbidities. In contrast, the incidence of HIV-associated CNS opportunistic processes including progressive multifocal leukoencephalopathy, tuberculosis, CNS toxoplasmosis, cytomegalovirus encephalitis, cryptococcosis and primary CNS lymphoma has declined dramatically with the introduction of HAART. This review briefly summarizes our current understanding of HAND and the pathological mechanisms involved, namely direct injury from HIV-1 and viral proteins, indirect neurotoxicity from proinflammatory cytokines and chronic, sustained immune activation in the CNS. To date, only HAART has been shown to benefit HAND despite numerous controlled trials of adjunctive 'anti-inflammatory' agents. Although HAART has a profound impact on the incidence and severity of HAND, there exists a 'therapeutic gap' as even HAART that is effective at inducing durable virological suppression may only partially reverse HAND. In addition, there may be potential CNS adverse effects of antiretroviral agents. There is an ongoing multicentre clinical trial to investigate the role of the CNS Penetration-Effectiveness index, an indicator of drug permeability and availability in the CNS, to help guide the choice of antiretroviral agents in the treatment of HAND. With recent recommendations for earlier treatment intervention with HAART for HIV-1 infection, it remains to be seen the effects of this on HAND. There is an urgent need to better define the therapeutic guidelines for the prevention and treatment of HAND. PMID:22201342

  10. Injury to white matter tracts in relapsing–remitting multiple sclerosis: A possible therapeutic window within the first 5 years from onset using diffusion-tensor imaging tract-based spatial statistics

    PubMed Central

    Asaf, Achiron; Evan, Stone; Anat, Achiron

    2015-01-01

    DTI studies in multiple sclerosis (MS) reveal white matter (WM) injury that occurs with disease progression. In the present study we aimed to elucidate the relationship of microstructural WM damage in patients with varying periods of disease duration. DTI scans were acquired from 90 MS patients and 25 healthy controls. Patients were grouped to short (<1 year), moderate (1 up to 6 years) and long (6–10 years) disease duration periods. Statistical analyses of the fractional anisotropy (FA) data were performed using tract-based spatial statistics (TBSS). Whole-brain skeletal FA measurements showed a significant decrease between healthy controls and the short MS disease duration group, as well as between moderate disease duration and long disease duration groups, but failed to show a significant difference between short and moderate disease duration groups. Voxelwise analysis revealed clusters of diffuse FA reductions in 40 WM tracts when comparing healthy controls and MS short disease duration group, with the point of maximal significant difference located in the left inferior longitudinal fasciculus. Comparing short with long disease duration groups, progressive FA reduction was demonstrated across 30 WM tracts, with the point of maximal significant difference migrating to the body of the corpus callosum. A non-linear pattern of WM microstructure disruption occurs in RRMS. Alterations are seen early in the disease course within 1 year from onset, reach a plateau within the next 5 years, and only later additional WM changes are detected. An important period of a possible therapeutic window therefore exists within the early disease stage. PMID:26106550

  11. [HIV infection].

    PubMed

    Cordero, G C

    1995-01-01

    Questions and answers about HIV infection are explained using a boxing analogy, with T4 and T8 cells attacking the opponent, HIV-antibodies. How B cells and lymph nodes attack the protein exterior of the HIV virus is described. Viral RNA combines with the cell's DNA to allow the virus to reproduce. It remains there until the cell overflows, reappearing in the blood as the victim notices the first symptoms of AIDS. PMID:11363196

  12. Dendritic cell based vaccines for HIV infection

    PubMed Central

    Garca, Felipe; Plana, Montserrat; Climent, Nuria; Len, Agathe; Gatell, Jose M; Gallart, Teresa

    2013-01-01

    Dendritic cells have a central role in HIV infection. On one hand, they are essential to induce strong HIV-specific CD4+ helper T-cell responses that are crucial to achieve a sustained and effective HIV-specific CD8+ cytotoxic T-lymphocyte able to control HIV replication. On the other hand, DCs contribute to virus dissemination and HIV itself could avoid a correct antigen presentation. As the efficacy of immune therapy and therapeutic vaccines against HIV infection has been modest in the best of cases, it has been hypothesized that ex vivo generated DC therapeutic vaccines aimed to induce effective specific HIV immune responses might overcome some of these problems. In fact, DC-based vaccine clinical trials have yielded the best results in this field. However, despite these encouraging results, functional cure has not been reached with this strategy in any patient. In this Commentary, we discuss new approaches to improve the efficacy and feasibility of this type of therapeutic vaccine. PMID:23912672

  13. Get Tested for HIV

    MedlinePlus

    ... Submit Home > HIV/AIDS > Get tested for HIV HIV/AIDS This information in Spanish ( en español ) Get tested for HIV When should I get tested for HIV? Types ... to top More information on Get tested for HIV Explore other publications and websites HIV Anonymous Testing, ...

  14. Just Diagnosed: Next Steps After Testing Positive for HIV

    MedlinePlus

    ... infections. Treatment with HIV medicines (called antiretroviral therapy [ART] ) prevents HIV from destroying CD4 cells. The higher a person’s CD4 count is, the better. ART is recommended as soon as possible for everyone ...

  15. [Application of HIV drug resistance testing according to guidelines].

    PubMed

    Oette, M; Göbels, K; Reuter, S; Koch, S; Kaiser, R; Häussinger, D

    2009-11-01

    Guidelines for application of HIV drug resistance testing have recently been develeped in Europe and the USA. This article discusses these recommendations. Since the widespread use of highly active antiretroviral therapy (HAART), quality of life has been improved for the majority of HIV-infected patients and the mortality rate has declined significantly. However, an incomplete suppression of viral replication results in selection of resistant viral strains resulting in a loss of HAART efficacy and worsening in the quality of life. Resistance testing is likely to improve virological monitoring of untreated but especially in pre-treated patients. Genotypical and phenotypical assays present similar results, but genotypical testing is the method of choice initially. Translation of resistance testing into clinical decisions-making requires consideration of a patient's history, interpretation of results by a validated algorithm, and expert advice. Problems of adherence should be avoided by counselling and therapeutic drug monitoring. Resistance testing or storage of a patient's plasma sample should be undertaken as early as possible in the disease history. If this is not possible, treatment with HAART, including a boosted protease inhibitor, is warranted. European and USA guidelines present similar recommendations. HIV drug resistance is preventable by rational choice of drug combinations in HAART. After development of resistance-associated mutations, drug resistance testing can preserve future treatment options and preventing further clinical deterioration. The method has been incorporated into national and international guidelines on the basis of good scientific evidence. PMID:19894202

  16. HIV-specific changes in the motor performance of HIV-positive intravenous drug abusers.

    PubMed

    von Giesen, H J; Hefter, H; Roick, H; Mauss, S; Arendt, G

    1994-12-01

    Motor tests comprising the analysis of postural tremor, most rapid voluntary alternating index finger movements (MRAM) and the rise time of most rapid index finger extensions (CT) allow us to quantify HIV-associated minor motor deficits electrophysiologically. The electrophysiological results in 57 HIV-positive individuals who acquired HIV infection by intravenous drug abuse (IVDA) were compared with those of 57 matched HIV-positive homosexuals and 98 HIV-negative controls to evaluate a possible additional influence of IVDA on motor performance. Motor deficits showed no differences between HIV-positive i.v. drug abusers and homosexuals, revealing a highly significant slowing of MRAM and prolongation of CT to an almost identical extent. Thus, in HIV-infected individuals minor motor deficits are characteristic early signs of subclinical central nervous system involvement regardless of the mode of HIV infection. PMID:7897448

  17. The G-quadruplex-forming aptamer AS1411 potently inhibits HIV-1 attachment to the host cell

    PubMed Central

    Perrone, Rosalba; Butovskaya, Elena; Lago, Sara; Garzino-Demo, Alfredo; Pannecouque, Christophe; Palù, Giorgio; Richter, Sara N.

    2016-01-01

    AS1411 is a G-rich aptamer that forms a stable G-quadruplex structure and displays antineoplastic properties both in vitro and in vivo. This oligonucleotide has undergone phase 2 clinical trials. The major molecular target of AS1411 is nucleolin (NCL), a multifunctional nucleolar protein also present in the cell membrane where it selectively mediates the binding and uptake of AS1411. Cell-surface NCL has been recognised as a low-affinity co-receptor for human immunodeficiency virus type 1 (HIV-1) anchorage on target cells. Here we assessed the anti-HIV-1 properties and underlying mechanism of action of AS1411. The antiviral activity of AS1411 was determined towards different HIV-1 strains, host cells and at various times post-infection. Acutely, persistently and latently infected cells were tested, including HIV-1-infected peripheral blood mononuclear cells from a healthy donor. Mechanistic studies to exclude modes of action other than virus binding via NCL were performed. AS1411 efficiently inhibited HIV-1 attachment/entry into the host cell. The aptamer displayed antiviral activity in the absence of cytotoxicity at the tested doses, therefore displaying a wide therapeutic window and favourable selectivity indexes. These findings, besides validating cell-surface-expressed NCL as an antiviral target, open the way for the possible use of AS1411 as a new potent and promisingly safe anti-HIV-1 agent. PMID:27032748

  18. The G-quadruplex-forming aptamer AS1411 potently inhibits HIV-1 attachment to the host cell.

    PubMed

    Perrone, Rosalba; Butovskaya, Elena; Lago, Sara; Garzino-Demo, Alfredo; Pannecouque, Christophe; Palù, Giorgio; Richter, Sara N

    2016-04-01

    AS1411 is a G-rich aptamer that forms a stable G-quadruplex structure and displays antineoplastic properties both in vitro and in vivo. This oligonucleotide has undergone phase 2 clinical trials. The major molecular target of AS1411 is nucleolin (NCL), a multifunctional nucleolar protein also present in the cell membrane where it selectively mediates the binding and uptake of AS1411. Cell-surface NCL has been recognised as a low-affinity co-receptor for human immunodeficiency virus type 1 (HIV-1) anchorage on target cells. Here we assessed the anti-HIV-1 properties and underlying mechanism of action of AS1411. The antiviral activity of AS1411 was determined towards different HIV-1 strains, host cells and at various times post-infection. Acutely, persistently and latently infected cells were tested, including HIV-1-infected peripheral blood mononuclear cells from a healthy donor. Mechanistic studies to exclude modes of action other than virus binding via NCL were performed. AS1411 efficiently inhibited HIV-1 attachment/entry into the host cell. The aptamer displayed antiviral activity in the absence of cytotoxicity at the tested doses, therefore displaying a wide therapeutic window and favourable selectivity indexes. These findings, besides validating cell-surface-expressed NCL as an antiviral target, open the way for the possible use of AS1411 as a new potent and promisingly safe anti-HIV-1 agent. PMID:27032748

  19. Therapeutic imprinting of the immune system: towards a remission of AIDS in primates?

    PubMed Central

    2012-01-01

    Our inability to cure HIV/AIDS is related to the ability of the virus to establish reservoirs during treatment. In order to develop new strategies, it is certainly essential that a suitable animal model be implemented. In the recent work of Shytaj et al., it has been possible to inhibit viral replication to levels below the assay detection limit in the macaque AIDS model. Moreover, different therapeutic regimens applied to the rhesus macaque AIDS model (herein reviewed), including ours, are starting to show the potential to induce, following therapy suspension, conditions reminiscent of a drug-free control of the infection. PMID:22978787

  20. [Care for women with HIV: gender perspectives].

    PubMed

    Ko, Nai-Ying

    2011-12-01

    When women face social and cultural inequality they inevitably bear increased HIV infection risks. The success of antiretroviral therapies in suppressing HIV's viral load and prolonging patient lives has made HIV a treatable chronic disease. Given the same follow-up treatments, research shows no significant differences between men and women in terms of either clinical, immunological or virological parameters at baseline or mortality after one year of antiretroviral therapy. Also, advances in assisted reproductive technologies now makes having HIV-free children possible for HIV couples. Gender equality and human right are essential to effective HIV prevention. Nurses must take all appropriate measures to eliminate discrimination against women in HIV prevention, treatment and care programs in order to ensure equal gender access to critical healthcare services. PMID:22113630

  1. HIV-1 infection and cognitive impairment in the cART era: a review.

    PubMed

    Schouten, Judith; Cinque, Paola; Gisslen, Magnus; Reiss, Peter; Portegies, Peter

    2011-03-13

    With the introduction of combination antiretroviral therapy AIDS dementia complex or HIV-associated dementia, as it was termed later, largely disappeared in clinical practice. However, in the past few years, patients, long-term infected and treated, including those with systemically well controlled infection, started to complain about milder memory problems and slowness, difficulties in concentration, planning, and multitasking. Neuropsychological studies have confirmed that cognitive impairment occurs in a substantial (15-50%) proportion of patients. Among HIV-1-infected patients cognitive impairment was and is one of the most feared complications of HIV-1 infection. In addition, neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity for systemic disease. So what may be going on in the CNS after so many years of apparently controlled HIV-1 infection is an urgent and important challenge in the field of HIV medicine. In this review we summarize the key currently available data. We describe the clinical neurological and neuropsychological findings, the preferred diagnostic approach with new imaging techniques and cerebrospinal fluid analysis. We try to integrate data on pathogenesis and finally discuss possible therapeutic interventions. PMID:21160410

  2. Partner Characteristics Predicting HIV-1 Set Point in Sexually Acquired HIV-1 Among African Seroconverters

    PubMed Central

    Thomas, Katherine K.; Hughes, James P.; Baeten, Jared M.; Wald, Anna; Farquhar, Carey; de Bruyn, Guy; Fife, Kenneth H.; Campbell, Mary S.; Kapiga, Saidi; Mullins, James I.; Celum, Connie

    2013-01-01

    Abstract Plasma HIV-1 RNA set point is an important predictor of HIV-1 disease progression. We hypothesized that inoculum size and HIV-1 exposure prior to HIV-1 transmission may modulate set point. We evaluated predictors of set point among 141 African HIV-1 seroconverters and their HIV-1-infected study partners. We compared characteristics of seroconverters and their HIV-1-infected partners and HIV-1 set point. Data were from a clinical trial of genital HSV-2 suppression with acyclovir to reduce HIV-1 transmission in HIV-1 serodiscordant couples with HIV-1 transmission linkage assigned through virus sequencing. Our analysis includes data from all transmissions including those with transmission linkage to the HIV-1-infected “source partner” and those that were not linked to their HIV-1-infected study partner. In multivariable analysis, higher plasma HIV-1 in source partners was associated with higher seroconverter set point (+0.44 log10 copies/ml per log10 source partner plasma HIV-1, p<0.001). In addition, bacterial vaginosis (BV) among female source partners near the time of infection was associated with higher set point in their male seroconverters (+0.49 log10, p=0.04). Source partner characteristics associated with lower set point included male circumcision (−0.63 log10, p=0.03) and assignment to acyclovir (−0.44 log10, p=0.02). The proportion of variation in set point explained by plasma HIV-1 RNA of the source partner, after controlling for other factors, was 0.06. Source partner plasma HIV-1 level is the most significant predictor of seroconverter set point, possibly reflecting characteristics of the transmitted virus. Acyclovir use, BV among women source partners, and circumcision among male source partners may alter the set point by affecting transmitted virus inoculum in the source partners' genital compartment. PMID:23061422

  3. A novel antiretroviral class (fusion inhibitors) in the management of HIV infection. Present features and future perspectives of enfuvirtide (T-20).

    PubMed

    Manfredi, Roberto; Sabbatani, Sergio

    2006-01-01

    Enfuvirtide (Fuzeon, Roche), is the first member of a novel class of antiretroviral agents, the so-called fusion inhibitors, which act against HIV with a completely novel (extra cellular) mechanism of action, and can therefore be easily added to all anti-HIV association therapies including all other antiretroviral agents belonging to nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, since no interactions of any type are expected with enfuvirtide. Despite the need of a twice-daily parenteral (subcutaneous) delivery due to the polypeptide structure of the drug, and its proportionally short elimination lifetime, two extensive multicentre randomized clinical trials and a huge amount of other clinical and laboratory experiences confirmed the elevated potency and the safety profile of enfuvirtide in appropriate samples of HIV-infected patients (both adults and children), who failed and/or became intolerant to all previously available anti-HIV regimens, and had a very restricted choice of antiviral compounds showing residual activity. As a consequence, enfuvirtide is recommended as an adjunct to an "optimized background" containing at least one or two antiretroviral drugs, which are still active against the isolated viral strain, as assessed by resistance testing. The extremely promising profile of this novel anti-HIV drug and the reduced potential for the development of viral resistance (with no possibility of cross-resistance with the other anti-HIV classes) however warrant further pharmacokinetic, pharmacodynamic, pharmacogenomic, and pharmacoeconomic investigation. Also more extensive and prolonged clinical and quality of life studies are strongly needed to establish the best positioning of enfuvirtide in the current therapeutic guidelines of HIV disease and its future role, besides its current approval for salvage therapy of adult and pediatric HIV-infected patients with limited therapeutic options. PMID:16918361

  4. HIV Transmission Risk

    MedlinePlus

    ... HIV Prevention Linkage to, Retention in, and Re-engagement in HIV Care (LRC) Chapter Medication Adherence (MA) ... Get Email Updates on HIV Syndicated Content Website Feedback HIV Transmission Risk Recommend on Facebook Tweet Share ...

  5. Children and HIV

    MedlinePlus

    ... HIV Testing Day HIV Vaccine Awareness Day National Asian & Pacific Islander Awareness Day Hepatitis Testing Day HIV ... long-term (50-60 years) infection. But many young adults and adolescents who have lived with HIV ...

  6. HIV and Rheumatic Disease

    MedlinePlus

    ... A Patient / Caregiver Diseases & Conditions HIV & Rheumatic Diseases HIV and Rheumatic Disease Fast Facts Rheumatic diseases related ... knows he or she has HIV. What are HIV-associated rheumatic diseases? Some diseases of the joints ...

  7. HIV transmission.

    PubMed

    Shaw, George M; Hunter, Eric

    2012-11-01

    HIV-1 is transmitted by sexual contact across mucosal surfaces, by maternal-infant exposure, and by percutaneous inoculation. For reasons that are still incompletely understood, CCR5-tropic viruses (R5 viruses) are preferentially transmitted by all routes. Transmission is followed by an orderly appearance of viral and host markers of infection in the blood plasma. In the acute phase of infection, HIV-1 replicates exponentially and diversifies randomly, allowing for an unambiguous molecular identification of transmitted/founder virus genomes and a precise characterization of the population bottleneck to virus transmission. Sexual transmission of HIV-1 most often results in productive clinical infection arising from a single virus, highlighting the extreme bottleneck and inherent inefficiency in virus transmission. It remains to be determined if HIV-1 transmission is largely a stochastic process whereby any reasonably fit R5 virus can be transmitted or if there are features of transmitted/founder viruses that facilitate their transmission in a biologically meaningful way. Human tissue explant models of HIV-1 infection and animal models of SIV/SHIV/HIV-1 transmission, coupled with new challenge virus strains that more closely reflect transmitted/founder viruses, have the potential to elucidate fundamental mechanisms in HIV-1 transmission relevant to vaccine design and other prevention strategies. PMID:23043157

  8. HIV Transmission

    PubMed Central

    Shaw, George M.; Hunter, Eric

    2012-01-01

    HIV-1 is transmitted by sexual contact across mucosal surfaces, by maternal-infant exposure, and by percutaneous inoculation. For reasons that are still incompletely understood, CCR5-tropic viruses (R5 viruses) are preferentially transmitted by all routes. Transmission is followed by an orderly appearance of viral and host markers of infection in the blood plasma. In the acute phase of infection, HIV-1 replicates exponentially and diversifies randomly, allowing for an unambiguous molecular identification of transmitted/founder virus genomes and a precise characterization of the population bottleneck to virus transmission. Sexual transmission of HIV-1 most often results in productive clinical infection arising from a single virus, highlighting the extreme bottleneck and inherent inefficiency in virus transmission. It remains to be determined if HIV-1 transmission is largely a stochastic process whereby any reasonably fit R5 virus can be transmitted or if there are features of transmitted/founder viruses that facilitate their transmission in a biologically meaningful way. Human tissue explant models of HIV-1 infection and animal models of SIV/SHIV/HIV-1 transmission, coupled with new challenge virus strains that more closely reflect transmitted/founder viruses, have the potential to elucidate fundamental mechanisms in HIV-1 transmission relevant to vaccine design and other prevention strategies. PMID:23043157

  9. Infection with human retroviruses other than HIV-1: HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4.

    PubMed

    Nicolás, David; Ambrosioni, Juan; Paredes, Roger; Marcos, M Ángeles; Manzardo, Christian; Moreno, Asunción; Miró, José M

    2015-08-01

    HIV-1 is the most prevalent retrovirus, with over 30 million people infected worldwide. Nevertheless, infection caused by other human retroviruses like HIV-2, HTLV-1, HTLV-2, HTLV-3 and HTLV-4 is gaining importance. Initially confined to specific geographical areas, HIV-2, HTLV-1 and HTLV-2 are becoming a major concern in non-endemic countries due to international migration flows. Clinical manifestations of retroviruses range from asymptomatic carriers to life-threatening conditions, such as AIDS in HIV-2 infection or adult T-cell lymphoma/leukemia or tropical spastic paraparesis in HTLV-1 infection. HIV-2 is naturally resistant to some antiretrovirals frequently used to treat HIV-1 infection, but it does have effective antiretroviral therapy options. Unfortunately, HTLV still has limited therapeutic options. In this article, we will review the epidemiological, clinical, diagnostic, pathogenic and therapeutic aspects of infections caused by these human retroviruses. PMID:26112187

  10. Screening and diagnosis for HIV

    MedlinePlus

    HIV testing; HIV screening; HIV screening test; HIV confirmatory test ... A positive result on a screening test does not confirm that the person has HIV infection. More tests are needed to confirm HIV infection. A negative test ...

  11. [Options in HIV therapy: present and future].

    PubMed

    Röling, J; Draenert, R; Goebel, F D

    2005-08-01

    Highly active antiretroviral therapy (HAART) has markedly decreased HIV-associated mortality. It consists of a combination of three antiretroviral drugs from four different classes: nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and inhibitors of virus-cell fusion. Increasing resistance against antiretroviral drugs calls for the development of new compounds and drug classes. The growing understanding of molecular mechanisms in HIV-replication led to the identification of further steps which might serve as novel antiretroviral targets. Uninfected cells could be protected from HIV by inhibiting extracellular binding mechanisms. Improvement of existing antiretroviral drugs and further development of novel therapeutic targets will enrich antiretroviral treatment. PMID:15968521

  12. Inhibitors of HIV-1 protease.

    PubMed

    Meek, T D

    1992-01-01

    The human immunodeficiency virus (HIV), the etiological agent for the acquired immune deficiency syndrome (AIDS), is a retrovirus which makes use of a virally-encoded aspartic protease to perform specific proteolytic processing of two of its gene products in order to form active enzymes and structural proteins within the mature virion. Accordingly, specific, exogenous inhibition of the HIV-1 protease is thought to be a viable approach for the development of novel therapeutics for the treatment of AIDS. Indeed, this hypothesis has been validated in virally-infected cell culture with synthetic inhibitors of HIV-1 protease. This chapter reviews the current status of the development of inhibitors of this enzyme. PMID:1285304

  13. HIV / AIDS

    MedlinePlus

    ... Marketing Share this: Main Content Area Understanding HIV/AIDS AIDS was first reported in the United States in ... and has since become a major worldwide epidemic. AIDS is caused by the human immunodeficiency virus, or ...

  14. Role of calmodulin in HIV-potentiated Fas-mediated apoptosis.

    PubMed Central

    Pan, Z.; Radding, W.; Zhou, T.; Hunter, E.; Mountz, J.; McDonald, J. M.

    1996-01-01

    The recently demonstrated extraordinary rate of turnover of T cells in human immunodeficiency virus (HIV)-1-infected patients and the apparently concomitant high rate of viral production and death are consistent with a large amount of cell death directly due to infection. Apoptosis may be one of the major forms of T cell death in HIV-1 infection. Many apoptotic pathways depend on calcium and therefore would be expected to involve calmodulin. As the HIV-1 envelope glycoprotein, gp160, contains two known calmodulin-binding domains, we investigated the possibility that the cytoplasmic domain of the HIV-1 envelope protein gp160 could enhance Fas-mediated apoptosis, the major form of apoptosis in lymphocytes. Our studies have shown that 1) transfection of H9 and MOLT-4 cells with a non-infectious HIV proviral clone, pFN, which expresses wild-type gp160, leads to enhanced Fas-mediated apoptosis, 2) transfection of MOLT-4 cells with a pFN construct pFN delta 147, which expresses a carboxyl-terminally truncated gp160 lacking the calmodulin-binding domains, produces less Fas-mediated apoptosis than transfection with pFN, and 3) the calmodulin antagonists trifluoperazine and tamoxifen completely inhibit the pFN enhancement of Fas-mediated apoptosis in MOLT-4 cells. We have replicated all of these results using the vectors pSRHS and pSRHS delta 147, which express wild-type gp160 and truncated gp160, respectively, in the absence of other viral proteins. These investigations provide a mechanism by which HIV-1 may induce apoptosis and a possible intracellular target for future therapeutics. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8780394

  15. Stem cell based anti-HIV Gene therapy

    PubMed Central

    Kitchen, Scott G.; Shimizu, Saki; An, Dong Sung

    2011-01-01

    Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self-renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately eradicate HIV from patients by a single or minimal treatment. Recent progress in the development of new technologies and clinical trials sets the stage for the current generation of gene therapy approaches to combat HIV infection. In this review, we will discuss two major approaches that are currently underway in the development of stem cell-based gene therapy to target HIV: One that focuses on the protection of cells from productive infection with HIV, and the other that focuses on targeting immune cells to directly combat HIV infection. PMID:21247612

  16. Molecular mechanisms of HIV latency.

    PubMed

    Cary, Daniele C; Fujinaga, Koh; Peterlin, B Matija

    2016-02-01

    HIV seeds reservoirs of latent proviruses in the earliest phases of infection. These reservoirs are found in many sites, including circulating cells, the lymphoid system, the brain, and other tissues. The "shock and kill" strategy, where HIV transcription is reactivated so that antiretroviral therapy and the immune system clear the infection, has been proposed as one approach to curing AIDS. In addition to many defective viruses, resting hematopoietic cells harbor transcriptionally latent HIV. Understanding basic mechanisms of HIV gene expression provides a road map for this strategy, allowing for manipulation of critical cellular and viral transcription factors in such a way as to maximize HIV gene expression while avoiding global T cell activation. These transcription factors include NF-κB and the HIV transactivator of transcription (Tat) as well as the cyclin-dependent kinases CDK13 and CDK11 and positive transcription elongation factor b (P-TEFb). Possible therapies involve agents that activate these proteins or release P-TEFb from the inactive 7SK small nuclear ribonucleoprotein (snRNP). These proposed therapies include PKC and MAPK agonists as well as histone deacetylase inhibitors (HDACis) and bromodomain and extraterminal (BET) bromodomain inhibitors (BETis), which act synergistically to reactivate HIV in latently infected cells. PMID:26731470

  17. HIV-1 infection and AIDS.

    PubMed

    Belman, Anita L

    2002-11-01

    Since the initial descriptions of AIDS in the late 1970s, much has been learned about the biology of HIV-1 and the cells it infects. Much has also been learned about mother-to-infant viral transmission and the natural history of HIV-1 infection. Key studies led to strategies for interrupting mother-to-infant transmission, resulting in a significant decline in neonatal HIV-1 infection. More proficient diagnostic techniques made early diagnosis of HIV-1-infected neonates and infants possible during asymptomatic or mildly symptomatic disease stages. Major advances in treatment led to the control of viral replication and thereby altered the course of disease progression. HIV-1/AIDS-associated neurologic disorders declined in parallel. In countries where these therapies are readily available, a dramatic decline in the number of infants born HIV-1 infected has been realized as has a markedly improved survival rate of those infected. Many questions remain, however. The long-term effects of prenatal exposure to antiretroviral agents are not yet known and continue to be studied. Just exactly how HAART therapy may affect early signs of pediatric HIV-1/AIDS-associated CNS disease, should they develop, is unclear. As new anti-retroviral agents are developed and new combination drug regimens are instituted, the potential for neurologic complications, toxicities, and adverse drug interactions (e.g., with antiepileptic drugs (AEDS)) exists and needs to be identified and monitored. PMID:12616678

  18. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism.

    PubMed

    Hudson, Brian D; Shimpukade, Bharat; Mackenzie, Amanda E; Butcher, Adrian J; Pediani, John D; Christiansen, Elisabeth; Heathcote, Helen; Tobin, Andrew B; Ulven, Trond; Milligan, Graeme

    2013-11-01

    TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca²⁺ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca²⁺ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4. PMID:23979972

  19. Newer gene editing technologies toward HIV gene therapy.

    PubMed

    Manjunath, N; Yi, Guohua; Dang, Ying; Shankar, Premlata

    2013-11-01

    Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called "Berlin patient" who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

  20. Newer Gene Editing Technologies toward HIV Gene Therapy

    PubMed Central

    Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata

    2013-01-01

    Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy. PMID:24284874

  1. Adolescents with HIV and facial lipoatrophy: response to facial stimulation

    PubMed Central

    Gabana-Silveira, Jesus Claudio; Mangilli, Laura Davison; Sassi, Fernanda C.; Braga, Arnaldo Feitosa; Andrade, Claudia Regina Furquim

    2014-01-01

    OBJECTIVES: This study evaluated the effects of facial stimulation over the superficial muscles of the face in individuals with facial lipoatrophy associated with human immunodeficiency virus (HIV) and with no indication for treatment with polymethyl methacrylate. METHOD: The study sample comprised four adolescents of both genders ranging from 13 to 17 years in age. To participate in the study, the participants had to score six or less points on the Facial Lipoatrophy Index. The facial stimulation program used in our study consisted of 12 weekly 30-minute sessions during which individuals received therapy. The therapy consisted of intra- and extra-oral muscle contraction and stretching maneuvers of the zygomaticus major and minor and the masseter muscles. Pre- and post-treatment results were obtained using anthropometric static measurements of the face and the Facial Lipoatrophy Index. RESULTS: The results suggest that the therapeutic program effectively improved the volume of the buccinators. No significant differences were observed for the measurements of the medial portion of the face, the lateral portion of the face, the volume of the masseter muscle, or Facial Lipoatrophy Index scores. CONCLUSION: The results of our study suggest that facial maneuvers applied to the superficial muscles of the face of adolescents with facial lipoatrophy associated with HIV improved the facial area volume related to the buccinators muscles. We believe that our results will encourage future research with HIV patients, especially for patients who do not have the possibility of receiving an alternative aesthetic treatment. PMID:25141118

  2. Long-acting injectable antiretrovirals for HIV treatment and prevention

    PubMed Central

    Spreen, William R.; Margolis, David A.; Pottage, John C.

    2013-01-01

    Purpose of review Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents. Recent findings The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials. Summary Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents – different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses – offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis. PMID:24100877

  3. Complement and HIV-I infection/ HIV-associated neurocognitive disorders

    PubMed Central

    Liu, Fengming; Dai, Shen; Gordon, Jennifer; Qin, Xuebin

    2014-01-01

    The various neurological complications associated with HIV-1 infection, specifically HIV-associated neurocognitive disorders (HAND) persist as a major public health burden worldwide. Despite the widespread use of anti-retroviral therapy, the prevalence of HAND is significantly high. HAND results from the direct effects of an HIV-1 infection as well as secondary effects of HIV-1-induced immune reaction and inflammatory response. Complement, a critical mediator of innate and acquired immunity, plays important roles in defeating many viral infections by the formation of a lytic pore or indirectly by opsonization and recruitment of phagocytes. While the role of complement in the pathogenesis of HIV-1 infection and HAND has been previously recognized for over fifteen years, it has been largely underestimated thus far. Complement can be activated through HIV-1 envelope proteins, mannose binding lectins (MBL) and anti-HIV-1 antibodies. Complement not only fights against HIV-1 infection but also enhances HIV-1 infection. Also, HIV-1 can hijack complement regulators such as CD59 and CD55 and can utilize these regulators and factor H to escape from complement attack. Normally, complement levels in brain are much lower than plasma levels and there is no or little complement deposition in brain cells. Interestingly, local production and deposition of complement are dramatically increased in HIV-1-infected brain, indicating that complement may contribute to the pathogenesis of HAND. Here, we review the current understanding of the role of complement in HIV-1 infection and HAND as well as potential therapeutic approaches targeting to the complement system for the treatment and eradications of HIV-1 infection. PMID:24639397

  4. Kinase Control of Latent HIV-1 Infection: PIM-1 Kinase as a Major Contributor to HIV-1 Reactivation

    PubMed Central

    Duverger, Alexandra; Wolschendorf, Frank; Anderson, Joshua C.; Wagner, Frederic; Bosque, Alberto; Shishido, Takao; Jones, Jennifer; Planelles, Vicente; Willey, Christopher; Cron, Randall Q.

    2014-01-01

    Despite the clinical relevance of latent HIV-1 infection as a block to HIV-1 eradication, the molecular biology of HIV-1 latency remains incompletely understood. We recently demonstrated the presence of a gatekeeper kinase function that controls latent HIV-1 infection. Using kinase array analysis, we here expand on this finding and demonstrate that the kinase activity profile of latently HIV-1-infected T cells is altered relative to that of uninfected T cells. A ranking of altered kinases generated from these kinome profile data predicted PIM-1 kinase as a key switch involved in HIV-1 latency control. Using genetic and pharmacologic perturbation strategies, we demonstrate that PIM-1 activity is indeed required for HIV-1 reactivation in T cell lines and primary CD4 T cells. The presented results thus confirm that kinases are key contributors to HIV-1 latency control. In addition, through mutational studies we link the inhibitory effect of PIM-1 inhibitor IV (PIMi IV) on HIV-1 reactivation to an AP-1 motif in the CD28-responsive element of the HIV-1 long terminal repeat (LTR). The results expand our conceptual understanding of the dynamic interactions of the host cell and the latent HIV-1 integration event and position kinome profiling as a research tool to reveal novel molecular mechanisms that can eventually be targeted to therapeutically trigger HIV-1 reactivation. PMID:24155393

  5. Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers

    PubMed Central

    Goda, Jayant S.; Pachpor, Tejaswini; Basu, Trinanjan; Chopra, Supriya; Gota, Vikram

    2016-01-01

    Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies. PMID:27121513

  6. Therapeutic misadventure.

    PubMed

    Langford, N J

    2010-10-01

    Therapeutic misadventure can be defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Within the National Health Service there were over 86,000 reported adverse incidents in 2007. In the USA medication errors have been rated as the fourth highest cause of death. Unfortunately one of the greatest contributors to iatrogenic injury is human error. The potential types of misadventure are infinite. Medication errors are a major part of this, being responsible for over 70% of cases that cause serious harm. However, many medication errors caused by slips, lapses, technical errors and mistakes are preventable; intentional violations of safe operating procedures are not. While medication errors were tolerated by society in the past, the readiness to institute criminal proceedings against health-care professionals has increased greatly in the UK over the last decade. The medication process consists of writing prescriptions, dispensing the product, administering it and monitoring its effects. Prescription errors arise owing to incomplete information, lack of appropriate labelling, environmental factors and human blunders. Even with a perfect prescription the right medication must be dispensed and appropriately labelled. Dispensing errors are not uncommon and may be compounded by non-clinical considerations. Administration of a drug by injection is one of the most dangerous aspects of the medication process, especially in inexperienced hands. The final component of medication supply is monitoring the effect of the medication. With short courses of medication such monitoring is easy, but with long-term medication, particularly with potent drugs where the margin between efficacy and toxicity is small, active procedures may be required to ensure toxicity does not ensue. Despite the endeavour of health-care professions to stick to the rule of 'first, do no harm', in reality this is difficult to achieve all of the time. When errors occur the natural thoughts of wanting to blame an individual at the sharp end (active error) should be tempered. Identifying and correcting system (latent) errors will, in the end, provide a safer health-care system. PMID:21539282

  7. A synthetic globotriaosylceramide analogue inhibits HIV-1 infection in vitro by two mechanisms.

    PubMed

    Harrison, Amanda L; Olsson, Martin L; Jones, R Brad; Ramkumar, Stephanie; Sakac, Darinka; Binnington, Beth; Henry, Stephen; Lingwood, Clifford A; Branch, Donald R

    2010-07-01

    Previously, it was shown that the cell-membrane-expressed glycosphingolipid, globotriaosylceramide (Gb(3)/P(k)/CD77), protects against HIV-1 infection and may be a newly described natural resistance factor against HIV infection. We have now investigated the potential of a novel, water soluble, non-toxic and completely synthetic analogue of Gb(3)/P(k) (FSL-Gb(3)) to inhibit HIV-1 infection in vitro. A uniquely designed analogue, FSL-Gb(3), of the natural Gb(3)/P(k) molecule was synthesized. HIV-1(IIIB) (X4 virus) and HIV-1(Ba-L) (R5 virus) infection of PHA/interleukin-2-activated, peripheral blood mononuclear cells (PBMCs) and Jurkat T cells in vitro was assessed, as well as infection of U87.CD4.CCR5 by various clinical R5 tropic viruses after treatment with FSL-Gb(3). We monitored Gb(3), CD4 and CXCR4 expression by fluorescent antibody cell sorting and viral replication by p24(gag) ELISA. Total cellular Gb(3) was examined by glycosphingolipid extraction and thin layer chromatography. In vivo toxicity was monitored in mice by histological assessment of vital organs and lymphoid tissue. FSL-Gb(3) blocked X4 and R5 of both lab and clinical viral strains in activated PBMCs or the U87.CD4.CCR5 cell line with a 50% inhibitory concentration (IC(50)) of approximately 200-250 microM. FACS and TLC overlay showed that FSL-Gb(3) can insert itself into cellular plasma membranes and that cellular membrane-absorbed FSL-Gb(3) is able to inhibit subsequent HIV-1 infection. There was no effect of FSL-Gb(3) on cell surface levels of CD4 or CXCR4. Thus, FSL-Gb(3) can inhibit HIV-1 by two mechanisms: direct inhibition of virus and inhibition of viral entry. Infusion of FSL-Gb(3) into laboratory mice at doses well in excess of theoretical therapeutic doses was tolerated with no untoward reactions. Our results demonstrate the potential utility of using a completely synthetic, water soluble globotriaosylceramide analogue, FSL-Gb(3), having low toxicity, for possible future use as a novel therapeutic approach for the systemic treatment of HIV/AIDS. PMID:20582467

  8. Short Communication: High Cellular Iron Levels Are Associated with Increased HIV Infection and Replication

    PubMed Central

    Chang, Hsiang-Chun; Bayeva, Marina; Taiwo, Babafemi; Palella, Frank J.; Hope, Thomas J.

    2015-01-01

    Abstract HIV is a pandemic disease, and many cellular and systemic factors are known to alter its infectivity and replication. Earlier studies had suggested that anemia is common in HIV-infected patients; however, higher iron was also observed in AIDS patients prior to the introduction of antiretroviral therapy (ART). Therefore, the relationship between iron and viral infection is not well delineated. To address this issue, we altered the levels of cellular iron in primary CD4+ T cells and showed that higher iron is associated with increased HIV infection and replication. In addition, HIV infection alone leads to increased cellular iron, and several ART drugs increase cellular iron independent of HIV infection. Finally, HIV infection is associated with increased serum iron in HIV-positive patients regardless of treatment with ART. These results establish a relationship between iron and HIV infection and suggest that iron homeostasis may be a viable therapeutic target for HIV. PMID:25291189

  9. Current Advances in Virus-Like Particles as a Vaccination Approach against HIV Infection.

    PubMed

    Zhao, Chongbo; Ao, Zhujun; Yao, Xiaojian

    2016-01-01

    HIV-1 virus-like particles (VLPs) are promising vaccine candidates against HIV-1 infection. They are capable of preserving the native conformation of HIV-1 antigens and priming CD4+ and CD8+ T cell responses efficiently via cross presentation by both major histocompatibility complex (MHC) class I and II molecules. Progress has been achieved in the preclinical research of HIV-1 VLPs as prophylactic vaccines that induce broadly neutralizing antibodies and potent T cell responses. Moreover, the progress in HIV-1 dendritic cells (DC)-based immunotherapy provides us with a new vision for HIV-1 vaccine development. In this review, we describe updates from the past 5 years on the development of HIV-1 VLPs as a vaccine candidate and on the combined use of HIV particles with HIV-1 DC-based immunotherapy as efficient prophylactic and therapeutic vaccination strategies. PMID:26805898

  10. Current Advances in Virus-Like Particles as a Vaccination Approach against HIV Infection

    PubMed Central

    Zhao, Chongbo; Ao, Zhujun; Yao, Xiaojian

    2016-01-01

    HIV-1 virus-like particles (VLPs) are promising vaccine candidates against HIV-1 infection. They are capable of preserving the native conformation of HIV-1 antigens and priming CD4+ and CD8+ T cell responses efficiently via cross presentation by both major histocompatibility complex (MHC) class I and II molecules. Progress has been achieved in the preclinical research of HIV-1 VLPs as prophylactic vaccines that induce broadly neutralizing antibodies and potent T cell responses. Moreover, the progress in HIV-1 dendritic cells (DC)-based immunotherapy provides us with a new vision for HIV-1 vaccine development. In this review, we describe updates from the past 5 years on the development of HIV-1 VLPs as a vaccine candidate and on the combined use of HIV particles with HIV-1 DC-based immunotherapy as efficient prophylactic and therapeutic vaccination strategies. PMID:26805898

  11. Uneven Genetic Robustness of HIV-1 Integrase

    PubMed Central

    Rihn, Suzannah J.; Hughes, Joseph; Wilson, Sam J.

    2014-01-01

    ABSTRACT Genetic robustness (tolerance of mutation) may be a naturally selected property in some viruses, because it should enhance adaptability. Robustness should be especially beneficial to viruses like HIV-1 that exhibit high mutation rates and exist in immunologically hostile environments. Surprisingly, however, the HIV-1 capsid protein (CA) exhibits extreme fragility. To determine whether fragility is a general property of HIV-1 proteins, we created a large library of random, single-amino-acid mutants in HIV-1 integrase (IN), covering >40% of amino acid positions. Despite similar degrees of sequence variation in naturally occurring IN and CA sequences, we found that HIV-1 IN was significantly more robust than CA, with random nonsilent IN mutations only half as likely to cause lethal defects. Interestingly, IN and CA were similar in that a subset of mutations with high in vitro fitness were rare in natural populations. IN mutations of this type were more likely to occur in the buried interior of the modeled HIV-1 intasome, suggesting that even very subtle fitness effects suppress variation in natural HIV-1 populations. Lethal mutations, in particular those that perturbed particle production, proteolytic processing, and particle-associated IN levels, were strikingly localized at specific IN subunit interfaces. This observation strongly suggests that binding interactions between particular IN subunits regulate proteolysis during HIV-1 virion morphogenesis. Overall, use of the IN mutant library in conjunction with structural models demonstrates the overall robustness of IN and highlights particular regions of vulnerability that may be targeted in therapeutic interventions. IMPORTANCE The HIV-1 integrase (IN) protein is responsible for the integration of the viral genome into the host cell chromosome. To measure the capacity of IN to maintain function in the face of mutation, and to probe structure/function relationships, we created a library of random single-amino-acid IN mutations that could mimic the types of mutations that naturally occur during HIV-1 infection. Previously, we measured the robustness of HIV-1 capsid in this manner and determined that it is extremely intolerant of mutation. In contrast to CA, HIV-1 IN proved relatively robust, with far fewer mutations causing lethal defects. However, when we subsequently mapped the lethal mutations onto a model of the structure of the multisubunit IN-viral DNA complex, we found the lethal mutations that caused virus morphogenesis defects tended to be highly localized at subunit interfaces. This discovery of vulnerable regions of HIV-1 IN could inform development of novel therapeutics. PMID:25339768

  12. [Achievement of therapeutic objectives].

    PubMed

    Mantilla, Teresa

    2014-07-01

    Therapeutic objectives for patients with atherogenic dyslipidemia are achieved by improving patient compliance and adherence. Clinical practice guidelines address the importance of treatment compliance for achieving objectives. The combination of a fixed dose of pravastatin and fenofibrate increases the adherence by simplifying the drug regimen and reducing the number of daily doses. The good tolerance, the cost of the combination and the possibility of adjusting the administration to the patient's lifestyle helps achieve the objectives for these patients with high cardiovascular risk. PMID:25043543

  13. [Therapeutic plasmas available worldwide].

    PubMed

    Martinaud, C; Cauet, A; Sailliol, A

    2013-05-01

    Therapeutic plasma is a current product; French guidelines were reviewed in 2012. Connections between more or less closed countries are frequent, during relief disasters as well as in war settings. This is associated with the increasing use of plasma in the management of casualties. Additionally, The real possibility of lack of plasma supply in some countries provides a fundamental interest of the knowledge of foreign blood supply organizations. We present here the main divergences and mutual point between plasmas available worldwide. We present the main characteristics of each product. PMID:23522688

  14. Global epidemiology of HIV.

    PubMed

    Fettig, Jade; Swaminathan, Mahesh; Murrill, Christopher S; Kaplan, Jonathan E

    2014-09-01

    The number of persons living with HIV worldwide reached approximately 35.3 million in 2012. Meanwhile, AIDS-related deaths and new HIV infections have declined. Much of the increase in HIV prevalence is from rapidly increasing numbers of people on antiretroviral treatment who are now living longer. There is regional variation in epidemiologic patterns, major modes of HIV transmission, and HIV program response. It is important to focus on HIV incidence, rather than prevalence, to provide information about HIV transmission patterns and populations at risk. Expanding HIV treatment will function as a preventive measure through decreasing horizontal and vertical transmission of HIV. PMID:25151559

  15. Recent developments in clinical trial designs for HIV vaccine research

    PubMed Central

    Richert, Laura; Lhomme, Edouard; Fagard, Catherine; Lévy, Yves; Chêne, Geneviève; Thiébaut, Rodolphe

    2015-01-01

    HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later –stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development. PMID:25751670

  16. Recent developments in clinical trial designs for HIV vaccine research.

    PubMed

    Richert, Laura; Lhomme, Edouard; Fagard, Catherine; Lvy, Yves; Chne, Genevive; Thibaut, Rodolphe

    2015-01-01

    HIV vaccine strategies are expected to be a crucial component for controlling the HIV epidemic. Despite the large spectrum of potential candidate vaccines for both prophylactic and therapeutic use, the overall development process of an efficacious HIV vaccine strategy is lengthy. The design of clinical trials and the progression of a candidate strategy through the different clinical development stages remain methodologically challenging, mainly due to the lack of validated correlates of protection. In this review, we describe recent advances in clinical trial designs to increase the efficiency of the clinical development of candidate HIV vaccine strategies. The methodological aspects of the designs for early- (phase I and II) and later -stage (phase IIB and III) development are discussed, taking into account the specificities of both prophylactic and therapeutic HIV vaccine development. PMID:25751670

  17. Clinical management of HIV-associated hematologic malignancies.

    PubMed

    Wang, Chia-Ching J; Kaplan, Lawrence D

    2016-04-01

    HIV is associated with an excess risk for lymphoid malignancies. Although the risk of lymphoma has decreased in HIV-infected individuals in the era of effective combination antiretroviral therapy, it remains high. Treatment outcomes have improved due to improvements in HIV and cancer therapeutics for the common HIV-associated lymphomas. R-CHOP/R-EPOCH are the standard of care for HIV-associated diffuse large B-cell lymphoma. HIV-infected patients with Burkitt lymphoma and good performance status should receive dose-intensive regimens. HIV-infected patients with primary central nervous system lymphoma can respond favorably to high-dose methotrexate-based therapy. In many cases, treatment and expected outcomes for HIV-infected patients with either Hodgkin or non-Hodgkin's lymphomas are very similar to HIV-negative patients. There is currently no standard treatment for HIV-associated multicentric Castleman disease or primary effusion lymphoma. For those hematologic cancers in which transplantation is part of standard care, this modality should be considered an option in those with well-controlled HIV infection. PMID:26652941

  18. The Therapeutic School.

    ERIC Educational Resources Information Center

    Rice, John Steadman

    2002-01-01

    Contributes to the recent research on specific institutional carriers of the therapeutic culture, such as the state, the corporation, and the self- help movement, defining therapeutic discourse and discussing the therapeutic ethic, the therapeutic school, schools of education and their critics, and disappointing results of therapeutic schooling.…

  19. Adjuvant therapies for HIV-associated neurocognitive disorders

    PubMed Central

    McGuire, Jennifer L; Barrett, Jeffrey S; Vezina, Heather E; Spitsin, Sergei; Douglas, Steven D

    2014-01-01

    Objective HIV-associated neurocognitive disorder (HAND) is a frequent and heterogeneous complication of HIV, affecting nearly 50% of infected individuals in the combined antiretroviral therapy (cART) era. This is a particularly devastating statistic because the diagnosis of HAND confers an increased risk of HIV-associated morbidity and mortality in affected patients. While cART is helpful in the treatment of the more severe forms of HAND, there is a therapeutic gap in the milder forms of HAND, where cART is less effective. Multiple adjuvant therapies with various mechanisms of action have been studied (N-methyl D-aspartate [NMDA]-receptor antagonists, MAO-B inhibitors, tetracycline-class antibiotics, and others), but none have shown a clear positive effect in HAND. While this lack of efficacy may be because the appropriate therapeutic targets have not yet been determined, we aimed to discuss that study results may also influenced by clinical trial design. Methods This report is a systematic review of clinical trials of adjuvant therapies for HAND performed from January 1996 through June 2014. Results Possible drawbacks in study design, including lack of standardized case definitions, poorly defined target populations, inappropriate dose selection and measurable outcomes, and brief study durations may have masked true underlying mechanistic effects of previously investigated adjuvant therapies for HAND in specific patient populations. Conclusions A proposal for streamlining and maximizing the likelihood of success in future clinical studies using a ‘learning and confirming’ investigational paradigm, incorporating stronger adaptive Phase I/II study designs, computerized modeling, and population/goal of treatment-specific Phase III clinical trials is presented. PMID:25540809

  20. Stages of HIV Infection

    MedlinePlus

    ... Opportunities How To Get Funding How We’re Spending PEPFAR & Global AIDS Global HIV/AIDS Overview PEPFAR U.S. Government Global AIDS Activities Global HIV/AIDS Organizations CIA HIV/AIDS Data National HIV/AIDS Strategy Overview National HIV/AIDS ...

  1. HIV Life Cycle

    MedlinePlus

    HIV Overview The HIV Life Cycle (Last updated 9/22/2015; last reviewed 9/22/2015) Key Points HIV gradually destroys the immune ... life cycle. What is the connection between the HIV life cycle and HIV medicines? Antiretroviral therapy (ART) ...

  2. Continuous Antigenic Stimulation of DO11.10 TCR Transgenic Mice in the Presence or Absence of IL-1β: Possible Implications for Mechanisms of T Cell Depletion in HIV Disease.

    PubMed

    Ladell, Kristin; Hazenberg, Mette D; Fitch, Mark; Emson, Claire; McEvoy-Hein Asgarian, Bridget K; Mold, Jeff E; Miller, Corey; Busch, Robert; Price, David A; Hellerstein, Marc K; McCune, Joseph M

    2015-11-01

    Untreated HIV disease is associated with chronic immune activation and CD4(+) T cell depletion. A variety of mechanisms have been invoked to account for CD4(+) T cell depletion in this setting, but the quantitative contributions of these proposed mechanisms over time remain unclear. We turned to the DO11.10 TCR transgenic mouse model, where OVA is recognized in the context of H-2(d), to explore the impact of chronic antigenic stimulation on CD4(+) T cell dynamics. To model dichotomous states of persistent Ag exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, IL-1β. In both cases, circulating Ag-specific CD4(+) T cells were depleted. However, in the absence of IL-1β, there was limited proliferation and effector/memory conversion of Ag-specific T cells, depletion of peripheral CD4(+) T cells in hematolymphoid organs, and systemic induction of regulatory Foxp3(+)CD4(+) T cells, as often observed in late-stage HIV disease. By contrast, when OVA peptide was administered in the presence of IL-1β, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between Ag-stimulated DO11.10 TCR transgenic mice and HIV-infected humans, our data suggest that CD4(+) T cell depletion in the setting of HIV disease may reflect, at least in part, chronic Ag exposure in the absence of proinflammatory signals and/or appropriate APC functions. PMID:26416271

  3. Continuous antigenic stimulation of DO11.10 TCR transgenic mice in the presence or absence of IL-1β: possible implications for mechanisms of T cell depletion in HIV disease1

    PubMed Central

    Ladell, Kristin; Hazenberg, Mette D.; Fitch, Mark; Emson, Claire; McEvoy-Hein Asgarian, Bridget K.; Mold, Jeff E.; Miller, Corey; Busch, Robert; Price, David A.; Hellerstein, Marc K.; McCune, Joseph M.

    2015-01-01

    Untreated HIV disease is associated with chronic immune activation and CD4+ T cell depletion. A variety of mechanisms have been invoked to account for CD4+ T cell depletion in this context, but the quantitative contributions of these proposed mechanisms over time remains unclear. We turned to the DO11.10 TCR transgenic (tg) mouse model, where OVA is recognized in the context of H-2d, to explore the impact of chronic antigenic stimulation on CD4+ T cell dynamics. To model dichotomous states of persistent antigen exposure in the presence or absence of proinflammatory stimulation, we administered OVA peptide (OVAp) to these mice on a continuous basis with or without the prototypic proinflammatory cytokine, interleukin 1β (IL-1β). In both cases, circulating antigen-specific CD4+ T cells were depleted. However, in the absence of IL-1β, there was limited proliferation and effector/memory conversion of antigen-specific T cells, depletion of peripheral CD4+ T cells in hematolymphoid organs, and systemic induction of regulatory FoxP3+CD4+ T cells, as often observed in late-stage HIV disease. By contrast, when OVAp was administered in the presence of IL-1β, effector/memory phenotype T cells expanded and the typical symptoms of heightened immune activation were observed. Acknowledging the imperfect and incomplete relationship between antigen-stimulated DO11.10 TCR tg mice and HIV-infected humans, our data suggest that CD4+ T cell depletion in the setting of HIV disease may reflect, at least in part, chronic antigen exposure in the absence of proinflammatory signals and/or appropriate antigen-presenting cell functions. PMID:26416271

  4. Applications and limitations of inflammatory biomarkers for studies on neurocognitive impairment in HIV infection.

    PubMed

    Cassol, Edana; Misra, Vikas; Morgello, Susan; Gabuzda, Dana

    2013-12-01

    Despite reduced prevalence of severe forms of HIV-associated neurocognitive disorders (HAND) on current antiretroviral therapy (ART) regimens, milder forms of neurocognitive impairment (NCI) remain prevalent in HIV-infected populations. These mild forms of HAND consist of subtypes, probably reflecting distinct, though possibly overlapping, pathophysiological mechanisms. Factors associated with HAND in HIV patients with prolonged viral suppression on ART include older age, low nadir CD4, active HCV co-infection, and cardiovascular risk factors, but underlying mechanisms and their relationship to innate immune activation, chronic inflammation, and other features of systemic disease are poorly understood. In this article, we discuss applications and limitations of plasma inflammatory biomarkers for studies on HAND in HIV patients on ART and describe an analysis pipeline to reduce common sources of noise and increase likelihood of identifying relevant inflammatory biomarkers. Clinical covariates and comorbidities that influence inflammatory biomarkers, such as aging, obesity, metabolic abnormalities, HCV co-infection, and substance abuse, are also reviewed. As an example for using this analytic pipeline, we present an exploratory study of 22 plasma inflammatory biomarkers (IFN-α 2b and -γ, 16 cytokines/chemokines, sIL-2R, sCD14, HA, and YKL-40) in a cohort of HIV-infected individuals with advanced disease, frequent HCV co-infection, and viral suppression on ART. The identification of inflammatory biomarkers associated with HAND in HIV+ patients on ART may be useful to distinguish between HAND subtypes with distinct pathophysiology, and is important for achieving a systems-level understanding of the biology of these disorders, developing effective therapies, and evaluating therapeutic outcomes. PMID:24259252

  5. HIV Medicines and Side Effects

    MedlinePlus

    Side Effects of HIV Medicines HIV Medicines and Side Effects (Last updated 1/7/2016; last reviewed 1/ ... a person’s individual needs. Can HIV medicines cause side effects? HIV medicines help people with HIV live longer, ...

  6. HIV-associated eosinophilic folliculitis in an infant.

    PubMed

    Ramdial, P K; Morar, N; Dlova, N C; Aboobaker, J

    1999-06-01

    HIV-associated eosinophilic folliculitis (HIV-EF), which is a well-known entity in adults, has not been described in children. Although Ofuji's disease (OD) or eosinophilic pustular folliculitis (EPF) has been described in children and shares histopathologic features with HIV-EF, it is a distinct entity with characteristic clinical features. We report the occurrence of eosinophilic folliculitis in an 8-month-old HIV-positive patient and discuss the clinical, pathologic and possible pathogenetic aspects thereof. In addition, differences in the clinical manifestations of the present case and that of I-EPF are addressed. Because of clinicopathologic similarities between the present case and HIV-associated eosinophilic folliculitis (HIV-EF) in adults, we believe that eosinophilic folliculitis in this patient represents a cutaneous manifestation of HIV infection, rather than co-incidental occurrence of the infantile form of Ofuji's disease in an HIV-positive patient. PMID:10380045

  7. Fungal infections associated with HIV infection.

    PubMed

    Samaranayake, L P; Fidel, P L; Naglik, J R; Sweet, S P; Teanpaisan, R; Coogan, M M; Blignaut, E; Wanzala, P

    2002-01-01

    Oral candidiasis is perhaps the commonest infection seen in HIV disease. The aim of this workshop was to provide a sketch of the multifarious aspects of the disease from a global perspective. To this end the panellists addressed issues such as the virulence of Candida, emergence of antifungal resistance, management of candidiasis and other exotic, oral mycotic diseases. An all-pervasive theme was the dramatic differences in the management of fungal infections consequential to the availability (or the lack) of anti-HIV drugs in the developed and the developing world. Further, the social stigmata associated with the HIV disease in many developing regions in Africa and Asia appears to modify the therapeutic strategies. Additionally, the lesser-known regional variations in the disease manifestations and therapeutic approaches were stark. Further work is direly needed to address these issues. PMID:12164650

  8. HIV Drug to Aid Melanoma Therapies?

    PubMed

    Kim, Hyungsoo; Ronai, Ze'ev A

    2016-03-14

    The HIV1 protease inhibitor nelfinavir is being investigated as a cancer therapeutic. In this issue of Cancer Cell, Smith et al. (2016) report that nelfinavir suppresses MITF expression induced by MAPK pathway inhibition in melanoma cells and sensitizes melanoma cells with NRAS or BRAF plus NRAS mutations to MEK inhibitors. PMID:26977874

  9. The metabolic syndrome and HIV infection.

    PubMed

    Li Vecchi, Valentina; Maggi, Paolo; Rizzo, Manfredi; Montalto, Giuseppe

    2014-01-01

    The metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease and type 2 diabetes, has become an important public health problem. Considerable differences in the prevalence of the MetS in human immunodeficiency virus (HIV)-infected subjects have been reported, as a consequence of several limitations regarding the diagnostic critera for MetS. New evidence suggests that the use of optimal waist cut-off points specific for the various ethnic populations could represent a step forward in overcoming these limitations. Also the use of specific cut-off points for measuring upper trunk fat as an adjunctive criterion of MetS in HIV patients with lipodystrophy could represent an interesting new research topic. Although metabolic disorders have been associated indirectly with highly active antiretroviral therapy (HAART), directly with HIV infection per se or with host conditions, current circumstances could change the framework of MetS in the HIV setting: For example, the aging HIV population and newer, less metabolically toxic antiretroviral drugs. Lipotoxicity and adipokines have been focused as key issues for explaining MetS in HIV patients. Several studies have investigated the pathophysiology of MetS and cardiovascular complications in HIV infection. Evidence shows that both HIV infection per se and HIV-related chronic immune activation despite antiretroviral therapy are critical factors linking MetS and cardiovascular complications. Current epidemiological and pathogenetic data on MetS in HIV infection, prevention strategies and therapeutic options for all MetS components are reviewed in the light of the recent Adult Treatment Panel IV recommendations and the new antiretroviral drugs. PMID:24320034

  10. Naturally derived anti-HIV agents.

    PubMed

    Asres, Kaleab; Seyoum, Ameha; Veeresham, Ciddi; Bucar, Franz; Gibbons, Simon

    2005-07-01

    The urgent need for new anti-HIV/AIDS drugs is a global concern. In addition to obvious economical and commercial hurdles, HIV/AIDS patients are faced with multifarious difficulties associated with the currently approved anti-HIV drugs. Adverse effects, the emergence of drug resistance and the narrow spectrum of activity have limited the therapeutic usefulness of the various reverse transcriptase and protease inhibitors that are currently available on the market. This has driven many scientists to look for new anti-retrovirals with better efficacy, safety and affordability. As has always been the case in the search for cures, natural sources offer great promise. Several natural products, mostly of plant origin have been shown to possess promising activities that could assist in the prevention and/or amelioration of the disease. Many of these anti-HIV agents have other medicinal values as well, which afford them further prospective as novel leads for the development of new drugs that can deal with both the virus and the various disorders that characterize HIV/AIDS. The aim of this review is to report new discoveries and updates pertaining to anti-HIV natural products. In the review anti-HIV agents have been classified according to their chemical classes rather than their target in the HIV replicative cycle, which is the most frequently encountered approach. Perusal of the literature revealed that most of these promising naturally derived anti-HIV compounds are flavonoids, coumarins, terpenoids, alkaloids, polyphenols, polysaccharides or proteins. It is our strong conviction that the results and experiences with many of the anti-HIV natural products will inspire and motivate even more researchers to look for new leads from plants and other natural sources. PMID:16161055

  11. Quality of life in HIV/AIDS.

    PubMed

    Basavaraj, K H; Navya, M A; Rashmi, R

    2010-07-01

    Given the longevity achievable with current prophylactic and therapeutic strategies for persons with HIV infection, quality of life (QOL) has emerged as a significant medical outcome measure, and its enhancement has an important goal. This review highlights the relevance and complexity of physical, psychological, and social factors as determinants of health-related quality of life in HIV-infected persons. Existing data suggest that physical manifestations, antiretroviral therapy, psychological well-being, social support systems, coping strategies, spiritual well-being, and psychiatric comorbidities are important predictors of QOL in this population. Consequently, the impact of HIV infection on the dimensions of QOL, including physical and emotional well-being, social support systems, and life roles, has emerged as a key issue for persons infected with HIV. PMID:21716787

  12. The epidemiology of HIV infection in Zambia.

    PubMed

    Kandala, N-B; Ji, C; Cappuccio, P F; Stones, R W

    2008-08-01

    Population surveys of health and fertility are an important source of information about demographic trends and their likely impact on the HIV/AIDS epidemic. In contrast to groups sampled at health facilities they can provide nationally and regionally representative estimates of a range of variables. Data on HIV-sero-status were collected in the 2001 Zambia Demographic and Health Survey (ZDHS) and made available in a separate data file in which HIV status was linked to a very limited set of demographic variables. We utilized this data set to examine associations between HIV prevalence, gender, age and geographical location. We applied the generalized geo-additive semi-parametric model as an alternative to the common linear model, in the context of analyzing the prevalence of HIV infection. This model enabled us to account for spatial auto-correlation, non-linear, location effects on the prevalence of HIV infection at the disaggregated provincial level (nine provinces) and assess temporal and geographical variation in the prevalence of HIV infection, while simultaneously controlling for important risk factors. Of the overall sample of 3950, 54% was female. The overall HIV-positivity rate was 565 (14.3%). The mean age at HIV diagnosis for male was 30.3 (SD=11.2) and 27.7 (SD=9.3) for female respectively. Lusaka and Copperbelt have the first and second highest prevalence of AIDS/HIV (marginal odds ratios of 3.24 and 2.88, respectively) but when the younger age of the urban population and the spatial auto-correlation was taken into account, Lusaka and Copperbelt were no longer among the areas with the highest prevalence. Non-linear effects of age at HIV diagnosis are also discussed and the importance of spatial residual effects and control of confounders on the prevalence of HIV infection. The study was conducted to assess the spatial pattern and the effect of confounding risk factors on AIDS/HIV prevalence and to develop a means of adjusting estimates of AIDS/HIV prevalence on the important risk factors. Controlling for important risk factors, such as geographical location (spatial auto-correlation), age structure of the population and gender, gave estimates of prevalence that are statistically robust. Researchers should be encouraged to use all available information in the data to account for important risk factors when reporting AIDS/HIV prevalence. Where this is not possible, correction factors should be applied, particularly where estimates of AIDS/HIV prevalence are pooled in systematic reviews. Our maps can be used for policy planning and management of AIDS/HIV in Zambia. PMID:18608086

  13. HIV Testing

    MedlinePlus

    ... interest. For more information, see the Guttmacher Institute’s State Policies in Brief: Minors’ Access to STI Services . Employers In most cases, your employer will not know your HIV status unless you tell them. But your employer does have a right to ask if you have any health conditions ...

  14. HIV Prevention

    MedlinePlus

    ... and other STDs when used by men or women for anal sex. But we do know that HIV can’t travel through the nitrile barrier. It is safe to use any kind of lubricant with nitrile female condoms. Even if you use condoms the right way every time you have sex, there’s still ...

  15. HIV-related neuropathy: current perspectives

    PubMed Central

    Schütz, Sonja G; Robinson-Papp, Jessica

    2013-01-01

    Distal symmetric polyneuropathy (DSP) related to human immunodeficiency virus (HIV) is one of the most common neurologic complications of HIV, possibly affecting as many as 50% of all individuals infected with HIV. Two potentially neurotoxic mechanisms have been proposed to play a crucial role in the pathogenesis of HIV DSP: neurotoxicity resulting from the virus and its products; as well as adverse neurotoxic effects of medications used in the treatment of HIV. Clinically, HIV DSP is characterized by a combination of signs and symptoms that include decreased deep tendon reflexes at the ankles and decreased sensation in the distal extremities as well as paresthesias, dysesthesias, and pain in a symmetric stocking–glove distribution. These symptoms are generally static or slowly progressive over time, and depending on the severity, may interfere significantly with the patient’s daily activities. In addition to the clinical picture, nerve conduction studies and skin biopsies are often pursued to support the diagnosis of HIV DSP. Anticonvulsants, antidepressants, topical agents, and nonspecific analgesics may help relieve neuropathic pain. Specifically, gabapentin, lamotrigine, pregabalin, amitriptyline, duloxetine, and high-dose topical capsaicin patches have been used in research and clinical practice. Further research is needed to elucidate the pathogenesis of HIV DSP, thus facilitating the development of novel treatment strategies. This review discusses the epidemiology, pathophysiology, clinical findings, diagnosis, and management of DSP in the setting of HIV. PMID:24049460

  16. How HIV Causes AIDS

    MedlinePlus

    ... Share this: Main Content Area How HIV Causes AIDS HIV destroys CD4 positive (CD4+) T cells, which ... and disease, ultimately resulting in the development of AIDS. Most people who are infected with HIV can ...

  17. HIV-AIDS Connection

    MedlinePlus

    ... Marketing Share this: Main Content Area The HIV-AIDS Connection AIDS was first recognized in 1981 and ... is there overwhelming scientific consensus that HIV causes AIDS? Before HIV infection became widespread in the human ...

  18. HIV/AIDS Basics

    MedlinePlus

    ... Enter ZIP code or city Follow Act Against AIDS Act Against AIDS @talkHIV Act Against AIDS Get Email Updates on AAA Anonymous Feedback HIV/AIDS Media Infographics Syndicated Content Podcasts Slide Sets HIV/ ...

  19. HIV/AIDS

    MedlinePlus

    HIV stands for human immunodeficiency virus. It kills or damages the body's immune system cells. AIDS stands for acquired immunodeficiency syndrome. It is the most advanced stage of infection with HIV. HIV most ...

  20. Preventing HIV with Medicine

    MedlinePlus

    ... information in Spanish ( en español ) Preventing HIV with medicine Get medicine right after you are exposed to ... to top More information on Preventing HIV with medicine Explore other publications and websites National HIV and ...

  1. HIV Medication Adherence

    MedlinePlus

    ... HIV treatment failure. What is drug resistance? Drug resistance can develop as HIV multiplies in the body. When HIV multiplies, the virus sometimes mutates (changes form) and makes variations of itself. Variations of ...

  2. HIV Antibody Test

    MedlinePlus

    ... test is performed that detects the genetic material ( RNA ) of the virus. An HIV RNA test will detect HIV in most people by ... next test to perform is an HIV-1 RNA test (nucleic acid amplification test, NAAT). If the ...

  3. Children and HIV

    MedlinePlus

    ... in Revised April 29, 2014 Select a Language: Fact Sheet 612 Children and HIV HOW SERIOUS IS HIV ... and most pregnant women are taking ARVs. See fact sheet 611 for more information on pregnancy and HIV. ...

  4. HIV among Transgender People

    MedlinePlus

    ... Latinos Native Hawaiians and Other Pacific Islanders Age Youth People Aged 50 and Older Incarcerated Populations Sex Workers Economically Disadvantaged HIV Risk and Prevention HIV Risk and Prevention Estimates HIV ...

  5. HIV among Women

    MedlinePlus

    ... Latinos Native Hawaiians and Other Pacific Islanders Age Youth People Aged 50 and Older Incarcerated Populations Sex Workers Economically Disadvantaged HIV Risk and Prevention HIV Risk and Prevention Estimates HIV ...

  6. HIV transmission risk behavior among HIV-positive patients receiving antiretroviral therapy in KwaZulu-Natal, South Africa.

    PubMed

    Shuper, Paul A; Kiene, Susan M; Mahlase, Gethwana; MacDonald, Susan; Christie, Sarah; Cornman, Deborah H; Fisher, William A; Greener, Ross; Lalloo, Umesh G; Pillay, Sandy; van Loggerenberg, Francois; Fisher, Jeffrey D

    2014-08-01

    The aim of this investigation was to identify factors associated with HIV transmission risk behavior among HIV-positive women and men receiving antiretroviral therapy (ART) in KwaZulu-Natal, South Africa. Across 16 clinics, 1,890 HIV+ patients on ART completed a risk-focused audio computer-assisted self-interview upon enrolling in a prevention-with-positives intervention trial. Results demonstrated that 62 % of HIV-positive patients' recent unprotected sexual acts involved HIV-negative or HIV status unknown partners. For HIV-positive women, multivariable correlates of unprotected sex with HIV-negative or HIV status unknown partners were indicative of poor HIV prevention-related information and of sexual partnership-associated behavioral skills barriers. For HIV-positive men, multivariable correlates represented motivational barriers, characterized by negative condom attitudes and the experience of depressive symptomatology, as well as possible underlying information deficits. Findings suggest that interventions addressing gender-specific and culturally-relevant information, motivation, and behavioral skills barriers could help reduce HIV transmission risk behavior among HIV-positive South Africans. PMID:24158486

  7. In vitro translation to study HIV protease activity.

    PubMed

    Matsuda, Zene; Iga, Mutsunori; Miyauchi, Kosuke; Komano, Jun; Morishita, Kazuhiro; Okayama, Akihiko; Tsubouchi, Hirohito

    2007-01-01

    HIV-1 is an etiological agent of AIDS. One of the targets of the current anti-HIV-1 combination chemotherapy, called highly active antiretroviral therapy (HAART), is HIV-1 protease (PR), which is responsible for the processing of viral structural proteins and, therefore, essential for virus replication. Here, we describe an in vitro transcription/translation-based method of phenotyping HIV-1 PR. In this system, both substrate and PR for the assay can be prepared by in vitro transcription/translation. Protease activity is estimated by the cleavage of a substrate, as measured by enzyme-linked immunosorbent assay (ELISA). This assay is safe, rapid, and requires no special facility to be carried out. Our rapid phenotyping method of HIV-1 PR may help evaluate drug resistance, useful when choosing an appropriate therapeutic regiment, and could potentially facilitate the discovery of new drugs effective against HIV-1 PR. PMID:17634600

  8. Purinergic Receptors: Key Mediators of HIV-1 Infection and Inflammation

    PubMed Central

    Swartz, Talia H.; Dubyak, George R.; Chen, Benjamin K.

    2015-01-01

    Human immunodeficiency virus type 1 (HIV-1) causes a chronic infection that afflicts more than 30 million individuals worldwide. While the infection can be suppressed with potent antiretroviral therapies, individuals infected with HIV-1 have elevated levels of inflammation as indicated by increased T cell activation, soluble biomarkers, and associated morbidity and mortality. A single mechanism linking HIV-1 pathogenesis to this inflammation has yet to be identified. Purinergic receptors are known to mediate inflammation and have been shown to be required for HIV-1 infection at the level of HIV-1 membrane fusion. Here, we review the literature on the role of purinergic receptors in HIV-1 infection and associated inflammation and describe a role for these receptors as potential therapeutic targets. PMID:26635799

  9. Advances in non-peptidomimetic HIV protease inhibitors.

    PubMed

    Pang, X; Liu, Z; Zhai, G

    2014-06-01

    HIV protease plays a crucial role in the viral life cycle. It can cleave a series of heptamers in the viral Gag and GagPol precursor proteins to generate mature infectious virus particles. Successful inhibition of the protease will prevent this maturation step and hence block the spreading of HIV. However, the rapid emergence of drug resistance makes it urgent to develop new HIV protease inhibitors to combat the global disease. Besides, poor oral bioavailability, unacceptable side effects, high treatment cost and pill burden also trouble the application of HIV protease inhibitors. In such situations, non-peptidomimetic HIV protease inhibitors have drawn an increasing interest as a potential therapeutic option due to their small molecular weight, favorable bioavailability, high stability in vivo, low resistance and cost of production. In this review, we present the recent advances in non-peptidomimetic HIV protease inhibitors. Their design strategies, biological activities, resistance profiles, as well as clinical application will also be discussed. PMID:24533811

  10. Insulin resistance, lipodystrophy and cardiometabolic syndrome in HIV/AIDS.

    PubMed

    Galescu, Ovidiu; Bhangoo, Amrit; Ten, Svetlana

    2013-06-01

    HIV associated insulin resistance, lipodistrophy and cardiometabolic syndrome have been extensively studied and continue to be the scope of much research. There is compelling evidence that both the HIV itself and the therapeutical regimes are major contributors to all of these associated comorbidities. HIV has increasingly been recognized as a disease of accelerated aging, manifested by increased progression of vascular disease and cellular markers of aging. The antiretroviral medication can increase insulin resistance and cause lipotoxocity and HIV-associated lipodystrophy leading to cardiovascular pathology. In this article we review the pathogenesis, management, and prevention of the long-term complications of HIV and its therapies, including cardiovascular disease, lipodystrophy, and insulin resistance along with the growing focus on biomarkers to predict development of end-organ disease. Through a focused literature search we review the established evidence, the developing research about the treatment strategies in treated HIV infection as well as identify potential areas for future research. PMID:23700046

  11. HIV-1 differentially modulates autophagy in neurons and astrocytes.

    PubMed

    Mehla, Rajeev; Chauhan, Ashok

    2015-08-15

    Autophagy, a lysosomal degradative pathway that maintains cellular homeostasis, has emerged as an innate immune defense against pathogens. The role of autophagy in the deregulated HIV-infected central nervous system (CNS) is unclear. We have found that HIV-1-induced neuro-glial (neurons and astrocytes) damage involves modulation of the autophagy pathway. Neuro-glial stress induced by HIV-1 led to biochemical and morphological dysfunctions. X4 HIV-1 produced neuro-glial toxicity coupled with suppression of autophagy, while R5 HIV-1-induced toxicity was restricted to neurons. Rapamycin, a specific mTOR inhibitor (autophagy inducer) relieved the blockage of the autophagy pathway caused by HIV-1 and resulted in neuro-glial protection. Further understanding of the regulation of autophagy by cytokines and chemokines or other signaling events may lead to recognition of therapeutic targets for neurodegenerative diseases. PMID:26198926

  12. Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes

    PubMed Central

    Heesters, Balthasar A.; Lindqvist, Madelene; Vagefi, Parsia A.; Scully, Eileen P.; Schildberg, Frank A.; Altfeld, Marcus; Walker, Bruce D.; Kaufmann, Daniel E.; Carroll, Michael C.

    2015-01-01

    Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans. PMID:26623655

  13. A review of vaccines for HIV prevention.

    PubMed

    Mwau, Matilu; McMichael, Andrew J

    2003-01-01

    HIV/AIDS has become the most devastating pandemic in recorded history. It has killed 40 million people in the last 20 years and the World Health Organisation estimated that at least 14,000 new infections occurred daily in 2001. There will be up to 100 million new infections in the next 10 years (for current updates, visit http://www.unaids.org/epidemic_update/). Most HIV infections occur in the developing world, and the adverse social and economic impact of the HIV/AIDS pandemic, particularly in the developing world, is unprecedented. Highly active antiretroviral therapy (HAART) has had significant effects on HIV/AIDS in the developed world. The drugs have acted to prolong survival, reduce the viral load, and to alleviate suffering. However, the incidence of side effects and resistance is high and the drugs are unaffordable and unavailable in the developing world. HAART regimens are difficult to comply with. Public health efforts to modify the behaviour, attitude and culture that accelerate the spread of HIV/AIDS have had only modest success. There is urgent need for a prophylactic and/or therapeutic HIV vaccine. This is a review of the obstacles and current trends in HIV vaccine development. PMID:12516046

  14. Hemiparesis in HIV infection. Rehabilitation approach.

    PubMed

    O'Dell, M W; Sasson, N L

    1992-10-01

    Persons with acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection demonstrate a wide array of central nervous system impairments and may be at a significantly increased risk for cerebrovascular disease. Cerebrovascular disease can be the first manifestation of HIV infection and may be associated with a treatable etiology. Anticipating more referrals for HIV-related physical disability, we detail the rehabilitation management of three persons with HIV infection and hemiparesis. Onset of hemiparesis ranged from just before to 24 months after an AIDS-defining illness. No specific underlying etiology was identified in two of three patients, consistent with previous observations. Rehabilitation interventions included lower and upper extremity orthoses, assistive devices to aid gait and activities of daily living, therapeutic exercise and use of antispasticity medication. All patients made at least mild, temporary gains in functional status. Survival ranged from 3 to >6 months from initial contact with rehabilitation services. Neurologic and nonneurologic considerations in the rehabilitation of persons with HIV infection are discussed. We conclude that selected individuals with HIV infection and hemiparesis can benefit from rehabilitation intervention. HIV infection should be considered in any young adult presenting with stroke. PMID:1388977

  15. Human Immunodeficiency Virus (HIV) Latency: The Major Hurdle in HIV Eradication

    PubMed Central

    Tyagi, Mudit; Bukrinsky, Michael

    2012-01-01

    Failure of highly active antiretroviral therapy to eradicate the human immunodeficiency virus (HIV), even in patients who suppress the virus to undetectable levels for many years, underscores the problems associated with fighting this infection. The existence of persistent infection in certain cellular and anatomical reservoirs appears to be the major hurdle in HIV eradication. The development of therapeutic interventions that eliminate or limit the latent viral pools or prevent the reemergence of the viruses from producing cells will therefore be required to enhance the effectiveness of current antiretroviral strategies. To achieve this goal, there is a pressing need to understand HIV latency at the molecular level to design novel and improved therapies to either eradicate HIV or find a functional cure in which patients could maintain a manageable viral pool without AIDS in the absence of antiretroviral therapy. The integrated proviral genome remains transcriptionally silent for a long period in certain subsets of T cells. This ability to infect cells latently helps HIV to establish a persistent infection despite strong humoral and cellular immune responses against the viral proteins. The main purpose of this report is to provide a general overview of the HIV latency. We will describe the hurdles being faced in eradicating latent HIV proviruses. We will also briefly discuss the ongoing strategies aimed toward curing HIV infection. PMID:22692576

  16. Humoral immunity in HIV-1 exposure: cause or effect of HIV resistance?

    PubMed

    Lopalco, Lucia

    2004-04-01

    More than two decades since its discovery, human immunodeficiency virus (HIV) epidemic is still a major burden for health, social and economical reasons on all over the world. Despite the huge effort in basic and applied research, aimed to control virus spread and to design effective therapeutic strategies, an HIV vaccine is not available yet and current therapeutics approaches cannot prevent the infection. To date, both host genetic repertoire, innate and acquired immune responses, viral mutation or attenuation have been invoked to explain the higher or lower individual susceptibility to the infection. The existence of some people somewhat "immune" from infection, despite dealing with repeated HIV exposure, as well as the extremely slow disease progression in some HIV infected individuals, offers valuable clues to elucidate mechanisms underlying natural HIV resistance. Strikingly, both such cohorts, the so-called Exposed Seronegative (ESN, EU, HEPS) and the Slow Progressor (SP, LTNP, LTS) individuals have common immune responses, e.g. the generation of neutralising antibodies directed against common targets, which can play a protective role in virus entry and/or spread. This review focuses on naturally occurring humoral responses to HIV exposure/infection. Moreover, whether such antibodies are induced in response to a peculiar scenario of HIV infection or are generated in the context of an individual innate mode to clear virus infection is a puzzling question, which will be addressed here. The comprehension of mechanisms of natural resistance to HIV infection may have implications for the identification of anti-viral novel strategies and in particular for the development of innovative diagnostics, therapeutics and vaccine design. PMID:15078177

  17. HIV infection and advanced age emerging epidemiological, clinical, and management issues.

    PubMed

    Manfredi, Roberto

    2004-01-01

    While the mean age of HIV/AIDS patients at first diagnosis is progressively rising, no updated epidemiological estimates, controlled clinical data, and randomized therapeutic trials, are available regarding clinical and laboratory response to antiretroviral therapy, safety of anti-HIV compounds and their associations, potential drug-drug interactions, short- and long-term toxicity, consequences on underlying disorders, or interactions with concomitant pharmacological regimens, in the elderly. The life expectancy of HIV-infected persons treated with highly active antiretroviral therapy (HAART) now approximates that of general population matched for age, while also AIDS definition itself has lost most of its epidemiological and clinical significance, thanks to the immunoreconstitution resulting from the large-scale use of potent HAART regimens. The increased survival of HIV-infected patients, the late recognition of other subjects with missed or delayed diagnosis are responsible for a further expected rise of mean age of HIV-infected individuals, so that the patient population aged 60-70 years or more is expected to increase in coming years. Unfortunately, the majority of therapeutic trials involving antiretroviral therapy, as well as antimicrobial chemoprophylaxis for AIDS-related opportunistic complications, have advanced age and/or concurrent end-organ disorders among main exclusion criteria, or the design of these studies does not allow to extrapolate data regarding older patients, compared with younger ones. The very limited data presently available seem to demonstrate that HAART has a virological efficacy in the elderly comparable with that of younger adults, but immunological recovery is often slower and blunted, although several studies clearly demonstrated that thymic function is preserved until late adult age. When facing an HIV-infected patient with advanced age, health care givers have to pay careful attention to eventual end-organ disorders, all possible pharmacological interactions, overlapping toxicity due to concurrent drug administration. All these issues may significantly interfere with HAART activity, patient's adherence to prescribed medications, and frequency and severity of untoward effects. The guidelines of antiretroviral therapy and those of treatment and prophylaxis of AIDS-related diseases deserve appropriate updates, paralleling the increasing mean age of HIV-infected population. Moreover, epidemiological figures need an increased focus on older age, while clinical trials specifically targeting on the elderly population are mandatory to have reliable data on all aspects of HAART administration in advanced age. PMID:15164725

  18. DYNAMIC EQUILIBRIUM IN THERAPEUTIC SITUATIONS.

    ERIC Educational Resources Information Center

    CARROLL, EDWARD J.

    THE CONCEPT OF DYNAMIC EQUILIBRIUM IS USED TO EXAMINE THE OCCURRENCE OF CHANGE IN A THERAPEUTIC INTERVIEW AND TO PROPOSE A THEORY OF THERAPY. BY ANALYZING THE WORKINGS OF THE PSYCHOSOCIAL SYSTEM THROUGH THE GENERAL SYSTEMS THEORY, IT IS POSSIBLE TO SEE HOW CHANGE OCCURS IN AN INDIVIDUAL FAMILY OR COMMUNITY. APPLIED TO A FAMILY INTERVIEW, THE MODEL…

  19. Stabilized therapeutic radiopharmaceutical complexes

    SciTech Connect

    Wolfangel, R.G.

    1993-06-15

    A method of preparing a stable radioactive therapeutic radiopharmaceutical composition is described which comprises providing a therapeutic amount of an alpha- or beta-emitting radionuclide forming a complex between said therapeutic amount of said radionuclide and a ligand in an aqueous medium, and then lyophilizing the medium so as to form a stable radioactive therapeutic radiopharmaceutical composition.

  20. Induction of HIV-1-specific immunity after vaccination with apoptotic HIV-1/murine leukemia virus-infected cells.

    PubMed

    Spetz, Anna-Lena; Sörensen, Anna Smed; Walther-Jallow, Lilian; Wahren, Britta; Andersson, Jan; Holmgren, Lars; Hinkula, Jorma

    2002-11-15

    Ag-presenting dendritic cells present viral Ags to T cells after uptake of apoptotic bodies derived from virus-infected cells in vitro. However, it is unclear whether apoptotic virus-infected cells are capable of generating immunity in vivo. In this study, we show that inoculation of mice with apoptotic HIV-1/murine leukemia virus (MuLV)-infected cells induces HIV-1-specific immunity. Immunization with apoptotic HIV-1/MuLV-infected syngeneic splenocytes resulted in strong Nef-specific CD8(+) T cell proliferation and p24-induced CD4(+) and CD8(+) T cell proliferation as well as IFN-gamma production. In addition, systemic IgG and IgA as well as mucosa-associated IgA responses were generated. Moreover, mice vaccinated with apoptotic HIV-1/MuLV cells were protected against challenge with live HIV-1/MuLV-infected cells, whereas mice vaccinated with apoptotic noninfected or MuLV-infected splenocytes remained susceptible to HIV-1/MuLV. These data show that i.p. immunization with apoptotic HIV-1-infected cells induces high levels of HIV-1-specific systemic immunity, primes for mucosal immunity, and induces protection against challenge with live HIV-1-infected cells in mice. These findings may have implications for the development of therapeutic and prophylactic HIV-1 vaccines. PMID:12421957

  1. Laser palliation of the HIV+ patient

    NASA Astrophysics Data System (ADS)

    Convissar, Robert A.

    2003-12-01

    Many oral manifestations of HIV infection can be used as markers for degree of immunosupression. These manifestations may be treated with antibiotics, analgesics, and antineoplastics, which may interact and interfere with antiviral agents used to treat the disease, and possibly exacerbate it. Dentists will see more HIV-infected patients as medical research transforms this disease into a chronic illness. Lasers have been shown to be effective instruments in palliation of oral manifestations of HIV infection. The use of lasers to palliate the painful symptoms of three oral manifestations of HIV infection is described. The advantages and benefits to both patient and dentist will be discussed. The paper does not address the use of lasers as a modality to treat or cure HIV infection -- only to palliate some of its symptoms.

  2. [Pain therapy in HIV-associated polyneuropathy].

    PubMed

    Husstedt, I W; Böckenholt, S; Kammer-Suhr, B; Evers, S

    2001-04-01

    Only some patients with HIV-infection receive an adequate pain therapy. In later stages of HIV-infection up to 50% 6 of patients perform extraordinary doctor visits because of pain. Principally primary and secondary neuromanifestations of HIV-infection have to be differentiated. Rare forms of HIV-associated polyneuropathies represent mononeuropathy or mononeuritis multiple acute and chronic inflammatory demyelinating polyneuropathy and polyneuropathy caused by opportunistic infections. HIV-associated distal-symmetric polyneuropathy represents the most common form during HIV-infection with a prevalence up to 50%. Typical clinical symptoms and signs are pain, hyp- and dysaesthesia, diminuted deep tendon reflexes, motor deficits and autonomic disturbances. Always neurological examination and neurophysiologic investigation on the sural and peronaeal nerve are necessary for monitoring progression of polyneuropathy and as basics before starting antiretroviral therapy with neurotoxic substances. According to momentary opinion, HIV-associated distal-symmetric polyneuropathy represents no indication for antiretroviral therapy. Symptomatic therapy includes antiepileptic medication as gabapentine, antidepressive drugs as amitiptyline and additionally retarded opiates. Depressive disorders ma y accentuate pain problems a n d need psychotherapeutic and thymoleptic therapy. Special problems occur when neurotoxic substances evoke or deteriorate polyneuropathy. In these cases an individual therapeutic proceeding about continuation or discontinuation of neurotoxic medication is necessary. Symptoms of myopathy during HIV-infection are muscle pain, elevation of CK and typical changes of motor units detected by electromyography. In most cases biopsy is necessary for diagnosis of specific forms of HN-associated myopathy. HIV-associated polymyositis is treated by non-steroid analgetics, corticoids, immunoglobulines and plasmapheresis, myopathy induced by neurotoxic medication analogous to polyneuropathy. PMID:11810345

  3. Polygyny and HIV in Malawi

    PubMed Central

    Reniers, Georges; Tfaily, Rania

    2011-01-01

    We review the relationship between polygyny and HIV and identify a positive individual-level correlation, and a negative ecological correlation. We subsequently examine two mechanisms that contribute to the individual-level correlation. First, we find that men in polygynous marriages have more extramarital sex than men in monogamous unions (both in terms of self reports and in terms of spousal reports of the suspicion of adultery). Second, we find evidence of adverse selection of HIV positive women into polygynous unions via an investigation of the relationship between marriage order and polygyny status. We conclude with reflections about possible explanations for the distinct individual and ecological correlations. PMID:21949484

  4. Gut Microbiota Linked to Sexual Preference and HIV Infection.

    PubMed

    Noguera-Julian, Marc; Rocafort, Muntsa; Guillén, Yolanda; Rivera, Javier; Casadellà, Maria; Nowak, Piotr; Hildebrand, Falk; Zeller, Georg; Parera, Mariona; Bellido, Rocío; Rodríguez, Cristina; Carrillo, Jorge; Mothe, Beatriz; Coll, Josep; Bravo, Isabel; Estany, Carla; Herrero, Cristina; Saz, Jorge; Sirera, Guillem; Torrela, Ariadna; Navarro, Jordi; Crespo, Manel; Brander, Christian; Negredo, Eugènia; Blanco, Julià; Guarner, Francisco; Calle, Maria Luz; Bork, Peer; Sönnerborg, Anders; Clotet, Bonaventura; Paredes, Roger

    2016-03-01

    The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n = 156) and Stockholm (n = 84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction. PMID:27077120

  5. Gut Microbiota Linked to Sexual Preference and HIV Infection

    PubMed Central

    Noguera-Julian, Marc; Rocafort, Muntsa; Guillén, Yolanda; Rivera, Javier; Casadellà, Maria; Nowak, Piotr; Hildebrand, Falk; Zeller, Georg; Parera, Mariona; Bellido, Rocío; Rodríguez, Cristina; Carrillo, Jorge; Mothe, Beatriz; Coll, Josep; Bravo, Isabel; Estany, Carla; Herrero, Cristina; Saz, Jorge; Sirera, Guillem; Torrela, Ariadna; Navarro, Jordi; Crespo, Manel; Brander, Christian; Negredo, Eugènia; Blanco, Julià; Guarner, Francisco; Calle, Maria Luz; Bork, Peer; Sönnerborg, Anders; Clotet, Bonaventura; Paredes, Roger

    2016-01-01

    The precise effects of HIV-1 on the gut microbiome are unclear. Initial cross-sectional studies provided contradictory associations between microbial richness and HIV serostatus and suggested shifts from Bacteroides to Prevotella predominance following HIV-1 infection, which have not been found in animal models or in studies matched for HIV-1 transmission groups. In two independent cohorts of HIV-1-infected subjects and HIV-1-negative controls in Barcelona (n = 156) and Stockholm (n = 84), men who have sex with men (MSM) predominantly belonged to the Prevotella-rich enterotype whereas most non-MSM subjects were enriched in Bacteroides, independently of HIV-1 status, and with only a limited contribution of diet effects. Moreover, MSM had a significantly richer and more diverse fecal microbiota than non-MSM individuals. After stratifying for sexual orientation, there was no solid evidence of an HIV-specific dysbiosis. However, HIV-1 infection remained consistently associated with reduced bacterial richness, the lowest bacterial richness being observed in subjects with a virological-immune discordant response to antiretroviral therapy. Our findings indicate that HIV gut microbiome studies must control for HIV risk factors and suggest interventions on gut bacterial richness as possible novel avenues to improve HIV-1-associated immune dysfunction. PMID:27077120

  6. HIV-Induced Epigenetic Alterations in Host Cells.

    PubMed

    Abdel-Hameed, Enass A; Ji, Hong; Shata, Mohamed Tarek

    2016-01-01

    Human immunodeficiency virus (HIV), a member of the Retroviridae family, is a positive-sense, enveloped RNA virus. HIV, the causative agent of acquired immunodeficiency syndrome (AIDS) has two major types, HIV-1 and HIV-2 In HIV-infected cells the single stranded viral RNA genome is reverse transcribed and the double-stranded viral DNA integrates into the cellular DNA, forming a provirus. The proviral HIV genome is controlled by the host epigenetic regulatory machinery. Cellular epigenetic regulators control HIV latency and reactivation by affecting the chromatin state in the vicinity of the viral promoter located to the 5' long terminal repeat (LTR) sequence. In turn, distinct HIV proteins affect the epigenotype and gene expression pattern of the host cells. HIV-1 infection of CD4(+) T cells in vitro upregulated DNMT activity and induced hypermethylation of distinct cellular promoters. In contrast, in the colon mucosa and peripheral blood mononuclear cells from HIV-infected patients demethylation of the FOXP3 promoter was observed, possibly due to the downregulation of DNA methyltransferase 1. For a curative therapy of HIV infected individuals and AIDS patients, a combination of antiretroviral drugs with epigenetic modifying compounds have been suggested for the reactivation of latent HIV-1 genomes. These epigenetic drugs include histone deacetylase inhibitors (HDACI), histone methyltransferase inhibitors (HMTI), histone demethylase inhibitors, and DNA methyltransferase inhibitors (DNMTI). PMID:26659262

  7. Therapeutic options or antiretroviral anarchy?

    PubMed

    Mascolini, M

    1999-01-01

    The number of drug combinations being used to treat HIV infections may produce a public health nightmare by creating multidrug resistance. The issue of whether to use aggressive multidrug combinations early in the infectious cycle or whether to delay treatment as long as possible remains controversial and unresolved. The use of viral markers to track disease progression is discussed. Tables illustrate the relationships between CD4+ counts and opportunistic infections, disease progression, and long-term viral load reduction. The effectiveness of different drugs combinations is discussed. Results of various clinical trials are presented. PMID:11366158

  8. A review of nanotechnological approaches for the prophylaxis of HIV/AIDS

    PubMed Central

    Date, Abhijit A.; Destache, Christopher J.

    2013-01-01

    Successful treatment and control of HIV/AIDS is one of the biggest challenges of 21st century. More than 33 million individuals are infected with HIV worldwide and more than 2 million new cases of HIV infection have been reported. The situation demands development of effective prevention strategies to control the pandemic of AIDS. Due to lack of availability of an effective HIV vaccine, antiretroviral drugs and nucleic acid therapeutics like siRNA have been explored for HIV prophylaxis. Clinical trials shave shown that antiretroviral drugs, tenofovir and emtricitabine can offer some degree of HIV prevention. However, complete prevention of HIV infection has not been achieved yet. Nanotechnology has brought a paradigm shift in the diagnosis, treatment and prevention of many diseases. The current review discusses potential of various nanocarriers such as dendrimers, polymeric nanoparticles, liposomes, lipid nanocarriers, drug nanocrystals, inorganic nanocarriers and nanofibers in improving efficacy of various modalities available for HIV prophylaxis. PMID:23726227

  9. Characterizing HIV epidemiology in stable couples in Cambodia, the Dominican Republic, Haiti, and India.

    PubMed

    Chemaitelly, H; Abu-Raddad, L J

    2016-01-01

    Using a set of statistical methods and HIV mathematical models applied on nationally representative Demographic and Health Survey data, we characterized HIV serodiscordancy patterns and HIV transmission dynamics in stable couples (SCs) in four countries: Cambodia, the Dominican Republic, Haiti, and India. The majority of SCs affected by HIV were serodiscordant, and about a third of HIV-infected persons had uninfected partners. Overall, nearly two-thirds of HIV infections occurred in individuals in SCs, but only about half of these infections were due to transmissions within serodiscordant couples. The majority of HIV incidence in the population occurred through extra-partner encounters in SCs. There is similarity in HIV epidemiology in SCs between these countries and countries in sub-Saharan Africa, despite the difference in scale of epidemics. It appears that HIV epidemiology in SCs may share similar patterns globally, possibly because it is a natural 'spillover' effect of HIV dynamics in high-risk populations. PMID:25916602

  10. A novel small-molecule inhibitor of HIV-1 entry

    PubMed Central

    Heredia, Alonso; Latinovic, Olga S; Barbault, Florent; de Leeuw, Erik PH

    2015-01-01

    Background Antiretroviral therapy has transformed HIV-1 infection into a managed condition with near-normal life expectancy. However, a significant number of patients remain with limited therapeutic options due to HIV-1 resistance, side effects, or drug costs. Further, it is likely that current drugs will not retain efficacy, due to risks of side effects and transmitted resistance. Results We describe compound 5660386 (3-ethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-2H-indol-2-ylidene)-1-propen-1-yl]-1,3-benzothiazol-3-ium) as a novel inhibitor of HIV-1 entry. Compound 5660386 inhibits HIV-1 entry in cell lines and primary cells, binds to HIV-1 envelope protein, and inhibits the interaction of GP120 to CD4. Further, compound 5660386 showed a unique and broad-range activity against primary HIV-1 isolates from different subtypes and geographical areas. Conclusion Development of small-molecule entry inhibitors of HIV-1 such as 5660386 may lead to novel classes of anti-HIV-1 therapeutics. These inhibitors may be particularly effective against viruses resistant to current antiretroviral drugs and could have potential applications in both treatment and prevention. PMID:26491257

  11. Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone-deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects?

    PubMed

    Iovino, M; Triggiani, V; Giagulli, V A; Iovine, N; Licchelli, B; Resta, F; Sabbà, C; Tafaro, E; Solimando, A; Tommasicchio, A; Guastamacchia, E

    2011-06-01

    The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 µg/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 µg GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion. PMID:20843274

  12. HIV protease inhibitors disrupt astrocytic glutamate transporter function and neurobehavioral performance

    PubMed Central

    Vivithanaporn, Pornpun; Asahchop, Eugene L.; Acharjee, Shaona; Baker, Glen B.; Power, Christopher

    2016-01-01

    Objective: The neurotoxic actions of the HIV protease inhibitors, amprenavir (APV) and lopinavir (LPV) were investigated. Design: With combination antiretroviral therapy (cART), HIV-infected persons exhibit neurocognitive impairments, raising the possibility that cART might exert adverse central nervous system (CNS) effects. We examined the effects of LPV and APV using in-vitro and in-vivo assays of CNS function. Methods: Gene expression, cell viability and amino-acid levels were measured in human astrocytes, following exposure to APV or LPV. Neurobehavioral performance, amino-acid levels and neuropathology were examined in HIV-1 Vpr transgenic mice after treatment with APV or LPV. Results: Excitatory amino-acid transporter-2 (EAAT2) expression was reduced in astrocytes treated with LPV or APV, especially LPV (P < 0.05), which was accompanied by reduced intracellular l-glutamate levels in LPV-treated cells (P < 0.05). Treatment of astrocytes with APV or LPV reduced the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 (P < 0.05) although cell survival was unaffected. Exposure of LPV to astrocytes augmented glutamate-evoked transient rises in [Cai] (P < 0.05). Vpr mice treated with LPV showed lower concentrations of l-glutamate, l-aspartate and l-serine in cortex compared with vehicle-treated mice (P < 0.05). Total errors in T-maze assessment were increased in LPV and APV-treated animals (P < 0.05). EAAT2 expression was reduced in the brains of protease inhibitor-treated animals, which was associated with gliosis (P < 0.05). Conclusion: These results indicated that contemporary protease inhibitors disrupt astrocyte functions at therapeutic concentrations with enhanced sensitivity to glutamate, which can lead to neurobehavioral impairments. ART neurotoxicity should be considered in future therapeutic regimens for HIV/AIDS. PMID:26558720

  13. HIV Structural Database

    National Institute of Standards and Technology Data Gateway

    SRD 102 HIV Structural Database (Web, free access)   The HIV Protease Structural Database is an archive of experimentally determined 3-D structures of Human Immunodeficiency Virus 1 (HIV-1), Human Immunodeficiency Virus 2 (HIV-2) and Simian Immunodeficiency Virus (SIV) Proteases and their complexes with inhibitors or products of substrate cleavage.

  14. HIV and AIDS

    MedlinePlus

    ... I Help a Friend Who Cuts? HIV and AIDS KidsHealth > For Teens > HIV and AIDS Print A A A Text Size What's in ... in human history. HIV causes a condition called acquired immunodeficiency syndrome — better known as AIDS . HIV destroys a type ...

  15. Infections in solid organ transplantation in special situations: HIV-infection and immigration.

    PubMed

    Miró, José M; Blanes, Marino; Norman, Francesca; Martín-Dávila, Pilar

    2012-03-01

    With the advent of highly active antiretroviral therapy in 1996, patients infected with HIV are now living longer and are dying from illnesses other than acquired immunodeficiency syndrome (AIDS). Liver disease due to chronic hepatitis C is now a leading cause of mortality among HIV-infected patients in the developed world. The prevalence of end-stage kidney or heart disease is also increasing among HIV-infected patients. For these patients, solid organ transplantation (SOT) is the only therapeutic option and HIV infection alone is not a contraindication. Accumulated experience in North America and Europe in the last few years indicates that 3- to 5-year survival in liver recipients coinfected with HIV and HCV is lower than that of HCV-monoinfected recipients. Conversely, 3- to 5-year survival of non-HCV-coinfected liver recipients and kidney recipients was similar to that of HIV-negative patients. Infections in the post-transplant period in HIV-infected recipients are similar to those seen in HIV-negative patients, although the incidence of some of them (e.g. tuberculosis and fungal infections) is higher. In the USA and Europe the number of immigrants from areas with endemic geographically-restricted infections has increased significantly in recent years. These changes in the population profile have led to an increase in the percentage of foreign-born transplant candidates and donors. Organ transplant recipients may develop endemic diseases in four ways: Transmission through the graft; de novo infection; reactivation of dormant infection; and reinfection/reactivation in a healthy graft. In foreign-born recipients, there is the possibility of endemic infections manifesting in the post-transplant period as a consequence of immunosuppression. These issues are modifying the criteria for donor selection and have also expanded pre-transplant screening for infectious diseases in both donors and transplant recipients. Some infectious diseases such as Chagas disease, endemic fungal infections, tuberculosis (which could be multidrug- or extensively drug-resistant according the origin of the recipient), leishmaniasis and other viral and parasitic diseases should always be considered in the differential diagnosis of post-transplant infections in foreign-born recipients. PMID:22542039

  16. Mucosal Immunology of HIV Infection

    PubMed Central

    Xu, Huanbin; Wang, Xiaolei; Veazey, Ronald S.

    2013-01-01

    Summary Recent advances in the immunology, pathogenesis, and prevention of human immunodeficiency virus (HIV) infection continue to reveal clues to the mechanisms involved in the progressive immunodeficiency attributed to infection but more importantly have shed light on the correlates of immunity to infection and disease progression. HIV selectively infects, eliminates, and/or dysregulates several key cells of the human immune system, thwarting multiple arms of the host immune response, and inflicting severe damage to mucosal barriers, resulting in tissue infiltration of ‘symbiotic’ intestinal bacteria and viruses that essentially become opportunistic infections promoting systemic immune activation. This leads to activation and recruitment or more target cells for perpetuating HIV infection, resulting in persistent, high level viral replication in lymphoid tissues, rapid evolution of resistant strains, and continued evasion of immune responses. However, vaccine studies and studies of spontaneous controllers are finally providing correlates of immunity from protection and disease progression, including virus-specific CD4+ T-cell responses, binding antibodies, innate immune responses, and generation of antibodies with potent antibody-dependent cell-mediated cytotoxicity activity. Emerging correlates of immunity indicate that prevention of HIV infection may be possible through effective vaccine strategies that protect and stimulate key regulatory cells and immune responses in susceptible hosts. Further, immune therapies specifically directed towards boosting specific aspects of the immune system may eventually lead to a cure for HIV-infected patients. PMID:23772612

  17. T-Cell Signaling in HIV-1 Infection

    PubMed Central

    Abbas, Wasim; Herbein, Georges

    2013-01-01

    HIV exploits the T-cell signaling network to gain access to downstream cellular components, which serves as effective tools to break the cellular barriers. Multiple host factors and their interaction with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. HIV-1 proteins gp120, Nef, Tat and Vpr alter the T-cell signaling pathways by activating multiple transcription factors including NF-?B, Sp1 and AP-1. HIV-1 evades the immune system by developing a multi-pronged strategy. Additionally, HIV-1 encoded proteins influence the apoptosis in the host cell favoring or blocking T-cell apoptosis. Thus, T-cell signaling hijacked by viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection. Here, we summarize past and present studies on HIV-1 T-cell signaling with special focus on the possible role of T cells in facilitating viral infection and pathogenesis PMID:23986795

  18. The role of enacted stigma in parental HIV disclosure among HIV-infected parents in China

    PubMed Central

    Qiao, Shan; Li, Xiaoming; Zhou, Yuejiao; Shen, Zhiyong; Tang, Zhenzhu; Stanton, Bonita

    2015-01-01

    Existing studies have delineated that HIV-infected parents face numerous challenges in disclosing their HIV infection to the children (“parental HIV disclosure”), and practices of parental HIV disclosure vary with individual characteristics, family contexts, and social environment. Using cross-sectional data from 1254 HIV-infected parents who had children aged 5–16 years in southwest China, the current study examined the association of parental HIV disclosure with mental health and medication adherence among parents and explored the possible effect of enacted stigma on such association. Multivariate analysis of variance revealed that parents who had experienced disclosure to children reported higher level enacted stigma, worse mental health conditions, and poorer medication adherence. Enacted stigma partially mediated the associations between disclosure and both mental health and medication adherence after controlling basic background characteristics. Our findings highlight the importance of providing appropriate disclosure-related training and counseling service among HIV-infected parents. In a social setting where HIV-related stigma is still persistent, disclosure intervention should address and reduce stigma and discrimination in the practice of parental HIV disclosure. PMID:26616123

  19. The role of enacted stigma in parental HIV disclosure among HIV-infected parents in China.

    PubMed

    Qiao, Shan; Li, Xiaoming; Zhou, Yuejiao; Shen, Zhiyong; Tang, Zhenzhu; Stanton, Bonita

    2015-01-01

    Existing studies have delineated that HIV-infected parents face numerous challenges in disclosing their HIV infection to the children ("parental HIV disclosure"), and practices of parental HIV disclosure vary with individual characteristics, family contexts, and social environment. Using cross-sectional data from 1254 HIV-infected parents who had children aged 5-16 years in southwest China, the current study examined the association of parental HIV disclosure with mental health and medication adherence among parents and explored the possible effect of enacted stigma on such association. Multivariate analysis of variance revealed that parents who had experienced disclosure to children reported higher level enacted stigma, worse mental health conditions, and poorer medication adherence. Enacted stigma partially mediated the associations between disclosure and both mental health and medication adherence after controlling basic background characteristics. Our findings highlight the importance of providing appropriate disclosure-related training and counseling service among HIV-infected parents. In a social setting where HIV-related stigma is still persistent, disclosure intervention should address and reduce stigma and discrimination in the practice of parental HIV disclosure. PMID:26616123

  20. Review: [corrected] The changing face of the HIV epidemic in sub-Saharan Africa.

    PubMed

    Mutevedzi, Portia C; Newell, Marie-Louise

    2014-09-01

    The widespread roll-out of antiretroviral therapy (ART) has substantially changed the face of human immunodeficiency virus (HIV). Timely initiation of ART in HIV-infected individuals dramatically reduces mortality and improves employment rates to levels prior to HIV infection. Recent findings from several studies have shown that ART reduces HIV transmission risk even with modest ART coverage of the HIV-infected population and imperfect ART adherence. While condoms are highly effective in the prevention of HIV acquisition, they are compromised by low and inconsistent usage; male medical circumcision substantially reduces HIV transmission but uptake remains relatively low; ART during pregnancy, delivery and breastfeeding can virtually eliminate mother-to-child transmission but implementation is challenging, especially in resource-limited settings. The current HIV prevention recommendations focus on a combination of preventions approach, including ART as treatment or pre- or post-exposure prophylaxis together with condoms, circumcision and sexual behaviour modification. Improved survival in HIV-infected individuals and reduced HIV transmission risk is beginning to result in limited HIV incidence decline at population level and substantial increases in HIV prevalence. However, achievements in HIV treatment and prevention are threatened by the challenges of lifelong adherence to preventive and therapeutic methods and by the ageing of the HIV-infected cohorts potentially complicating HIV management. Although current thinking suggests prevention of HIV transmission through early detection of infection immediately followed by ART could eventually result in elimination of the HIV epidemic, controversies remain as to whether we can treat our way out of the HIV epidemic. PMID:24976370

  1. Identification of Host Micro RNAs That Differentiate HIV-1 and HIV-2 Infection Using Genome Expression Profiling Techniques.

    PubMed

    Devadas, Krishnakumar; Biswas, Santanu; Haleyurgirisetty, Mohan; Ragupathy, Viswanath; Wang, Xue; Lee, Sherwin; Hewlett, Indira

    2016-01-01

    While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs) in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s) for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR) arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death. PMID:27144577

  2. Identification of Host Micro RNAs That Differentiate HIV-1 and HIV-2 Infection Using Genome Expression Profiling Techniques

    PubMed Central

    Devadas, Krishnakumar; Biswas, Santanu; Haleyurgirisetty, Mohan; Ragupathy, Viswanath; Wang, Xue; Lee, Sherwin; Hewlett, Indira

    2016-01-01

    While human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) share many similar traits, major differences in pathogenesis and clinical outcomes exist between the two viruses. The differential expression of host factors like microRNAs (miRNAs) in response to HIV-1 and HIV-2 infections are thought to influence the clinical outcomes presented by the two viruses. MicroRNAs are small non-coding RNA molecules which function in transcriptional and post-transcriptional regulation of gene expression. MiRNAs play a critical role in many key biological processes and could serve as putative biomarker(s) for infection. Identification of miRNAs that modulate viral life cycle, disease progression, and cellular responses to infection with HIV-1 and HIV-2 could reveal important insights into viral pathogenesis and provide new tools that could serve as prognostic markers and targets for therapeutic intervention. The aim of this study was to elucidate the differential expression profiles of host miRNAs in cells infected with HIV-1 and HIV-2 in order to identify potential differences in virus-host interactions between HIV-1 and HIV-2. Differential expression of host miRNA expression profiles was analyzed using the miRNA profiling polymerase chain reaction (PCR) arrays. Differentially expressed miRNAs were identified and their putative functional targets identified. The results indicate that hsa-miR 541-3p, hsa-miR 518f-3p, and hsa-miR 195-3p were consistently up-regulated only in HIV-1 infected cells. The expression of hsa-miR 1225-5p, hsa-miR 18a* and hsa-miR 335 were down modulated in HIV-1 and HIV-2 infected cells. Putative functional targets of these miRNAs include genes involved in signal transduction, metabolism, development and cell death. PMID:27144577

  3. Exosomes: Implications in HIV-1 Pathogenesis.

    PubMed

    Madison, Marisa N; Okeoma, Chioma M

    2015-07-01

    Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. The role of exosomes in viral pathogenesis, especially human immunodeficiency virus type 1 [HIV-1] is beginning to unravel. Recent research reports suggest that exosomes from various sources play important but different roles in the pathogenesis of HIV-1. From these reports, it appears that the source of exosomes is the defining factor for the exosomal effect on HIV-1. In this review, we will describe how HIV-1 infection is modulated by exosomes and in turn how exosomes are targeted by HIV-1 factors. Finally, we will discuss potentially emerging therapeutic options based on exosomal cargos that may have promise in preventing HIV-1 transmission. PMID:26205405

  4. Exosomes: Implications in HIV-1 Pathogenesis

    PubMed Central

    Madison, Marisa N.; Okeoma, Chioma M.

    2015-01-01

    Exosomes are membranous nanovesicles of endocytic origin that carry host and pathogen derived genomic, proteomic, and lipid cargos. Exosomes are secreted by most cell types into the extracellular milieu and are subsequently internalized by recipient cells. Upon internalization, exosomes condition recipient cells by donating their cargos and/or activating various signal transduction pathways, consequently regulating physiological and pathophysiological processes. The role of exosomes in viral pathogenesis, especially human immunodeficiency virus type 1 [HIV-1] is beginning to unravel. Recent research reports suggest that exosomes from various sources play important but different roles in the pathogenesis of HIV-1. From these reports, it appears that the source of exosomes is the defining factor for the exosomal effect on HIV-1. In this review, we will describe how HIV-1 infection is modulated by exosomes and in turn how exosomes are targeted by HIV-1 factors. Finally, we will discuss potentially emerging therapeutic options based on exosomal cargos that may have promise in preventing HIV-1 transmission. PMID:26205405

  5. Microbiome alterations in HIV infection a review.

    PubMed

    Williams, Brett; Landay, Alan; Presti, Rachel M

    2016-05-01

    Recent developments in molecular techniques have allowed researchers to identify previously uncultured organisms, which has propelled a vast expansion of our knowledge regarding our commensal microbiota. Interest in the microbiome specific to HIV grew from earlier findings suggesting that bacterial translocation from the intestines is the cause of persistent immune activation despite effective viral suppression with antiretroviral therapy (ART). Studies of SIV infected primates have demonstrated that Proteobacteria preferentially translocate and that mucosal immunity can be restored with probiotics. Pathogenic SIV infection results in a massive expansion of the virome, whereas non-pathogenic SIV infection does not. Human HIV infected cohorts have been shown to have microbiota distinctive from that of HIV negative controls and efforts to restore the intestinal microbiome via probiotics have often had positive results on host markers. The microbiota of the genital tract may play a significant role in acquisition and transmission of HIV. Modification of commensal microbial communities likely represents an important therapeutic adjunct to treatment of HIV. Here we review the literature regarding human microbiome in HIV infection. PMID:26945815

  6. [Status of HIV-infections 2005].

    PubMed

    Potthoff, Anja; Brockmeyer, Norbert H

    2005-09-01

    The course of HIV infection has changed dramatically since the beginning of the epidemic. In Germany, 19 antiretrovirally active substances are available. They prevent viral penetration into the cell, inhibit the reverse transcriptase or the protease that are necessary to release infectious viral particles. According to German-Austrian therapy guidelines highly active antiretroviral therapy (HAART) should be started at the onset of HIV-related symptoms and/or when the CD4 cell count is < 350/microl. Patients should be treated in specialized centers because of the complexity of HIV infection and its management. For monitoring, CD4 cell counts and viral load are determined. Potential reasons for therapeutic failure include drug interactions, resistance, or compliance problems. Although HIV infection is often compared to insulin-dependent diabetes mellitus, psychological and social impact on HIV patients is still high. Increasing viral multi-drug resistance, long-term toxicity like lipodystrophy, osteoporosis and cardiovascular disease are only some problems HIV-infected patients are facing in the next years. In Germany, 600-700 patients still die of AIDS every year. PMID:16170674

  7. HIV/dendritic cell interaction: consequences in the pathogenesis of HIV infection.

    PubMed

    Barroca, Pedro; Calado, Marta; Azevedo-Pereira, José M

    2014-01-01

    Dendritic cells are professional antigen-presenting cells and key elements of both innate and adaptive immunity. Tissues like skin and mucosal epithelium, more exposed to the environment, are particularly rich in dendritic cells. Given that HIV is mainly transmitted through mucosal surfaces, the cellular mechanisms governing the initial interactions between HIV and dendritic cells are crucial for establishing systemic infection in a new host. Upon HIV/dendritic cell interaction, viral particles carried by exposed dendritic cells are transmitted to activated CD4+ T-cells during the antigen presentation process. Such dendritic cell/T-cell transmission of HIV plays an important role in the viral dissemination and immune dysregulation associated with HIV infection, subverting the bridge between innate and adaptive immune responses. Thus, defining how HIV interacts with dendritic cells remains a critical area of research, with downstream implications in the knowledge of pathogenic mechanisms, transmission, vaccine development, and molecular targets for therapeutic intervention. In this review we will, therefore, delve into the mechanisms involved in HIV/dendritic cell interactions that govern viral persistence, cellular trafficking, transmission and restriction, compiling the present knowledge on these subjects and attempting to postulate how some uncertain pathways may shape up and intertwine. PMID:25350531

  8. Side Effects of HIV Medicines: HIV and Lactic Acidosis

    MedlinePlus

    Side Effects of HIV Medicines HIV and Lactic Acidosis (Last updated 1/7/2016; last reviewed 1/7/ ... blood. The condition is a rare but serious side effect of some HIV medicines. All HIV medicines in ...

  9. Side Effects of HIV Medicines: HIV and Rash

    MedlinePlus

    Side Effects of HIV Medicines HIV and Rash (Last updated 1/7/2016; last reviewed 1/7/2016) ... other medicines. Rash is among the most common side effects of HIV medicines. Rash due to HIV medicines ...

  10. Doctors Report Groundbreaking HIV-To-HIV Organ Transplants

    MedlinePlus

    ... medlineplus/news/fullstory_158039.html Doctors Report Groundbreaking HIV-to-HIV Organ Transplants One donor supplied a kidney to ... News) -- Trailblazing liver and kidney transplants from an HIV-positive donor to HIV-positive recipients were announced ...

  11. New drug regimens for HIV in pregnancy and a national strategic plan to manage HIV: A South African perspective.

    PubMed

    Ngene, Nnabuike C; Moodley, Jagidesa

    2015-10-01

    In South Africa, new drug regimens (WHO treatment Option B) used to manage HIV infection in pregnancy and the national strategic plan on HIV have resulted in improved health outcomes. Among these outcomes are reductions in the following: mother-to-child transmission (MTCT) of HIV to 2.4%; maternal deaths attributable to HIV; and adverse reactions due to antiretroviral therapy (ART). The present article describes these new drug regimens and the national strategic HIV management plan, as well as their challenges and the implications of improved health outcomes. Such outcomes imply that further decreases in MTCT of HIV, and HIV attributable maternal deaths are possible if potential challenges are addressed and treatment option B+ offered. A confidential enquiry into each case of MTCT is advocated to reduce vertical transmission rates to zero levels. PMID:26433498

  12. Oligonucleotide conjugates for therapeutic applications

    PubMed Central

    Winkler, Johannes

    2013-01-01

    Insufficient pharmacokinetic properties and poor cellular uptake are the main hurdles for successful therapeutic development of oligonucleotide agents. The covalent attachment of various ligands designed to influence the biodistribution and cellular uptake or for targeting specific tissues is an attractive possibility to advance therapeutic applications and to expand development options. In contrast to advanced formulations, which often consist of multiple reagents and are sensitive to a variety of preparation conditions, oligonucleotide conjugates are defined molecules, enabling structure-based analytics and quality control techniques. This review gives an overview of current developments of oligonucleotide conjugates for therapeutic applications. Attached ligands comprise peptides, proteins, carbohydrates, aptamers and small molecules, including cholesterol, tocopherol and folic acid. Important linkage types and conjugation methods are summarized. The distinct ligands directly influence biochemical parameters, uptake machanisms and pharmacokinetic properties. PMID:23883124

  13. Therapeutic and recreational methadone cardiotoxicity.

    PubMed

    Lusetti, Monia; Licata, Manuela; Silingardi, Enrico; Reggiani Bonetti, Luca; Palmiere, Cristian

    2016-04-01

    Several classes of drugs have been associated with an increased risk of cardiovascular disease and occurrence of arrhythmias potentially involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart possibly due to methadone use. 60 cases were included in the study in total and were divided into three groups (therapeutic methadone users: 20 cases, recreational methadone users: 20 cases, and sudden death group in subjects who had never taken methadone: 20 cases). Autopsies, histology, biochemistry and toxicology were performed in all cases. Macroscopic and microscopic investigation results in therapeutic methadone users were similar to those observed in sudden, unexpected deaths in non-methadone users. In recreational methadone consumers, macroscopic and microscopic examination of the heart failed to provide results consistent with acute or chronic myocardial or coronary damage, thereby corroborating the hypothesis of death most likely following respiratory depression. PMID:26859696

  14. Effect of mimetic CDK9 inhibitors on HIV-1 activated transcription

    PubMed Central

    Van Duyne, Rachel; Guendel, Irene; Jaworski, Elizabeth; Sampey, Gavin; Klase, Zachary; Chen, Hao; Zeng, Chen; Kovalskyy, Dmytro; el Kouni, Mahmoud H.; Lepene, Benjamin; Patanarut, Alexis; Nekhai, Sergei; Price, David H.; Kashanchi, Fatah

    2013-01-01

    Potent antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic manageable disease; however drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study we utilized a combination of structure based analysis of Cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket which showed the most stable binding site (Cavity 1) using in silico analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using in silico searches of a chemical library, followed by cell based biological assays. Using these methods we obtained the first generation mimetic drugs and tested these compounds on HIV-1 LTR activated transcription. Using biological assays followed by similar in silico analysis to find a 2nd generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the 2nd generation mimetic against various viral isolates, and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2-/-γc-/- with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using in silico analysis. PMID:23247501

  15. Therapeutic touch with adolescent psychiatric patients.

    PubMed

    Hughes, P P; Meize-Grochowski, R; Harris, C N

    1996-03-01

    Seven hospitalized, adolescent psychiatric patients who received a total of 31 Therapeutic Touch treatments over two 2-week periods were interviewed about their experience. Findings from the interviews were categorized within 2 overarching themes-the therapeutic relationship and the body/mind connection. The study participants enjoyed the Therapeutic Touch, and in fact, they wanted more of it. This research shows the possibility of Therapeutic Touch as a nursing intervention with adolescent psychiatric patients if all care is taken to obtain their consent and to provide them with a safe environment for touch therapy. PMID:8698982

  16. The two human CXCR4 isoforms display different HIV receptor activities: consequences for the emergence of X4 strains.

    PubMed

    Duquenne, Charline; Psomas, Christina; Gimenez, Sandrine; Guigues, Adeline; Carles, Marie-Josée; Barbuat, Claudine; Lavigne, Jean-Philippe; Sotto, Albert; Reynes, Jacques; Guglielmi, Paul; Mettling, Clément; François, Vincent; Corbeau, Pierre

    2014-10-15

    CXCR4 is a chemokine receptor that plays key roles with its specific ligand, CXCL12, in stem cell homing and immune trafficking. It is also used as a coreceptor by some HIV-1 strains (X4 strains), whereas other strains (R5 strains) use an alternative coreceptor, CCR5. X4 strains mainly emerge at late stages of the infection and are linked to disease progression. Two isoforms of this coreceptor have been described in humans: CXCR4-A and CXCR4-B, corresponding to an unspliced and a spliced mRNA, respectively. In this study, we show that CXCR4-B, but not CXCR4-A, mediates an efficient HIV-1 X4 entry and productive infection. Yet, the chemotactic activity of CXCL12 on both isoforms was similar. Furthermore, HIV-R5 infection favored CXCR4-B expression over that of CXCR4-A. In vitro infection with an R5 strain increased CXCR4-B/CXCR4-A mRNA ratio in PBMCs, and this ratio correlated with HIV RNA plasma level in R5-infected individuals. In addition, the presence of the CXCR4-B isoform favored R5 to X4 switch more efficiently than did CXCR4-A in vitro. Hence, the predominance of CXCR4-B over CXCR4-A expression in PBMCs was linked to the ability of circulating HIV-1 strains to use CXCR4, as determined by genotyping. These data suggest that R5 to X4 switch could be favored by R5 infection-induced overexpression of CXCR4-B. Finally, we achieved a specific small interfering RNA-mediated knockdown of CXCR4-B. This represents a proof of concept for a possible gene-therapeutic approach aimed at blocking the HIV coreceptor activity of CXCR4 without knocking down its chemotactic activity. PMID:25230750

  17. Influence of HIV and HCV on T cell antigen presentation and challenges in the development of vaccines.

    PubMed

    John, Mina; Gaudieri, Silvana

    2014-01-01

    Some of the central challenges for developing effective vaccines against HIV and hepatitis C virus (HCV) are similar. Both infections are caused by small, highly mutable, rapidly replicating RNA viruses with the ability to establish long-term chronic pathogenic infection in human hosts. HIV has caused 60 million infections globally and HCV 180 million and both viruses may co-exist among certain populations by virtue of common blood-borne, sexual, or vertical transmission. Persistence of both pathogens is achieved by evasion of intrinsic, innate, and adaptive immune defenses but with some distinct mechanisms reflecting their differences in evolutionary history, replication characteristics, cell tropism, and visibility to mucosal versus systemic and hepatic immune responses. A potent and durable antibody and T cell response is a likely requirement of future HIV and HCV vaccines. Perhaps the single biggest difference between the two vaccine design challenges is that in HCV, a natural model of protective immunity can be found in those who resolve acute infection spontaneously. Such spontaneous resolvers exhibit durable and functional CD4(+) and CD8(+) T cell responses (Diepolder et al., 1995; Cooper et al., 1999; Thimme et al., 2001; Grakoui et al., 2003; Lauer et al., 2004; Schulze Zur Wiesch et al., 2012). However, frequent re-infection suggests partial or lack of protective immunity against heterologous HCV strains, possibly indicative of the degree of genetic diversity of circulating HCV genotypes and subtypes. There is no natural model of protective immunity in HIV, however, studies of "elite controllers," or individuals who have durably suppressed levels of plasma HIV RNA without antiretroviral therapy, has provided the strongest evidence for CD8(+) T cell responses in controlling viremia and limiting reservoir burden in established infection. Here we compare and contrast the specific mechanisms of immune evasion used by HIV and HCV, which subvert adaptive human leukocyte antigen (HLA)-restricted T cell immunity in natural infection, and the challenges these pose for designing effective preventative or therapeutic vaccines. PMID:25352836

  18. What Is HIV/AIDS?

    MedlinePlus

    ... Subscribe Translate Text Size Print What Is HIV/AIDS? Human Immunodeficiency Virus (HIV) HIV stands for human ... use the HIV Testing & Care Services Locator. GO Acquired Immunodeficiency syndrome (AIDS) AIDS stands for acquired immunodeficiency syndrome. AIDSis ...

  19. Therapeutic liver repopulation for phenylketonuria.

    PubMed

    Harding, Cary O; Gibson, K M

    2010-12-01

    Problems with long-term dietary compliance in phenylketonuria (PKU) necessitate the development of alternative treatment approaches. Therapeutic liver repopulation with phenylalanine hydroxylase (PAH)-expressing cells following hepatocyte or haematopoietic stem cell transplantation has been investigated as a possible novel treatment approach for PKU. Successful therapeutic liver repopulation requires both a stimulus for liver regeneration at the time of cell transplantation and a selective growth advantage for the PAH+ donor cells. Unfortunately, wild-type PAH+ hepatocytes do not enjoy any growth advantage over PAH- cells. Successful correction of hyperphenylalaninemia following therapeutic liver repopulation has been accomplished only in an animal model that yields a selective advantage for the donor cells. Haematopoietic stem cell (HSC)-mediated therapeutic liver repopulation has not been reported in any hyperphenylalaninemic system, and the success of HSC-mediated liver repopulation for PKU may be limited by the slow kinetics of this approach. If therapeutic liver repopulation is to be employed successfully in humans with PKU, an effective method of providing a selective growth advantage for the donor cells must be developed. If this can be achieved, liver repopulation with 10-20% wild-type hepatocytes will likely completely normalize Phe clearance in individuals with PKU. PMID:20495959

  20. Small molecule inhibitors targeting HIV-1 reverse transcriptase dimerization.

    PubMed

    Grohmann, Dina; Corradi, Valentina; Elbasyouny, Mira; Baude, Annika; Horenkamp, Florian; Laufer, Sandra D; Manetti, Fabrizio; Botta, Maurizio; Restle, Tobias

    2008-04-14

    The enzymatic activities of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are strictly correlated with the dimeric forms of this vital retroviral enzyme. Accordingly, the development of inhibitors targeting the dimerization of RT represents a promising alternative antiviral strategy. Based on mutational studies, we applied a structure-based ligand design approach generating pharmacophoric models of the large subunit connection subdomain to possibly identify small molecules from the ASINEX database, which might interfere with the RT subunit interaction. Docking studies of the selected compounds identified several candidates, which were initially tested in an in vitro subunit association assay. One of these molecules (MAS0) strongly reduced the association of the two RT subunits p51 and p66. Most notably, the compound simultaneously inhibited both the polymerase as well as the RNase H activity of the retroviral enzyme, following preincubation with t(1/2) of about 2 h, indicative of a slow isomerization step. This step most probably represents a shift of the RT dimer equilibrium from an active to an inactive conformation. Taken together, to the best of our knowledge, this study represents the first successful rational screen for a small molecule HIV RT dimerization inhibitor, which may serve as attractive hit compound for the development of novel therapeutic agents. PMID:18318036

  1. Bone Marrow Abnormalities in HIV Disease

    PubMed Central

    Dhurve, Sharad A.; Dhurve, Alka S.

    2013-01-01

    Introduction Hematological abnormalities are a common complication of HIV infection. Bone marrow abnormalities occur in all stages of HIV infection. Present work was carried out to study the bone marrow abnormalities in patients with HIV/AIDS. Methods 160 patients of HIV +ve were included in the study. A complete blood count, relevant biochemical investigations, CD4 counts were done, besides a thorough history and clinical examination. HIV positive patients were classified as those having AIDS and those without AIDS according to NACO criteria. Bone marrow examination was performed for indication of anemia, leucopenia, pancytopenia and thrombocytopenia. Results As per CDC criteria 59.81% patients had AIDS in 107 patients. The most common hematological abnormality was anemia, seen in 93.12% patients. Bone marrow was normocellular in 79.06% of non-AIDS and 79.68% of AIDS, hypocellular in 13.95% of non-AIDS and 12.5% of AIDS, hypercellular in 06.97% of non-AIDS and 07.81 % of AIDS patients. Dysplasia was statistically and significantly associated with anemia. For myelodysplasia in bone marrow in HIV patients we noted granulocytic dysplasia in 4.65% in Non – AIDS and 14.06% AIDS patients. Erythroid dysplasia was found in 9.30% in Non – AIDS, 12.5% in AIDS group. Thrombocytopenia was seen in 4 cases of ART (4.93%) and 3 cases (4.68%) of AIDS group. Abnormal cells like plasma cell, histiocyte and toxic granule were found in bone marrow. Conclusions Myelodysplasia was more common in AIDS than in non AIDS patients. Granulocytic series is most commonly associated with evidence of dysplasia. Anemia in HIV patients can be a good clinical indicator to predict and access the underlying immune status. Thus bone marrow study is imperative to methodically observe and follow clinical and laboratory aberration in such patients in order to improve our diagnostic and therapeutic skills pertinent to HIV/AIDS. PMID:23795271

  2. Thymic HIV-2 Infection Uncovers Posttranscriptional Control of Viral Replication in Human Thymocytes

    PubMed Central

    Matoso, Paula; Foxall, Russell B.; Tendeiro, Rita; Pires, Ana R.; Carvalho, Tânia; Pinheiro, Ana I.; Soares, Rui S.

    2014-01-01

    ABSTRACT A unique HIV-host equilibrium exists in untreated HIV-2-infected individuals. This equilibrium is characterized by low to undetectable levels of viremia throughout the disease course, despite the establishment of disseminated HIV-2 reservoirs at levels comparable to those observed in untreated HIV-1 infection. Although the clinical spectrum is similar in the two infections, HIV-2 infection is associated with a much lower rate of CD4 T-cell decline and has a limited impact on the mortality of infected adults. Here we investigated HIV-2 infection of the human thymus, the primary organ for T-cell production. Human thymic tissue and suspensions of total or purified CD4 single-positive thymocytes were infected with HIV-2 or HIV-1 primary isolates using either CCR5 or CXCR4 coreceptors. We found that HIV-2 infected both thymic organ cultures and thymocyte suspensions, as attested to by the total HIV DNA and cell-associated viral mRNA levels. Nevertheless, thymocytes featured reduced levels of intracellular Gag viral protein, irrespective of HIV-2 coreceptor tropism and cell differentiation stage, in agreement with the low viral load in culture supernatants. Our data show that HIV-2 is able to infect the human thymus, but the HIV-2 replication cycle in thymocytes is impaired, providing a new model to identify therapeutic targets for viral replication control. IMPORTANCE HIV-1 infects the thymus, leading to a decrease in CD4 T-cell production that contributes to the characteristic CD4 T-cell loss. HIV-2 infection is associated with a very low rate of progression to AIDS and is therefore considered a unique naturally occurring model of attenuated HIV disease. HIV-2-infected individuals feature low to undetectable plasma viral loads, in spite of the numbers of circulating infected T cells being similar to those found in patients infected with HIV-1. We assessed, for the first time, the direct impact of HIV-2 infection on the human thymus. We show that HIV-2 is able to infect the thymus but that the HIV-2 replication cycle in thymocytes is impaired. We propose that this system will be important to devise immunotherapies that target viral production, aiding the design of future therapeutic strategies for HIV control. PMID:25473058

  3. CD4 mimetics sensitize HIV-1-infected cells to ADCC

    PubMed Central

    Richard, Jonathan; Veillette, Maxime; Brassard, Nathalie; Iyer, Shilpa S.; Roger, Michel; Martin, Loïc; Pazgier, Marzena; Schön, Arne; Freire, Ernesto; Routy, Jean-Pierre; Smith, Amos B.; Park, Jongwoo; Jones, David M.; Courter, Joel R.; Melillo, Bruno N.; Kaufmann, Daniel E.; Hahn, Beatrice H.; Permar, Sallie R.; Haynes, Barton F.; Madani, Navid; Sodroski, Joseph G.; Finzi, Andrés

    2015-01-01

    HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection. PMID:25941367

  4. HIV/AIDS in eastern and southern Africa.

    PubMed

    Akeroyd, A V

    1994-06-01

    "This article reviews some recent key books on HIV/AIDS in Africa. It does so by examining the debates relating to the extent and possible future development of HIV/AIDS referring to the discussions about demographic, economic and social impacts in especially eastern and southern Africa. It explores the so-called doomsday scenarios and addresses themes linked to the important and increasing attention being paid to the gendered aspects of HIV/AIDS." PMID:12346402

  5. Sentinel surveillance for HIV-2 infection in high-risk US populations.

    PubMed Central

    Onorato, I M; O'Brien, T R; Schable, C A; Spruill, C; Holmberg, S D

    1993-01-01

    OBJECTIVES. We conducted sentinel surveillance in persons practicing behaviors known to transmit retroviruses to determine the US presence and extent of human immunodeficiency virus type 2 (HIV-2). METHODS. Sentinel surveillance for HIV-2 was conducted by testing 31,533 anonymous blood specimens from patients at sexually transmitted disease clinics, injecting drug users at treatment centers, and clients at HIV counseling and testing sites in 14 US cities where West African immigrants often settle. Specimens were tested by HIV-1 and HIV-2 whole virus and synthetic peptide enzyme immunoassay and confirmed by HIV-1 and HIV-2 Western blots. RESULTS. Nearly 10% of 31,533 sera were positive for HIV-1. Two heterosexual Black male sexually transmitted disease patients were infected with HIV-2. One of the HIV-2 positive specimens did not cross-react on HIV-1 enzyme immunoassay screening. One client had antibodies consistent with malarial infection in West Africa; the other, who had syphilis, did not have antibodies to malaria or to any of 20 arboviruses present in Africa. CONCLUSIONS. Clinics serving clients from HIV-2 endemic areas should test persons practicing risk behaviors for both HIV-1 and HIV-2. Sentinel surveillance for HIV-2 serves as an early warning system for the possible spread of this virus in the United States. PMID:8460726

  6. DEFINING HOPE AMONG HIV-Positive AFRICAN AMERICAN FEMALES.

    PubMed

    Kennedy, Toshua W

    2015-01-01

    Human immunodeficiency virus (HIV) affects heterosexual African American females (AAFs) with morbidity and mortality rates higher than females of any other race, accounting for thefourth largest number of HIV infections in the United States. Defining hope is importantfor understanding and therapeutic use of the concept in AAFs with HITA literature review exploring uses for this concept among HIV-positive AAFs, and a dimensional analysis, revealed positive and negative influences for hope. Tuthful and positive messages need to be developed for this population. PMID:26211301

  7. RNA-based Therapeutics- Current Progress and Future Prospects

    PubMed Central

    Burnett, John C.; Rossi, John J.

    2012-01-01

    Summary Recent advances of biological drugs have broadened the scope of therapeutic targets for a variety of human diseases. This holds true for dozens of RNA-based therapeutics currently under clinical investigation for diseases ranging from genetic disorders to HIV infection to various cancers. These emerging drugs, which include therapeutic ribozymes, aptamers, and small interfering RNAs (siRNAs), demonstrate the unprecedented versatility of RNA. However, RNA is inherently unstable, potentially immunogenic, and typically requires a delivery vehicle for efficient transport to the targeted cells. These issues have hindered the clinical progress of some RNA-based drugs and have contributed to mixed results in clinical testing. Nevertheless, promising results from recent clinical trials suggest that these barriers may be overcome with improved synthetic delivery carriers and chemical modifications of the RNA therapeutics. This review focuses on the clinical results of siRNA, RNA aptamer, and ribozyme therapeutics and the prospects for future successes. PMID:22284355

  8. Cryptococcal meningitis and SLE: a diagnostic and therapeutic challenge.

    PubMed

    Khairullah, S; Sulaiman, H; Yahya, F; Jasmin, R; Cheah, T E; Sockalingam, S; Bick, J; Chin Teck, N G

    2014-01-01

    Cryptococcal meningitis is a rare occurrence in systemic lupus erythematosus (SLE). The risk factors of developing this infection are duration of SLE, intensity of glucocorticoid use, and SLE-related intrinsic immune abnormalities. Early recognition and prompt initiation of antifungals can prevent complications and improve survival. There is a dearth of evidence with regards to optimal treatment of cryptococcosis in non-HIV infected and non-transplant patients. The general consensus is to follow treatment guidelines for HIV-positive patients with cryptococcal meningitis. We describe a girl with active SLE and cryptococcal meningitis, and discuss the diagnostic and therapeutic challenges faced in this case. PMID:25326406

  9. Canadian consensus statement on HIV and its transmission in the context of criminal law

    PubMed Central

    Loutfy, Mona; Tyndall, Mark; Baril, Jean-Guy; Montaner, Julio SG; Kaul, Rupert; Hankins, Catherine

    2014-01-01

    INTRODUCTION: A poor appreciation of the science related to HIV contributes to an overly broad use of the criminal law against individuals living with HIV in cases of HIV nondisclosure. METHOD: To promote an evidence-informed application of the law in Canada, a team of six Canadian medical experts on HIV and transmission led the development of a consensus statement on HIV sexual transmission, HIV transmission associated with biting and spitting, and the natural history of HIV infection. The statement is based on a literature review of the most recent and relevant scientific evidence (current as of December 2013) regarding HIV and its transmission. It has been endorsed by >70 additional Canadian HIV experts and the Association of Medical Microbiology and Infectious Disease Canada. RESULTS: Scientific and medical evidence clearly indicate that HIV is difficult to transmit during sex. For the purpose of informing the justice system, the per-act possibility of HIV transmission through sex, biting or spitting is described along a continuum from low possibility, to negligible possibility, to no possibility of transmission. This possibility takes into account the impact of factors such as the type of sexual acts, condom use, antiretroviral therapy and viral load. Dramatic advances in HIV therapy have transformed HIV infection into a chronic manageable condition. DISCUSSION: HIV physicians and scientists have a professional and ethical responsibility to assist those in the criminal justice system to understand and interpret the science regarding HIV. This is critical to prevent miscarriage of justice and to remove unnecessary barriers to evidence-based HIV prevention strategies. PMID:25285108

  10. Toll gates: An emerging therapeutic target.

    PubMed

    Maheaswari, Rajendran; Sivasankar, Kiruthika; Subbarayan, Sathya

    2014-01-01

    Innate immune system forms the first line of defense against microbial infections, as it exerts an immediate response. Innate immunity works through Toll-like receptors (TLRs) which functions as primary sensors of pathogens. TLR activates multiple signaling cascades leading to the induction of genes responsible for the release of inflammatory cytokines and type I interferon. Thus, they induce antimicrobial responses and also have an instructive role in adaptive immunity. However, TLR-mediated inflammation is said to be responsible for many of the destructive host responses in inflammatory diseases like periodontitis. Hence, therapeutics targeting TLRs are being used to treat disease such as HIV, Hepatitis B, asthma etc. Recently, synthetic TLR agonists are tried as novel vaccine adjuvant in treating periodontal diseases. This paper reviews the scope of TLR-based therapeutics in treating periodontitis. PMID:25624622

  11. Diagnosing and treating HIV-associated sensory neuropathy: a global perspective.

    PubMed

    Cherry, Catherine L; Wadley, Antonia L; Kamerman, Peter R

    2016-04-01

    HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV and remains highly prevalent even with modern HIV management strategies, causing debilitating pain in millions globally. We review HIV-SN diagnosis and management. We suggest most HIV-SN cases are easily recognized using clinical screening tools, with physician assessment and/or specialized testing prioritized for atypical cases. Management aims to prevent further nerve damage and optimize symptom control. Symptom relief is difficult and rarely complete, with a lack of proven pharmacological strategies. Work is needed to clarify optimal use of available medications. This includes understanding the marked placebo effect in HIV-SN analgesic trials and exploring 'responder phenotypes'. Limited data support nondrug strategies including hypnosis, meditation, psychology, physical activity and a positive therapeutic relationship. PMID:26988147

  12. Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis

    PubMed Central

    Arcinue, Cheryl A.; Bartsch, Dirk-Uwe; El-Emam, Sharif Y.; Ma, Feiyan; Doede, Aubrey; Sharpsten, Lucie; Gomez, Maria Laura; Freeman, William R.

    2015-01-01

    Purpose To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula) compared with age-matched HIV-negative controls. Methods Cohort of patients with known HIV under CART (combination Antiretroviral Therapy) treatment were examined with a flood-illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT) to assess retinal layers and retinal thickness. Results Twenty-four eyes of 12 patients (n = 6 HIV-positive and 6 HIV-negative) were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior), the HIV group had significantly less mean cone photoreceptor density compared with age-matched controls (difference range, 4,308–6,872 cones/mm2). A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative) was included in the retinal thickness measurements and retinal layer segmentation with the SD-OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea). We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer) was also significantly thickened in all the different locations scanned compared with HIV-negative controls. Conclusion Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age-matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low-grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis. PMID:26244973

  13. Activation of HIV-1 with Nanoparticle-Packaged Small-Molecule Protein Phosphatase-1-Targeting Compound

    PubMed Central

    Smith, Kahli A.; Lin, Xionghao; Bolshakov, Oleg; Griffin, James; Niu, Xiaomei; Kovalskyy, Dmytro; Ivanov, Andrey; Jerebtsova, Marina; Taylor, Robert E.; Akala, Emmanuel; Nekhai, Sergei

    2015-01-01

    Complete eradication of HIV-1 infection is impeded by the existence of latent HIV-1 reservoirs in which the integrated HIV-1 provirus is transcriptionally inactive. Activation of HIV-1 transcription requires the viral Tat protein and host cell factors, including protein phosphatase-1 (PP1). We previously developed a library of small compounds that targeted PP1 and identified a compound, SMAPP1, which induced HIV-1 transcription. However, this compound has a limited bioavailability in vivo and may not be able to reach HIV-1-infected cells and induce HIV-1 transcription in patients. We packaged SMAPP1 in polymeric polyethylene glycol polymethyl methacrylate nanoparticles and analyzed its release and the effect on HIV-1 transcription in a cell culture. SMAPP1 was efficiently packaged in the nanoparticles and released during a 120-hr period. Treatment of the HIV-1-infected cells with the SMAPP1-loaded nanoparticles induced HIV-1 transcription. Thus, nanoparticles loaded with HIV-1-targeting compounds might be useful for future anti-HIV-1 therapeutics. PMID:26839837

  14. Activation of HIV-1 with Nanoparticle-Packaged Small-Molecule Protein Phosphatase-1-Targeting Compound.

    PubMed

    Smith, Kahli A; Lin, Xionghao; Bolshakov, Oleg; Griffin, James; Niu, Xiaomei; Kovalskyy, Dmytro; Ivanov, Andrey; Jerebtsova, Marina; Taylor, Robert E; Akala, Emmanuel; Nekhai, Sergei

    2015-01-01

    Complete eradication of HIV-1 infection is impeded by the existence of latent HIV-1 reservoirs in which the integrated HIV-1 provirus is transcriptionally inactive. Activation of HIV-1 transcription requires the viral Tat protein and host cell factors, including protein phosphatase-1 (PP1). We previously developed a library of small compounds that targeted PP1 and identified a compound, SMAPP1, which induced HIV-1 transcription. However, this compound has a limited bioavailability in vivo and may not be able to reach HIV-1-infected cells and induce HIV-1 transcription in patients. We packaged SMAPP1 in polymeric polyethylene glycol polymethyl methacrylate nanoparticles and analyzed its release and the effect on HIV-1 transcription in a cell culture. SMAPP1 was efficiently packaged in the nanoparticles and released during a 120-hr period. Treatment of the HIV-1-infected cells with the SMAPP1-loaded nanoparticles induced HIV-1 transcription. Thus, nanoparticles loaded with HIV-1-targeting compounds might be useful for future anti-HIV-1 therapeutics. PMID:26839837

  15. Mechanisms and Modifications of Naturally Occurring Host Defense Peptides for Anti-HIV Microbicide Development

    PubMed Central

    Eade, Colleen R.; Wood, Matthew P.; Cole, Alexander M.

    2014-01-01

    Despite advances in the treatment of HIV infection, heterosexual transmission of HIV remains high, and vaccines to prevent HIV acquisition have been unfruitful. Vaginal microbicides, on the other hand, have demonstrated considerable potential for HIV prevention, and a variety of compounds have been screened for their activity and safety as anti-HIV microbicides. Among these are the naturally occurring host defense peptides, small peptides from diverse lineages with intrinsic antiviral activity. Naturally occurring host defense peptides with anti-HIV activity are promising candidates for vaginal microbicide development. Their structural variance and accompanying mechanistic diversity provide a wide range of inhibitors whose antiviral activity can be exerted at nearly every stage of the HIV lifecycle. Additionally, peptide modification has been explored as a method for improving the anti-HIV activity of host defense peptides. Structure- and sequence-based alterations have achieved varying success in improving the potency and specificity of anti-HIV peptides. Overall, peptides have been discovered or engineered to inhibit HIV with therapeutic indices of >1000, encouraging their advancement toward clinical trials. Here we review the naturally occurring anti-HIV host defense peptides, demonstrating their breadth of mechanistic diversity, and exploring approaches to enhance and optimize their activity in order to expedite their development as safe and effective anti-HIV vaginal microbicides. PMID:22264047

  16. HIV-1 Prevention for HIV-1 Serodiscordant Couples

    PubMed Central

    Curran, Kathryn; Baeten, Jared M.; Coates, Thomas J.; Kurth, Ann; Mugo, Nelly R.

    2013-01-01

    A substantial proportion of HIV-1-infected individuals in sub-Saharan Africa are in stable relationships with HIV-1-uninfected partners, and HIV-1 serodiscordant couples thus represent an important target population for HIV-1 prevention. Couple-based HIV-1 testing and counseling facilitates identification of HIV-1 serodiscordant couples, counseling about risk reduction, and referrals to HIV-1 treatment, reproductive health services, and support services. Maximizing HIV-1 prevention for HIV-1 serodiscordant couples requires a combination of strategies, including counseling about condoms, sexual risk, fertility, contraception, and the clinical and prevention benefits of antiretroviral therapy (ART) for the HIV-1-infected partner; provision of clinical care and ART for the HIV-1-infected partner; antenatal care and services to prevent mother to child transmission for HIV-1- infected pregnant women; male circumcision for HIV-1-uninfected men; and, pending guidelines and demonstration projects, oral pre-exposure prophylaxis (PrEP) for HIV-1-uninfected partners. PMID:22415473

  17. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

    PubMed

    Nakagawa, Saki; Miki, Yasuhiro; Miyashita, Minoru; Hata, Shuko; Takahashi, Yayoi; Rai, Yoshiaki; Sagara, Yasuaki; Ohi, Yasuyo; Hirakawa, Hisashi; Tamaki, Kentaro; Ishida, Takanori; Watanabe, Mika; Suzuki, Takashi; Ohuchi, Noriaki; Sasano, Hironobu

    2016-01-01

    Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and ?SMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC. PMID:26715212

  18. [Probiotics: history, definition, requirements and possible therapeutic applications].

    PubMed

    Montalto, Massimo; Arancio, Fabiola; Izzi, Donatello; Cuoco, Lucio; Curigliano, Valentina; Manna, Raffaele; Gasbarrini, Giovanni

    2002-01-01

    The ingestion of probiotics is associated with various beneficial effects on human health and modifies the physiological homeostasis of the intestinal flora. Probiotics are microorganisms with some particular characteristics: human origin, safety in human use, bile and acid resistance, survival in the intestine, at least temporary colonization of the human gut, adhesion to the mucosa and bacteriocine production. Thanks to these characteristics, probiotics block the invasion of human intestinal cells by the enteroinvasive bacteria. Furthermore, they should be able to stimulate and modulate the intestinal immune response, and to protect and stabilize the mucosal barrier. Finally, the efficacy of probiotics should be evident and documented with valid studies. All their properties should be maintained during processing and storage. Probiotics are usually used to protect the host from pathogens. With regard to this, they are useful in the prevention of antibiotic and traveler's diarrhea and they may play a role in the management of gastric Helicobacter pylori infection. Furthermore, their efficacy in the treatment of infectious diarrhea, in inflammatory bowel diseases, in pouchitis and in food allergy has been shown. Probiotics can improve the symptoms of irritable bowel syndrome and of lactose malabsorption. Finally, it has been suggested that such microorganisms may play a role in the prevention of carcinogenesis and of tumor growth. PMID:12402663

  19. [Diagnosis and therapeutic possibilities of descending perineum syndrome].

    PubMed

    Girona, J

    1992-03-01

    The Descending-Perineum-Syndrome (DPS) is a quite common disease in the coloproctological outpatient clinic. In some cases it is difficult to get the correct diagnosis. The treatment success is depending on the condition of the muscle of the floor of the pelvis and on the condition of the sphincter internus- and externus muscle and on the various operation methods. One of these operation-methods is the rectopexy with suspension of the anterior wall of the rectum and in some cases in combination with a colon-resection. After this kind of operation 75% of these patients had no pain and less defecation problems. PMID:1583989

  20. Possible people.

    PubMed

    Hare, R M

    1988-10-01

    Where we have a choice between bringing someone into existence and not doing so, the interests of the possible person must be considered. The implications of this view for population policy are explored, concluding with a version of utilitarianism that proposes increasing the population of a society while increasing the total utility, without altering its proportionate distribution, until the lowest segment of the population comes below the break-even point at which life is just worth living. Questions of whether poverty is the chief cause of misery and how great an obligation is owed to reducing social and economic inequalities are examined. PMID:11651921

  1. HIV and employment.

    PubMed

    McGoldrick, C

    2012-06-01

    According to 2009 statistics, the human immunodeficiency virus (HIV) infected an estimated 86,500 individuals within the UK, although around one-quarter were unaware of their infection. In the majority of cases, it is now considered a long-term controllable but incurable infection. Indeed, most HIV-positive individuals are able to work. Employment is across most, if not all, workforce sectors and protection against workplace discrimination is provided by the Equality Act 2010. Issues including confidentiality, workplace adjustments, vaccinations and travel restrictions may be relevant to the occupational health of HIV-positive workers. There are special considerations concerning HIV-infected health care workers, including avoidance of performing exposure-prone procedures. Prevention of HIV acquisition in the workplace is relevant to a diverse range of occupational environments, and HIV post-exposure prophylaxis should be considered after potential HIV exposure incidents. If a worker contracts HIV by occupational means, financial help may be available. PMID:22661659

  2. HIV/AIDS

    MedlinePlus

    ... Fact sheets Features Commentaries 2014 Multimedia Contacts HIV/AIDS Fact sheet N°360 Updated November 2015 Key ... 2015, new HIV infections have fallen by 35%, AIDS-related deaths have fallen by 24% with some ...

  3. HIV/AIDS

    MedlinePlus

    ... immunodeficiency virus (HIV) is the virus that causes AIDS. When a person becomes infected with HIV, the ... cancers. When that happens, the illness is called AIDS. Once a person has the virus, it stays ...

  4. Smoking and HIV

    MedlinePlus

    ... 28, 2014 Select a Language: Fact Sheet 803 Smoking and HIV WHY IS SMOKING MORE DANGEROUS FOR ... It can also worsen liver problems like hepatitis. Smoking and Side Effects People with HIV who smoke ...

  5. Travelers' Health: HIV Infection

    MedlinePlus

    ... formal program, or may have inadequate technology for testing blood or biological products for contamination with HIV. If transfusion is necessary, the blood should be tested for HIV antibodies ...

  6. Women and HIV

    MedlinePlus

    ... in the vagina, persistent yeast infections, and severe pelvic inflammatory disease (PID) can be signs of HIV. Hormone changes, birth ... Women with HIV get vaginal infections, genital ulcers, pelvic inflammatory disease, and genital warts more often and more severely ...

  7. Microbiome in HIV infection

    PubMed Central

    Salas, January T.; Chang, Theresa L.

    2014-01-01

    HIV primary infection occurs at mucosa tissues, suggesting an intricate interplay between microbiome and HIV infection. Recent advanced technologies of high-throughput sequencing and bioinformatics allow researchers to explore nonculturable microbes including bacteria, virus and fungi and their association with diseases. HIV/SIV infection is associated with microbiome shifts and immune activation that may affect the outcome of disease progression. Similarly, altered microbiome and inflammation are associated with increased risks of HIV acquisition, suggesting the role of microbiome in HIV transmission. In this review, we will focus on microbiome in HIV infection at various mucosal compartments. Understanding the relationship between microbiome and HIV may offer insights into development of better strategies for HIV prevention and treatment. PMID:25439273

  8. Testing for HIV

    MedlinePlus

    ... Medical Devices Radiation-Emitting Products Vaccines, Blood & Biologics Animal & Veterinary Cosmetics Tobacco Products Vaccines, Blood & Biologics Home Vaccines, Blood & Biologics Safety & Availability (Biologics) HIV Home Test Kits Testing for HIV Share Tweet Linkedin Pin it More ...

  9. Older People and HIV

    MedlinePlus

    ... in Revised August 10, 2014 Select a Language: Fact Sheet 616 Older People and HIV HOW MANY OLDER ... of the risk factors for getting HIV (see Fact Sheets 150 and 152 ) Many older people are newly ...

  10. HIV and Cardiovascular Disease

    MedlinePlus

    ... in Reviewed February 24, 2014 Select a Language: Fact Sheet 652 HIV and Cardiovascular Disease HIV AND CARDIOVASCULAR ... Stopping ART and letting the viral load (see fact sheet 125 ) rise increases CVD risk. WHAT CAUSES CVD? ...

  11. HIV and AIDS

    MedlinePlus

    ... that causes the disease AIDS. HIV Hurts the Immune System People who are HIV positive have been tested ... to everyone in the world. When the person's immune system has weakened and more of the blood's T ...

  12. HIV and Pulmonary Hypertension

    MedlinePlus

    HIV Pulmonary & PH Hypertension Did you know that if you are HIV-positive, you are at risk for pulmonary hypertension? www.PHAssociation.org About Pulmonary Hypertension PULMONARY HYPERTENSION, OR PH, is complex and often misunderstood. PH means high ...

  13. Silence, Sexuality and HIV/AIDS in South African Schools

    ERIC Educational Resources Information Center

    Morrell, Robert

    2003-01-01

    In South Africa where there is a very high HIV infection rate among teenagers and young adults, it is surprising to find that students and teachers are very unwilling to talk about the possibility of being or becoming HIV positive. While AIDS messages dominate public discourse, there is a silence in schools about the personal in relation to AIDS.…

  14. Oral manifestation of HIV/AIDS.

    PubMed

    Arotiba, J T; Arowojolu, M O; Fasola, A O; Denloye, O O; Obiechina, A E

    2006-12-01

    The Human Immunodeficiency Virus (HIV) infection and Acquired Deficiency Syndrome (AIDS) have become a pandemic with about 40 million infected people world-wide. The virus attacks the immune cells resulting in a defective cell-mediated immune response thus exposing the host to opportunistic infections. Oral and peri-oral lesions are often seen in HIV infections and sometimes, appear as the first indicators of the disease. The appearance of these lesions in a known HIV infected person could also be a signal of the deterioration of the infection into a full-blown AIDS. It is therefore necessary that Health care givers should have a good working knowledge of the possible oral manifestations of the disease. This write-up highlights the clinical features and treatment of oral lesions associated with HIV infections. PMID:18050772

  15. Antiretroviral Therapy as HIV Prevention: Status and Prospects

    PubMed Central

    Venkatesh, Kartik K.

    2010-01-01

    As antiretroviral treatment of HIV infection has become increasingly accessible, attention has focused on whether these drugs can used for prevention because of increased tolerability of newer medications, decreased cost, and the limitations of other approaches. We review the status of antiretroviral HIV prevention, including chemoprophylaxis, as well as the effects of treatment of infected individuals on prevention. It is possible that the life-saving agents that have transformed the natural history of AIDS can be a critical component of HIV prevention efforts, but their ultimate role in affecting HIV transmission dynamics remains to be defined. PMID:20724682

  16. A Multiplex PCR Approach for Detecting Dual Infections and Recombinants Involving Major HIV Variants.

    PubMed

    Cappy, Pierre; De Oliveira, Fabienne; Gueudin, Marie; Alessandri-Gradt, Elodie; Plantier, Jean-Christophe

    2016-05-01

    The cocirculation of different HIV types and groups can lead to dual infections and recombinants, which hinder diagnosis and therapeutic management. We designed two multiplex PCRs (mPCRs) coupled with capillary electrophoresis to facilitate the detection of such infections. The first, MMO2, targets three variants (HIV-1/M, HIV-1/O, and HIV-2), and the second, MMO, targets HIV-1/M and HIV-1/O. These mPCRs were validated on DNA and RNA extracts from 19 HIV-1/M, 12 HIV-1/O, and 13 HIV-2 cultures and from mixtures simulating dual infections. They were then assessed with DNA and RNA extracts from samples of 47 clinical monoinfections and HIV-1/M+O dual infections or infections with HIV-1/MO recombinants. Both mPCRs had excellent specificity. Sensitivities ranged from 80 to 100% for in vitro samples and from 58 to 100% for clinical samples, with the results obtained depending on the material used and the region of the genome concerned. Sensitivity was generally lower for DNA than for RNA and for amplifications of the integrase and matrix regions. In terms of global detection (at least one target gene for each strain), both mPCRs yielded a detection rate of 100% for in vitro samples. MMO2 detected 100% of the clinical strains from DNA and 97% from RNA, whereas MMO detected 100% of the strains from both materials. Thus, for in vitro and clinical samples, MMO2 was a useful tool for detecting dual infections with HIV-1 and HIV-2 (referred to as HIV-1+HIV-2) and HIV-1/M+O, and MMO was useful for detecting both MO dual infections and MO mosaic patterns. PMID:26912747

  17. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    SciTech Connect

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-10-25

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

  18. HIV eradication: combinatorial approaches to activate latent viruses.

    PubMed

    De Crignis, Elisa; Mahmoudi, Tokameh

    2014-11-01

    The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence of a reservoir of latent HIV infected cells, which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling various depressors and activators will likely be the most effective in promoting HIV replication while avoiding pleiotropic effects at the cellular level. Moreover, in light of differences among HIV subtypes and variability in integration sites, the combination of multiple agents targeting multiple pathways will increase likelihood of therapeutic effectiveness and prevent mutational escape. This review provides an overview of the mechanisms that can be targeted to induce HIV activation focusing on potential combinatorial approaches. PMID:25421889

  19. HIV Eradication: Combinatorial Approaches to Activate Latent Viruses

    PubMed Central

    De Crignis, Elisa; Mahmoudi, Tokameh

    2014-01-01

    The concept of eradication of the Human Immune Deficiency Virus (HIV) from infected patients has gained much attention in the last few years. While combination Anti-Retroviral Therapy (c-ART) has been extremely effective in suppressing viral replication, it is not curative. This is due to the presence of a reservoir of latent HIV infected cells, which persist in the presence of c-ART. Recently, pharmaceutical approaches have focused on the development of molecules able to induce HIV-1 replication from latently infected cells in order to render them susceptible to viral cytopathic effects and host immune responses. Alternative pathways and transcription complexes function to regulate the activity of the HIV promoter and might serve as molecular targets for compounds to activate latent HIV. A combined therapy coupling various depressors and activators will likely be the most effective in promoting HIV replication while avoiding pleiotropic effects at the cellular level. Moreover, in light of differences among HIV subtypes and variability in integration sites, the combination of multiple agents targeting multiple pathways will increase likelihood of therapeutic effectiveness and prevent mutational escape. This review provides an overview of the mechanisms that can be targeted to induce HIV activation focusing on potential combinatorial approaches. PMID:25421889

  20. Role of HIV in amyloid metabolism.

    PubMed

    Ortega, Mario; Ances, Beau M

    2014-09-01

    HIV infection has changed from an acute devastating disease to a more chronic illness due to combination anti-retroviral treatment (cART). In the cART era, the life expectancy of HIV-infected (HIV+) individuals has increased. More HIV + individuals are aging with current projections suggesting that 50% of HIV + individuals will be over 50 years old by 2015. With advancing age, HIV + individuals may be at increased risk of developing other potential neurodegenerative disorders [especially Alzheimer's disease (AD)]. Pathology studies have shown that HIV increases intra and possibly extracellular amyloid beta (Aβ42), a hallmark of AD. We review the synthesis and clearance of Aβ42; the effects of HIV on the amyloid pathway; and contrast the impact of AD and HIV on Aβ42 metabolism. Biomarker studies (cerebrospinal fluid AB and amyloid imaging) in HIV + participants have shown mixed results. CSF Aβ42 has been shown to be either normal or diminished in with HIV associated neurocognitive disorders (HAND). Amyloid imaging using [(11)C] PiB has also not demonstrated increased extracellular amyloid fibrillar deposits in HAND. We further demonstrate that Aβ42 deposition is not increased in older HIV + participants using [(11)C] PiB amyloid imaging. Together, these results suggest that HIV and aging each independently affect Aβ42 deposition with no significant interaction present. Older HIV + individuals are probably not at increased risk for developing AD. However, future longitudinal studies of older HIV + individuals using multiple modalities (including the combination of CSF markers and amyloid imaging) are necessary for investigating the effects of HIV on Aβ42 metabolism. PMID:24816714

  1. Oral candidosis in HIV-infected patients.

    PubMed

    Egusa, Hiroshi; Soysa, Niroshani S; Ellepola, Arjuna N; Yatani, Hirofumi; Samaranayake, Lakshman P

    2008-11-01

    Oral candidosis (syn. Oral candidiasis; OC), is a collective term given to a group of oral mucosal disorders caused by the fugal pathogen belonging to the genus Candida. The association of OC with the human immunodeficiency virus (HIV) infection has been known since the advent of the acquired immune deficiency syndrome (AIDS) pandemic. OC is one of the earliest manifestations of HIV disease in high risk individuals not undergoing chemotherapy and is also a strong predictor of the subsequent risk of AIDS-related illness or death. With the advances in HIV therapy, such as highly active anti-retroviral therapy (HAART), the prevalence and presenting features of OC have changed in HIV-infected individuals, especially those in industrialized countries. The presence of OC in "controlled" HIV-positive individuals may be indicative of a patient nonadherence to therapy or possible failure. The factors contributing to the genesis of OC and its progression in these individuals are poorly understood, but may include an interrelationship between HIV and Candida and/or a dysfunction in the local immunity, superimposed on weakened cell-mediated immunity and depletion of CD4 T cells. The dramatic increase in publications on this topic matches the increased importance and awareness of this opportunistic infection in HIV-infected individuals. In this review we first address the epidemiologic and clinical features of OC in HIV-infected persons, followed by the current understanding of the pathogenesis of OC in the context of HIV infection with a concluding section on the current management concepts of OC. PMID:18991614

  2. Perceived Risk Modifies the Effect of HIV Knowledge on Sexual Risk Behaviors

    PubMed Central

    Noroozinejad, Gholamhossein; Yarmohmmadi Vasel, Mosaieb; Bazrafkan, Fatemeh; Sehat, Mahmoud; Rezazadeh, Majid; Ahmadi, Khodabakhsh

    2013-01-01

    Background: There is a large controversy in the literature about the inter-relations between perceived risk, knowledge, and risk behavior in different settings, and people at HIV risk are not an exception. Aim: To assess additive and multiplicative effect of perceived HIV risk and HIV knowledge on sexual risk behavior of Injecting Drug Users (IDUs). Method: We enrolled 162 street based IDUs to this analysis. Data came from a national survey of IDUs in Iran, with a cross sectional design. Socio-demographics (employment, education, marital status), HIV knowledge, perceived HIV risk, and four different sexual risk behavior were registered. In the first step, using spearman test, the association of HIV knowledge and risk behavior were tested, then possible moderating effect of perceived HIV risk on this association was determined. Results: Although among IDUs with low perceived HIV risk, HIV knowledge was negatively associated with sexual risk behavior (P < 0.05 for all), this association was not significant among IDUs with high perceived HIV risk (P > 0.05 for all). Thus perceived HIV risk moderated the association between HIV knowledge and sexual risk behavior. Conclusion: Perceived risk should be taken into consideration when studying the effect of HIV knowledge on sexual risk behavior of IDUs. Findings may help us better understand negative effects of fear arousing interventions as a part of HIV prevention media campaigns. PMID:24350202

  3. Immunogenetics of HIV and HIV associated tuberculosis.

    PubMed

    Raghavan, S; Alagarasu, K; Selvaraj, P

    2012-01-01

    Tuberculosis (TB) is the frequent major opportunistic infection in HIV-infected patients, and is the leading cause of mortality among HIV-infected patients. Genetic susceptibility to TB in HIV negative subjects is well documented. Since coinfections can influence the way in which immune system respond to different pathogens, genetic susceptibility to TB in HIV patients might also change. Studies from India and other parts of the world have shown that genetic susceptibility to TB is influenced by HIV infection. In the present review, we emphasize the role of genetic factors in determining susceptibility to HIV infection, disease progression and development of TB in HIV-infected patients. Polymorphisms in human leukocyte antigen (HLA), MBL2, CD209, vitamin D receptor, cytokine, chemokine and chemokine receptor genes have been shown to be associated with development of TB in HIV patients. However, the results are inconclusive and larger well-defined studies with precise clinical data are required to validate these associations. Apart from candidate gene approach, genome-wide association studies are also needed to unravel the unknown or to establish the previously reported genetic associations with HIV associated TB. Despite the preliminary status of the reported associations, it is becoming clear that susceptibility to development of TB in HIV patients is influenced by both environmental and genetic components. Understanding the genetic and immunologic factors that influence susceptibility to TB in HIV patients could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. PMID:21943869

  4. Reproductive concerns of women at risk for HIV infection.

    PubMed

    Williams, A B

    1990-01-01

    This qualitative, exploratory study investigated knowledge about perinatal transmission of human immunodeficiency virus (HIV) and perceptions of the childbearing role among women at risk for acquired immunodeficiency syndrome (AIDS) through injection drug use. Content analysis was used to analyze the results of 21 face-to-face, semistructured interviews with women who had a personal history of injection drug use or who were the sexual partners of men who injected drugs. Contextual variables influencing women at risk for HIV infection that were identified included fear of HIV antibody testing, a belief that perinatal HIV transmission is inevitable, support for pregnancy termination in the event of HIV-associated pregnancy, a strong desire for children, pride in mothering behavior, and guilt about the possibility of transmitting HIV to unborn children. AIDS education and counseling for these women will be most effective if these variables are considered. PMID:2258758

  5. Care of Patients With HIV Infection: Medical Complications and Comorbidities.

    PubMed

    Bolduc, Philip; Roder, Navid; Colgate, Emily; Cheeseman, Sarah H

    2016-04-01

    Care of patients with HIV infection starts with diagnosis as soon as possible, preferably at or near the time of acute infection. Opportunistic infections, malignancies, and other conditions develop progressively over time, particularly in untreated patients. The AIDS-defining opportunistic infections most common in the United States include Pneumocystis jirovecii pneumonia, Candida esophagitis, toxoplasmic encephalitis, tuberculosis, disseminated Mycobacterium avium complex, cryptococcal meningitis, and cytomegalovirus retinitis. Specific prophylaxis regimens exist for several opportunistic infections, and effective antiretroviral therapy reduces the risk of most others. Other AIDS-defining conditions include wasting syndrome and HIV encephalopathy. AIDS-defining malignancies include Kaposi sarcoma, systemic non-Hodgkin lymphoma, primary central nervous system lymphoma, and invasive cervical cancer. Although not an AIDS-defining condition, anal cancer is common in patients with HIV infection. Other HIV-related conditions include thrombocytopenia, recurrent bacterial respiratory infections, HIV-associated nephropathy, and HIV-associated neurocognitive disorder. PMID:27092563

  6. Therapeutic Devices for Epilepsy

    PubMed Central

    Fisher, Robert S.

    2011-01-01

    Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation, which continues to develop new technology, is approved for use in the United States. Deep brain stimulation (DBS) of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to one or two seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS split on efficacy, and may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of “shake” detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of EEG is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience. PMID:22367987

  7. HIV Disease: Current Concepts.

    ERIC Educational Resources Information Center

    Keeling, Richard P.

    1993-01-01

    Describes human immunodeficiency virus (HIV), newly characterized human retrovirus which causes chronic, progressive, immune deficiency disease, the most severe phase of which is Acquired Immune Deficiency Syndrome (AIDS). Reviews most important current epidemiologic, clinical, and virologic information about HIV and HIV disease and provides…

  8. Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles

    SciTech Connect

    Peretti, Silvia; Schiavoni, Ilaria; Pugliese, Katherina; Federico, Maurizio . E-mail: federico@iss.it

    2006-02-05

    We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies.

  9. High-affinity recognition of HIV-1 frameshift-stimulating RNA alters frameshifting in vitro and interferes with HIV-1 infectivity.

    PubMed

    Ofori, Leslie O; Hilimire, Thomas A; Bennett, Ryan P; Brown, Nathaniel W; Smith, Harold C; Miller, Benjamin L

    2014-02-13

    The life cycle of the human immunodeficiency virus type 1 (HIV-1) has an absolute requirement for ribosomal frameshifting during protein translation in order to produce the polyprotein precursor of the viral enzymes. While an RNA stem-loop structure (the "HIV-1 Frameshift Stimulating Signal", or HIV-1 FSS) controls the frameshift efficiency and has been hypothesized as an attractive therapeutic target, developing compounds that selectively bind this RNA and interfere with HIV-1 replication has proven challenging. Building on our prior discovery of a "hit" molecule able to bind this stem-loop, we now report the development of compounds displaying high affinity for the HIV-1 FSS. These compounds are able to enhance frameshifting more than 50% in a dual-luciferase assay in human embryonic kidney cells, and they strongly inhibit the infectivity of pseudotyped HIV-1 virions. PMID:24387306

  10. [Health security--GMOs in therapeutics].

    PubMed

    Trouvin, J-H

    2003-03-01

    The recent progress in human therapeutics has been made possible thanks to molecular biology and its use in producing proteins having the same sequence and structure as that of human proteins. The use of GMOs allows production of proteins with high added value in therapeutics, which are of satisfactory quality. GMOs may also be directly administered to patients as gene therapy vectors. However, the use of GMOs in therapeutics must take into consideration some risks, particularly those of microbiological contamination, of neo-antigenicity as well as environmental risks with regard to the way of use of the GMO. Nevertheless, those risks are taken in due consideration in the development of these new medicinal products; solutions have been found to allow their use in therapeutics with a very positive benefit/risk ratio. Medicinal products from biotechnology have enabled considerable therapeutic progress without compromising health security. PMID:12668948

  11. [Sanitary safety of GMOs used in therapeutics].

    PubMed

    Trouvin, Jean-Hugues

    2002-01-01

    The recent progress in human therapeutics has been made possible thanks to molecular biology and its use in producing proteins having the same sequence and structure as that of human proteins. The use of GMOs allows production of proteins with high added value in therapeutics, which are of satisfactory quality. GMOs may also be directly administered to patients as gene therapy vectors. However, the use of GMOs in therapeutics must take into consideration some risks, particularly those of microbiological contamination, of neo-antigenicity as well as environmental risks with regard to the way of use of the GMO. Nevertheless, those risks are taken in due consideration in the development of those new medicinal products; solutions have been found to allow their use in therapeutics with a very positive benefit/risk ratio. Medicinal products from biotechnology have permitted considerable therapeutic progress without compromising health security. PMID:12669359

  12. Human Erythrocytes Selectively Bind and Enrich Infectious HIV-1 Virions

    PubMed Central

    Beck, Zoltan; Brown, Bruce K.; Wieczorek, Lindsay; Peachman, Kristina K.; Matyas, Gary R.; Polonis, Victoria R.; Rao, Mangala; Alving, Carl R.

    2009-01-01

    Although CD4(+) cells represent the major target for HIV infection in blood, claims of complement-independent binding of HIV-1 to erythrocytes and the possible role of Duffy blood group antigen, have generated controversy. To examine the question of binding to erythrocytes, HIV-1 was incubated in vitro with erythrocytes from 30 healthy leukapheresis donors, and binding was determined by p24 analysis and adsorption of HIV-1 with reduction of infectivity for CD4(+) target cells. All of the cells, regardless of blood group type, bound HIV-1 p24. A typical preparation of erythrocytes bound <2.4% of the added p24, but erythrocytes selectively removed essentially all of the viral infectivity as determined by decreased infection of CD4(+) target cells; however, cell-associated HIV-1 was approximately 100-fold more efficient, via trans infection, than unadsorbed virus for infection of CD4(+) cells. All of the bound HIV-1 p24 was released by treatment of the cells with EDTA, and binding was optimized by adding Ca2+ and Mg2+ during the washing of erythrocytes containing bound HIV-1. Although the small number of contaminating leukocytes in the erythrocyte preparation also bound HIV-1 p24, there was no significant binding to CD4, and it thus appears that the binding occurred on leukocytes at non-CD4 sites. Furthermore, binding occurred to erythrocyte ghosts from which contaminating leukocytes had been previously removed. The results demonstrate that erythrocytes incubated in vitro with HIV-1 differentially adsorb all of the infectious HIV-1 virions (as opposed to non-infectious or degraded virions) in the absence of complement and independent of blood group, and binding is dependent on divalent cations. By analogy with HIV-1 bound to DC-SIGN on dendritic cells, erythrocyte-bound HIV-1 might comprise an important surface reservoir for trans infection of permissive cells. PMID:20011536

  13. Oral mucosal immunity and HIV infection: current status.

    PubMed

    Challacombe, S J; Sweet, S P

    2002-01-01

    There is a paradox that profound HIV-induced immunodeficiency is present systemically, whereas the majority of infections associated with HIV disease are present or initiated at mucosal surfaces. There is therefore a need to understand both specific and non-specific mechanisms of mucosal protection against HIV and its copathogens. The majority of HIV infections occur as a result of the passage of virus across mucosal membranes. Resistance to HIV infection at mucosal surfaces may be related to HIV-specific CD8+ T cell responses in some individuals and may be the basis for protective vaccine design. However, T-cells, macrophages and dendritic cells in mucosa may be a portal of entry for HIV. Transcytosis of HIV can occur from the mucosal to the submucosal surface and vice versa, and may be inhibited by mucosal immunoglobulins and neutralizing IgA within epithelial cells. HIV-induced alterations to oral epithelial cells, together with impairment of mucosal CD4+ T-cells and consequent altered cytokine secretion, may contribute to secondary infections. It also appears that HIV infection is associated with decreased salivary IgA levels, although a dichotomy between IgA concentrations in saliva and serum has been reported. Mucosal antibody responses, however, seem to be maintained. Considerable attention has been given to the possibility of mucosal immunization against HIV and there is evidence that secretory IgA antibody is neutralizing to different HIV strains. In addition to specific immune factors, it is likely that innate nonspecific factors may be significant in protecting mucosal surfaces, including lactoferrin, secretory leukocyte protease inhibitor, mucins, proline rich proteins and cystatins. These may be useful candidate virucides in topical preparations. Thus humoral, cellular and innate immune mechanisms, as well as lymphocyte-epithelial interactions, may all be impaired at mucosal surfaces as a result of HIV infection and may contribute to the susceptibility of mucosa to infective processes. PMID:12164661

  14. HIV infection and immune defense of the penis.

    PubMed

    Anderson, Deborah; Politch, Joseph A; Pudney, Jeffrey

    2011-03-01

    Recent evidence that circumcision decreases HIV infection in heterosexual men by 50-60% has focused research on the foreskin as a target of HIV infection. In this review article, we discuss potential mechanisms underlying the circumcision effect and re-examine the assumption that the foreskin is the principle penile HIV infection site. HIV target cells are present in the foreskin epithelium, but are also found in the epithelia of the penile shaft, glans/corona, meatus and urethral introitus. Sexually transmitted infections (STIs) can affect any of these sites and increase susceptibility to HIV acquisition by eroding the protective epithelial layer and by attracting and activating HIV target cells in the epithelium. The moist subpreputial cavity, which encompasses the entire penile tip in most uncircumcised men including the glans, meatus and urethral introitus, plays an important role in STI acquisition. Circumcised men have a lower rate of STIs that infect not only the foreskin but also other distal penile sites, especially the urethra. Likewise, the foreskin may trap HIV and HIV-infected cells after intercourse thereby increasing the risk of HIV acquisition not only through the inner foreskin but also other sites covered by the foreskin. The subpreputial cavity also hosts a unique microbiome that may also play a role in HIV infection. We hypothesize that the penile urethra may be the primary HIV acquisition site in circumcised men and possibly also in non-circumcised men because of the presence of superficial HIV target cells and a high incidence of STIs at this site. Both innate and adaptive immune defense mechanisms are operative in the lower male genital region. The penile urethral mucosa contains accumulations of IgA(+) plasma cells and T lymphocytes and may provide a responsive target for future mucosal vaccines to prevent HIV sexual transmission. PMID:21214659

  15. HIV-negative Men-who-Have-Sex-with-Men who Bareback are Concerned about HIV Infection: Implications for HIV Risk Reduction Interventions

    PubMed Central

    Balán, Iván C.; Carballo-Diéguez, Alex; Ventuneac, Ana; Remien, Robert H.; Dolezal, Curtis; Ford, Jordan

    2012-01-01

    The emergence of barebacking (intentional unprotected anal intercourse in situations where there is risk of HIV infection) among men who have sex with men (MSM) has been partially attributed to a decrease in HIV-related concerns due to improved anti-retroviral treatment. It is important to understand the level of concern these men have regarding HIV infection because it can affect their interest in risk reduction behaviors as well as their possible engagement in risk reduction interventions. As part of a study on MSM who use the Internet to seek sexual partners, 89 ethnic and racially diverse men who reported never having an HIV-positive test result completed an in-depth qualitative interview and a computer-based quantitative assessment. Of the 82 men who were asked about concerns of HIV infection during the qualitative interviews, 30 expressed “significant concern” about acquiring HIV, while 42 expressed “moderate concern,” and 10 expressed “minimal concern. Themes that emerged across the different levels of concern were their perceptions of the severity of HIV infection, having friends who are HIV positive, and their own vulnerability to HIV infection. However, these themes differed depending on the level of concern. Among the most frequently mentioned approaches to decrease risk of HIV infection, participants mentioned avoiding HIV-positive sex partners, limiting the number of partners with whom they barebacked, and not allowing partners to ejaculate inside their rectum. Findings suggest that many MSM who bareback would be amenable to HIV prevention efforts that do not depend solely on condom use. PMID:22218787

  16. Proteomics in the investigation of HIV-1 interactions with host proteins

    PubMed Central

    Li, Ming

    2015-01-01

    Productive HIV-1 infection depends on host machinery, including a broad array of cellular proteins. Proteomics has played a significant role in the discovery of HIV-1 host proteins. In this review, after a brief survey of the HIV-1 host proteins that were discovered by proteomic analyses, we focus on analyzing the interactions between the virion and host proteins, as well as the technologies and strategies used in those proteomic studies. With the help of proteomics, the identification and characterization of HIV-1 host proteins can be translated into novel antiretroviral therapeutics. PMID:25523935

  17. Ribotoxin restrictocin manifests anti-HIV-1 activity through its specific ribonuclease activity.

    PubMed

    Yadav, Santosh K; Batra, Janendra K

    2015-05-01

    Restrictocin, a highly specific ribonuclease produced by Aspergillus restrictus, cleaves a single phosphodiester bond in a universally conserved stem and loop structure termed sarcin/ricin loop within the large ribosomal RNA of all organisms. In the current study, we demonstrate restrictocin to manifest anti-HIV-1 activity in two model cell systems. Using two mutants of restrictocin, we further show that the anti-HIV-1 activity of restrictocin is due to its specific ribonucleolytic activity. The study suggests that restrictocin is able to recognize region(s) within HIV-1 genome as its target. Restrictocin appears to have potential as a therapeutic antiviral agent against HIV-1. PMID:25709025

  18. Chicanoizing the Therapeutic Community

    ERIC Educational Resources Information Center

    Aron, William S.; And Others

    1974-01-01

    Focusing on the drug addiction problem and its antecedent conditions in a Chicano population, the article examines several therapeutic interventions suggested by these conditions and indicates how they might be incorporated into a drug addiction Therapeutic Community treatment program designed to meet the needs of Chicano drug addicts. (Author/NQ)

  19. Therapeutic Recreation Practicum Manual.

    ERIC Educational Resources Information Center

    Schneegas, Kay

    This manual provides information on the practicum program offered by Moraine Valley Community College (MVCC) for students in its therapeutic recreation program. Sections I and II outline the rationale and goals for providing practical, on-the-job work experiences for therapeutic recreation students. Section III specifies MVCC's responsibilities…

  20. Mother-to-Child HIV-1 Transmission Events Are Differentially Impacted by Breast Milk and Its Components from HIV-1-Infected Women

    PubMed Central

    Shen, Ruizhong; Achenbach, Jenna; Shen, Yue; Palaia, Jana; Rahkola, Jeremy T.; Nick, Heidi J.; Smythies, Lesley E.; McConnell, Michelle; Fowler, Mary G.; Smith, Phillip D.; Janoff, Edward N.

    2015-01-01

    Breast milk is a vehicle of infection and source of protection in post-natal mother-to-child HIV-1 transmission (MTCT). Understanding the mechanism by which breast milk limits vertical transmission will provide critical insight into the design of preventive and therapeutic approaches to interrupt HIV-1 mucosal transmission. However, characterization of the inhibitory activity of breast milk in human intestinal mucosa, the portal of entry in postnatal MTCT, has been constrained by the limited availability of primary mucosal target cells and tissues to recapitulate mucosal transmission ex vivo. Here, we characterized the impact of skimmed breast milk, breast milk antibodies (Igs) and non-Ig components from HIV-1-infected Ugandan women on the major events of HIV-1 mucosal transmission using primary human intestinal cells and tissues. HIV-1-specific IgG antibodies and non-Ig components in breast milk inhibited the uptake of Ugandan HIV-1 isolates by primary human intestinal epithelial cells, viral replication in and transport of HIV-1- bearing dendritic cells through the human intestinal mucosa. Breast milk HIV-1-specific IgG and IgA, as well as innate factors, blocked the uptake and transport of HIV-1 through intestinal mucosa. Thus, breast milk components have distinct and complementary effects in reducing HIV-1 uptake, transport through and replication in the intestinal mucosa and, therefore, likely contribute to preventing postnatal HIV-1 transmission. Our data suggests that a successful preventive or therapeutic approach would require multiple immune factors acting at multiple steps in the HIV-1 mucosal transmission process. PMID:26680219

  1. Vorinostat positively regulates synaptic plasticity genes expression and spine density in HIV infected neurons: role of nicotine in progression of HIV-associated neurocognitive disorder

    PubMed Central

    2014-01-01

    Background HIV-associated neurocognitive disorder (HAND) is characterized by development of cognitive, behavioral and motor abnormalities, and occurs in approximately 50% of HIV infected individuals. In the United States, the prevalence of cigarette smoking ranges from 35-70% in HIV-infected individuals compared to 20% in general population. Cognitive impairment in heavy cigarette smokers has been well reported. However, the synergistic effects of nicotine and HIV infection and the underlying mechanisms in the development of HAND are unknown. Results In this study, we explored the role of nicotine in the progression of HAND using SK-N-MC, a neuronal cell line. SK-N-MC cells were infected with HIV-1 in the presence or absence of nicotine for 7 days. We observed significant increase in HIV infectivity in SK-N-MC treated with nicotine compared to untreated HIV-infected neuronal cells. HIV and nicotine synergize to significantly dysregulate the expression of synaptic plasticity genes and spine density; with a concomitant increase of HDAC2 levels in SK-N-MC cells. In addition, inhibition of HDAC2 up-regulation with the use of vorinostat resulted in HIV latency breakdown and recovery of synaptic plasticity genes expression and spine density in nicotine/HIV alone and in co-treated SK-N-MC cells. Furthermore, increased eIF2 alpha phosphorylation, which negatively regulates eukaryotic translational process, was observed in HIV alone and in co-treatment with nicotine compared to untreated control and nicotine alone treated SK-N-MC cells. Conclusions These results suggest that nicotine and HIV synergize to negatively regulate the synaptic plasticity gene expression and spine density and this may contribute to the increased risk of HAND in HIV infected smokers. Apart from disrupting latency, vorinostat may be a useful therapeutic to inhibit the negative regulatory effects on synaptic plasticity in HIV infected nicotine abusers. PMID:24886748

  2. HIV-related stigma and health-related quality of life among children living with HIV in Sweden.

    PubMed

    Rydström, Lise-Lott; Wiklander, Maria; Navér, Lars; Ygge, Britt-Marie; Eriksson, Lars E

    2016-05-01

    The relationship between HIV-related stigma and health-related quality of life (HRQoL) among children living with HIV infection is unknown. The objectives of this study were to describe HIV-related stigma and HRQoL among children with perinatal HIV living in Sweden, and to investigate the relationship between these two factors in the same infection group. In a cross-sectional nationwide survey, HIV-related stigma was measured with the 8-item HIV Stigma Scale for Children. HRQoL was measured with the 37-item DISABKIDS Chronic Generic Module. Structural equation modeling was used to explore the relationship between HIV-related stigma and HRQoL. Fifty-eight children participated, age 9-18 years (mean = 13.9). The HIV stigma general scale showed a mean score of 17.6 (SD = 5.0; possible range 8-32). DISABKIDS Chronic Generic Module general scale showed a mean score of 80.7 (SD = 14.1; possible range 0-100). HIV-related stigma was negatively associated with HRQoL (standardized β = -0.790, p = .017). The results indicate that children's concerns related to disclosure of their HIV infection seem to be common (i.e. 75% agreed) which, together with the negative association between ratings of HIV-relatively stigma and HRQoL, might indicate that disclosure concerns would be a relevant target for interventions to decrease HIV-related stigma and increase HRQoL. PMID:26679064

  3. Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection.

    PubMed

    Ramezani, Ali; Dubrovsky, Larisa; Pushkarsky, Tatiana; Sviridov, Dmitri; Karandish, Sara; Raj, Dominic S; Fitzgerald, Michael L; Bukrinsky, Michael

    2015-09-01

    Previous studies demonstrated that liver X receptor (LXR) agonists inhibit human immunodeficiency virus (HIV) replication by upregulating cholesterol transporter ATP-binding cassette A1 (ABCA1), suppressing HIV production, and reducing infectivity of produced virions. In this study, we extended these observations by analyzing the effect of the LXR agonist T0901317 [N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide] on the ongoing HIV infection and investigating the possibility of using LXR agonist for pre-exposure prophylaxis of HIV infection in a humanized mouse model. Pre-exposure of monocyte-derived macrophages to T0901317 reduced susceptibility of these cells to HIV infection in vitro. This protective effect lasted for up to 4 days after treatment termination and correlated with upregulated expression of ABCA1, reduced abundance of lipid rafts, and reduced fusion of the cells with HIV. Pre-exposure of peripheral blood leukocytes to T0901317 provided only a short-term protection against HIV infection. Treatment of HIV-exposed humanized mice with LXR agonist starting 2 weeks postinfection substantially reduced viral load. When eight humanized mice were pretreated with LXR agonist prior to HIV infection, five animals were protected from infection, two had viral load at the limit of detection, and one had viral load significantly reduced relative to mock-treated controls. T0901317 pretreatment also reduced HIV-induced dyslipidemia in infected mice. In conclusion, these results reveal a novel link between LXR stimulation and cell resistance to HIV infection and suggest that LXR agonists may be good candidates for development as anti-HIV agents, in particular for pre-exposure prophylaxis of HIV infection. PMID:26126533

  4. Novel Approaches to Targeting Visceral and Hepatic Adiposities in HIV-Associated Lipodystrophy.

    PubMed

    Tien, Phyllis C

    2015-12-01

    Visceral and hepatic adiposities have been associated with both cardiovascular and liver disease and are of concern in HIV-infected persons in the modern era of combination antiretroviral therapy (ART). The development of therapeutic targets to reduce visceral and hepatic adiposities in HIV-infected persons has been slow, because of early reports that attributed the excess adiposity to specific antiretroviral drugs. Visceral adiposity was initially thought to occur as part of a protease inhibitor-induced "HIV-associated lipodystrophy syndrome." Subsequent studies show that visceral adiposity is likely a result of effective ART, recovery of health, and the normal aging process. Visceral adiposity is an established risk factor for hepatic adiposity. Identifying drug targets for non-alcoholic fatty liver disease is under active investigation. The present review summarizes the recent literature on the pathogenesis of visceral and hepatic adiposities in HIV-infected persons, current therapeutic strategies, and novel interventions in HIV-infected and uninfected persons. PMID:26493063

  5. Developing Combined HIV Vaccine Strategies for a Functional Cure.

    PubMed

    Noto, Alessandra; Trautmann, Lydie

    2013-01-01

    Increasing numbers of HIV-infected individuals have access to potent antiretroviral drugs that control viral replication and decrease the risk of transmission. However, there is no cure for HIV and new strategies have to be developed to reach an eradication of the virus or a natural control of viral replication in the absence of drugs (functional cure). Therapeutic vaccines against HIV have been evaluated in many trials over the last 20 years and important knowledge has been gained from these trials. However, the major obstacle to HIV eradication is the persistence of latent proviral reservoirs. Different molecules are currently tested in ART-treated subjects to reactivate these latent reservoirs. Such anti-latency agents should be combined with a vaccination regimen in order to control or eradicate reactivated latently-infected cells. New in vitro assays should also be developed to assess the success of tested therapeutic vaccines by measuring the immune-mediated killing of replication-competent HIV reservoir cells. This review provides an overview of the current strategies to combine HIV vaccines with anti-latency agents that could act as adjuvant on the vaccine-induced immune response as well as new tools to assess the efficacy of these approaches. PMID:26344343

  6. Developing Combined HIV Vaccine Strategies for a Functional Cure

    PubMed Central

    Noto, Alessandra; Trautmann, Lydie

    2013-01-01

    Increasing numbers of HIV-infected individuals have access to potent antiretroviral drugs that control viral replication and decrease the risk of transmission. However, there is no cure for HIV and new strategies have to be developed to reach an eradication of the virus or a natural control of viral replication in the absence of drugs (functional cure). Therapeutic vaccines against HIV have been evaluated in many trials over the last 20 years and important knowledge has been gained from these trials. However, the major obstacle to HIV eradication is the persistence of latent proviral reservoirs. Different molecules are currently tested in ART-treated subjects to reactivate these latent reservoirs. Such anti-latency agents should be combined with a vaccination regimen in order to control or eradicate reactivated latently-infected cells. New in vitro assays should also be developed to assess the success of tested therapeutic vaccines by measuring the immune-mediated killing of replication-competent HIV reservoir cells. This review provides an overview of the current strategies to combine HIV vaccines with anti-latency agents that could act as adjuvant on the vaccine-induced immune response as well as new tools to assess the efficacy of these approaches. PMID:26344343

  7. Expedient screening for HIV-1 protease inhibitors using a simplified immunochromatographic assay.

    PubMed

    Kitidee, Kuntida; Khamaikawin, Wannisa; Thongkum, Weeraya; Tawon, Yardpiroon; Cressey, Tim R; Jevprasesphant, Rachaneekorn; Kasinrerk, Watchara; Tayapiwatana, Chatchai

    2016-05-15

    A colloidal gold-based immunochromatographic (IC) strip test was developed and validated for the detection of HIV-1 protease (HIV-PR) activity and inhibitory effect of HIV-PR inhibitors (PIs). It is a unique 'two-step' process requiring the combination of proteolysis of HIV-PR and an immunochromatographic reaction. Monoclonal antibodies to the free C-terminus of HIV matrix protein (HIV-MA) conjugated to gold particles and a monoclonal antibody against intact and cleaved forms of the HIV-MA are immobilized on the 'Test'-line of the IC strip. Using lopinavir, a potent HIV protease inhibitor, the IC-strip was optimized to detect inhibitory activity against HIV-protease. At a lopinavir concentration of 1000ng/mL (its suggested minimum effective concentration), a HIV-PRH6 concentration of 6mg/mL and incubation period of 60min were the optimal conditions. A preliminary comparison between a validated high-performance liquid chromatography assay and the IC-strip to semi-quantify HIV protease inhibitor concentrations (lopinavir and atazanavir) demonstrated good agreement. This simplified method is suitable for the rapid screening of novel protease inhibitors for future therapeutic use. Moreover, the IC strip could also be optimized to semi-quantify PIs concentrations in plasma samples. PMID:26490422

  8. Strategies to Block HIV Transcription: Focus on Small Molecule Tat Inhibitors

    PubMed Central

    Mousseau, Guillaume; Valente, Susana

    2012-01-01

    After entry into the target cell, the human immunodeficiency virus type I (HIV) integrates into the host genome and becomes a proviral eukaryotic transcriptional unit. Transcriptional regulation of provirus gene expression is critical for HIV replication. Basal transcription from the integrated HIV promoter is very low in the absence of the HIV transactivator of transcription (Tat) protein and is solely dependent on cellular transcription factors. The 5' terminal region (+1 to +59) of all HIV mRNAs forms an identical stem-bulge-loop structure called the Transactivation Responsive (TAR) element. Once Tat is made, it binds to TAR and drastically activates transcription from the HIV LTR promoter. Mutations in either the Tat protein or TAR sequence usually affect HIV replication, indicating a strong requirement for their conservation. The necessity of the Tat-mediated transactivation cascade for robust HIV replication renders Tat one of the most desirable targets for transcriptional therapy against HIV replication. Screening based on inhibition of the Tat-TAR interaction has identified a number of potential compounds, but none of them are currently used as therapeutics, partly because these agents are not easily delivered for an efficient therapy, emphasizing the need for small molecule compounds. Here we will give an overview of the different strategies used to inhibit HIV transcription and review the current repertoire of small molecular weight compounds that target HIV transcription. PMID:24832514

  9. Tuberculosis and HIV Coinfection.

    PubMed

    Bruchfeld, Judith; Correia-Neves, Margarida; Källenius, Gunilla

    2015-07-01

    Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS). PMID:25722472

  10. High-efficiency transduction of rhesus hematopoietic repopulating cells by a modified HIV1-based lentiviral vector.

    PubMed

    Uchida, Naoya; Hargrove, Phillip W; Lap, Coen J; Evans, Molly E; Phang, Oswald; Bonifacino, Aylin C; Krouse, Allen E; Metzger, Mark E; Nguyen, Anh-Dao; Hsieh, Matthew M; Wolfsberg, Tyra G; Donahue, Robert E; Persons, Derek A; Tisdale, John F

    2012-10-01

    Human immunodeficiency virus type 1 (HIV1) vectors poorly transduce rhesus hematopoietic cells due to species-specific restriction factors, including the tripartite motif-containing 5 isoformα (TRIM5α) which targets the HIV1 capsid. We previously developed a chimeric HIV1 (χHIV) vector system wherein the vector genome is packaged with the simian immunodeficiency virus (SIV) capsid for efficient transduction of both rhesus and human CD34(+) cells. To evaluate whether χHIV vectors could efficiently transduce rhesus hematopoietic repopulating cells, we performed a competitive repopulation assay in rhesus macaques, in which half of the CD34(+) cells were transduced with standard SIV vectors and the other half with χHIV vectors. As compared with SIV vectors, χHIV vectors achieved higher vector integration, and the transgene expression rates were two- to threefold higher in granulocytes and red blood cells and equivalent in lymphocytes and platelets for 2 years. A recipient of χHIV vector-only transduced cells reached up to 40% of transgene expression rates in granulocytes and lymphocytes and 20% in red blood cells. Similar to HIV1 and SIV vectors, χHIV vector frequently integrated into gene regions, especially into introns. In summary, our χHIV vector demonstrated efficient transduction for rhesus long-term repopulating cells, comparable with SIV vectors. This χHIV vector should allow preclinical testing of HIV1-based therapeutic vectors in large animal models. PMID:22871664

  11. FDA-Approved HIV Medicines

    MedlinePlus

    ... but HIV medicines help people with HIV live longer, healthier lives. HIV medicines also reduce the risk of HIV transmission. The following table lists HIV medicines approved by the U.S. Food and Drug Administration (FDA) for the treatment of ...

  12. Basic HIV/AIDS Statistics

    MedlinePlus

    ... Abroad Treatment Basic Statistics Get Tested Find an HIV testing site near you. Enter ZIP code or city Follow HIV/AIDS CDC HIV CDC HIV/AIDS See RSS | ... Statistics Center . How many people are diagnosed with HIV each year in the United States? In 2014, ...

  13. Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia

    PubMed Central

    Johnson, Susan; Eller, Michael; Teigler, Jeffrey E.; Maloveste, Sebastien M.; Schultz, Bruce T.; Soghoian, Damien Z.; Lu, Richard; Oster, Alexander F.; Chenine, Agnès-Laurence; Alter, Galit; Dittmer, Ulf; Marovich, Mary; Robb, Merlin L.; Michael, Nelson L.; Bolton, Diane

    2015-01-01

    ABSTRACT CD4+ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4+ T cell functions beyond helper effects have been described, and a role for cytolytic CD4+ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4+ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4+ T cells revealed a distinct transcriptional signature compared to Th1 CD4+ cells but shared similar features with HIV-specific cytolytic CD8+ T cells. Furthermore, HIV-specific cytolytic CD4+ T cells showed comparable killing activity relative to HIV-specific CD8+ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4+ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4+ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8+ T cells in the long-term control of HIV infection. IMPORTANCE The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8+ T cells to control the virus, while CD4+ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4+ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4+ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8+ T cells. These findings are important for our understanding of HIV immunopathology. PMID:25972560

  14. Cross-Clade Ultrasensitive PCR-Based Assays To Measure HIV Persistence in Large-Cohort Studies

    PubMed Central

    Vandergeeten, Claire; Fromentin, Rémi; Merlini, Esther; Lawani, Mariam B.; DaFonseca, Sandrina; Bakeman, Wendy; McNulty, Amanda; Ramgopal, Moti; Michael, Nelson; Kim, Jerome H.; Ananworanich, Jintanat

    2014-01-01

    ABSTRACT A small pool of infected cells persists in HIV-infected individuals receiving antiretroviral therapy (ART). Here, we developed ultrasensitive assays to precisely measure the frequency of cells harboring total HIV DNA, integrated HIV DNA, and two long terminal repeat (2-LTR) circles. These assays are performed on cell lysates, which circumvents the labor-intensive step of DNA extraction, and rely on the coquantification of each HIV molecular form together with CD3 gene sequences to precisely measure cell input. Using primary isolates from HIV subtypes A, B, C, D, and CRF01_A/E, we demonstrate that these assays can efficiently quantify low target copy numbers from diverse HIV subtypes. We further used these assays to measure total HIV DNA, integrated HIV DNA, and 2-LTR circles in CD4+ T cells from HIV-infected subjects infected with subtype B. All samples obtained from ART-naive subjects were positive for the three HIV molecular forms (n = 15). Total HIV DNA, integrated HIV DNA, and 2-LTR circles were detected in, respectively, 100%, 94%, and 77% of the samples from individuals in which HIV was suppressed by ART. Higher levels of total HIV DNA and 2-LTR circles were detected in untreated subjects than individuals on ART (P = 0.0003 and P = 0.0004, respectively), while the frequency of CD4+ T cells harboring integrated HIV DNA did not differ between the two groups. These results demonstrate that these novel assays have the ability to quantify very low levels of HIV DNA of multiple HIV subtypes without the need for nucleic acid extraction, making them well suited for the monitoring of viral persistence in large populations of HIV-infected individuals. IMPORTANCE Since the discovery of viral reservoirs in HIV-infected subjects receiving suppressive ART, measuring the degree of viral persistence has been one of the greatest challenges in the field of HIV research. Here, we report the development and validation of ultrasensitive assays to measure HIV persistence in HIV-infected individuals from multiple geographical regions. These assays are relatively inexpensive, do not require DNA extraction, and can be completed in a single day. Therefore, they are perfectly adapted to monitor HIV persistence in large cohorts of HIV-infected individuals and, given their sensitivity, can be used to monitor the efficacy of therapeutic strategies aimed at interfering with HIV persistence after prolonged ART. PMID:25122785

  15. Recent advances in humanized mice: accelerating the development of an HIV vaccine.

    PubMed

    Tager, Andrew M; Pensiero, Michael; Allen, Todd M

    2013-11-01

    Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency virus (HIV) infection and to aid in the design of an effective HIV vaccine. This supplement of the Journal of Infectious Diseases summarizes work in the humanized mouse model presented at an HIV Humanized Mouse workshop in Boston, Massachusetts, in November 2012, including recent advances in the development of humanized mice, the trafficking of human immune cells following mucosal HIV transmission, the role of immune activation and Toll-like receptor agonists in the control of HIV, the induction and efficacy of HIV-specific cellular and humoral immune responses, and the preclinical modeling of novel anti-HIV therapeutics. Many gaps remain in our understanding of how to design an effective HIV vaccine and novel therapeutics to eliminate the viral reservoir. Promising early results from studies in humanized mice suggest great potential and enthusiasm for this model to accelerate these critical areas of HIV research. PMID:24151317

  16. Alternative (Complementary) Therapies for HIV/AIDS

    MedlinePlus

    ... AIDS » Alternative (Complementary) Therapies for HIV/AIDS HIV/AIDS Menu Menu HIV/AIDS HIV/AIDS Home For ... ZIP code here Alternative (Complementary) Therapies for HIV/AIDS for Veterans and the Public Alternative (Complementary) Therapies ...

  17. Types of HIV/AIDS Antiretroviral Drugs

    MedlinePlus

    ... reverse transcriptase (RT) from converting single-stranded HIV RNA into double-stranded HIV DNA―a process called ... RT, interfering with its ability to convert HIV RNA into HIV DNA Integrase Inhibitors block the HIV ...

  18. Foreign-Born Persons Diagnosed with HIV: Where are They From and Where Were They Infected?

    PubMed

    Wiewel, Ellen W; Torian, Lucia V; Hanna, David B; Bocour, Angelica; Shepard, Colin W

    2015-05-01

    We sought to calculate rates of HIV diagnoses by area of birth among foreign-born persons in a high-incidence US city with many immigrants, and determine probable place of HIV acquisition. Data from the New York City HIV surveillance registry and American Community Survey were used to calculate HIV diagnosis rates by area of birth and determine probable place of HIV acquisition among foreign-born diagnosed in 2006-2012. HIV diagnosis rates varied by area of birth and were highest among African-born persons; absolute numbers were highest among Caribbean-born persons. Probable place of acquisition was a foreign country for 23 % (from 9 % among Middle Easterners to 43 % among Africans), US for 61 % (from 34 % among Africans to 76 % among South Americans), and not possible to estimate for 16 %. HIV prevention and testing initiatives should take into account variability by foreign area of birth in HIV diagnosis rates and place of acquisition. PMID:25524308

  19. Hematopoietic cell transplantation and HIV cure: where we are and what next?

    PubMed Central

    Glynn, Simone; Kuritzkes, Daniel; Shah, Monica; Cook, Nakela; Berliner, Nancy; Berliner, Nancy; Kuritzkes, Daniel; Abrams, Charles; Ambinder, Richard; Busch, Michael; Deeks, Steven; Floris-Moore, Michelle; Kiem, Hans-Peter; Kitchen, Scott; Lederman, Michael; Lin, Nina; Narla, Mohandas; Pillai, Satish; Ragni, Margaret; Ribaudo, Heather; Scadden, David; Hoots, Keith; Dimichele, Donna; Glynn, Simone; Zou, Shimian

    2013-01-01

    The report of the so-called Berlin patient cured of HIV with hematopoietic stem cell transplantation and a few other studies raised tremendous hope, excitement, and curiosity in the field. The National Heart, Lung and Blood Institute of the National Institutes of Health convened a Working Group to address emerging heart, lung, and blood research priorities related to HIV infection. Hematopoietic cells could contribute to HIV cure through allogeneic or autologous transplantation of naturally occurring or engineered cells with anti-HIV moieties. Protection of central memory T cells from HIV infection could be a critical determinant of achieving a functional cure. HIV cure can only be achieved if the virus is eradicated from reservoirs in resting T cells and possibly other hematopoietic cells. The Working Group recommended multidisciplinary efforts leveraging HIV and cell therapy expertise to answer the critical need to support research toward an HIV cure. PMID:24009230

  20. Hematopoietic cell transplantation and HIV cure: where we are and what next?

    PubMed

    Zou, Shimian; Glynn, Simone; Kuritzkes, Daniel; Shah, Monica; Cook, Nakela; Berliner, Nancy

    2013-10-31

    The report of the so-called Berlin patient cured of HIV with hematopoietic stem cell transplantation and a few other studies raised tremendous hope, excitement, and curiosity in the field. The National Heart, Lung and Blood Institute of the National Institutes of Health convened a Working Group to address emerging heart, lung, and blood research priorities related to HIV infection. Hematopoietic cells could contribute to HIV cure through allogeneic or autologous transplantation of naturally occurring or engineered cells with anti-HIV moieties. Protection of central memory T cells from HIV infection could be a critical determinant of achieving a functional cure. HIV cure can only be achieved if the virus is eradicated from reservoirs in resting T cells and possibly other hematopoietic cells. The Working Group recommended multidisciplinary efforts leveraging HIV and cell therapy expertise to answer the critical need to support research toward an HIV cure. PMID:24009230

  1. Short Communication: HIV-1 Infection Suppresses Circulating Viral Restriction microRNAs.

    PubMed

    Zhou, Yu; Sun, Li; Wang, Xu; Liang, Hao; Ye, Li; Zhou, Li; Liang, Bing-Yu; Li, Jie-Liang; Liu, Man-Qing; Peng, Jin-Song; Zhou, Dun-Jin; Gui, Xi-En; Ho, Wen-Zhe

    2016-04-01

    MicroRNAs (miRNAs) participate in host innate immunity against HIV-1 infection. We examined the impact of HIV-1 infection on viral restriction miRNAs in plasma of HIV-1-infected subjects. HIV-1-infected subjects had significantly lower plasma levels of HIV-1 restriction miRNAs (miRs-29a, -29b, -125b, -223, -198, and -382) than control subjects. Further in vitro studies showed that HIV-1 infection of macrophages suppressed production of the extracellular miRs-29b, -125b, and -223. These data demonstrate the compelling evidence that HIV-1 infection impairs host innate immunity by inhibiting antiviral miRNAs, which provide a possible mechanism for HIV-1 persistence in the host. PMID:26607272

  2. Technologies of the HIV/AIDS corpse.

    PubMed

    Troyer, John Erik

    2010-04-01

    In the early 1980s, unprecedented numbers of gay men and intravenous drug users began dying of what would later become known as HIV/AIDS. What the HIV/AIDS corpse posed was a direct challenge to the institutional controls developed by funeral directors to normalize and transform the dead body. How the funeral service industry reacted and changed in response to the emergence of the HIV/AIDS corpse offers an opportunity to re-examine the productive potential of the dead human body. My article examines the epidemic's production of what I call the HIV/AIDS corpse, and the institutional affects those corpses had on the US funeral service industry. The theoretical concept I use to analyze the productive qualities of the HIV/AIDS corpse is the technologies of the corpse. These technologies are the machines, laws, and institutions that control the corpse by classifying, organizing, and physically transforming it. What emerges from the institutional challenges posed by the HIV/AIDS corpse is a specific kind of dead body that offers political possibilities for both the concept of a queer body and the broader subject of human death. PMID:20455141

  3. Is homeopathy possible?

    PubMed

    Milgrom, Lionel R

    2006-09-01

    As a therapeutic intervention, homeopathy is the target of increased scepticism because in the main, its remedies are diluted and succussed (potentized) out of material existence. This puts homeopathy seemingly at odds with the paradigm of conventional science, in particular, that atoms and molecules are the fundamental building blocks of all matter. Accordingly, homeopathy cannot work, so that any reported beneficial effects must, at best, be due to the placebo effect. The purpose of this article is to challenge that conclusion and to suggest that there may well be conventional science-based explanations of how homeopathy could be possible. Homeopathy's key principles are first described. Then the double-blind randomized controlled trial (RCT), the chief means by which homeopathic remedies and prescribing are tested, is shown to be based on a linear reductionism that is too blunt an instrument with which to test the efficacy of complex interventions such as homeopathy The memory of water hypothesis, as a mechanism for how potentized remedies might work, is reviewed, along with some evidence for its existence. A possible rationale for the water memory effect is proposed in terms of a dynamic 'ordering' of water's constantly switching network of intermolecular hydrogen bonds, induced by the manufacturing process of homeopathic remedies. This could lead to a long-range molecular 'coherence' between trillions of mobile water molecules. However, the water memory effect is an essentially pharmacological explanation of homeopathy's putative efficacy. It is pointed out that healing also entails an interaction between consenting beings. From this point of view, an explanation of any therapeutic procedure should include an attempt to describe the nature of the patient-practitioner interaction. From this perspective, a quantum theoretical treatment of the therapeutic process, involving a form of macro-entanglement between patient, practitioner and remedy (PPR), is advanced as another possible explanation of the homeopathy's efficacy. This shows that the reason double-blind RCTs deliver at best only equivocal results on homeopathy's efficacy is because it effectively breaks the PPR entangled state. A comparison is made between the entanglement-breaking effect of double-blind RCTs and the wave-function 'collapsing' effect of observation in orthodox quantum theory. The article concludes by suggesting that the memory of water and PPR entanglement are not competing but most likely complementary hypotheses, and that both are probably required in order to provide a complete description of the homeopathic process. While awaiting experimental evidence of these hypotheses, it is suggested that observations of clinical outcomes would be superior to RCTs for further testing homeopathy's efficacy. PMID:17004404

  4. Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility?

    PubMed Central

    Easley, Charles A.; Simerly, Calvin R.; Schatten, Gerald

    2013-01-01

    Recent advances in assisted reproduction treatment have enabled some couples with severe infertility issues to conceive, but the methods are not successful in all cases. Notwithstanding the significant financial burden of assisted reproduction treatment, the emotional scars from an inability to conceive a child enacts a greater toll on affected couples. While methods have circumvented some root causes for male and female infertility, often the underlying causes cannot be treated, thus true cures for restoring a patient’s fertility are limited. Furthermore, the procedures are only available if the affected patients are able to produce gametes. Patients rendered sterile by medical interventions, exposure to toxicants or genetic causes are unable to utilize assisted reproduction to conceive a child – and often resort to donors, where permitted. Stem cells represent a future potential avenue for allowing these sterile patients to produce offspring. Advances in stem cell biology indicate that stem cell replacement therapies or in-vitro differentiation may be on the horizon to treat and could cure male and female infertility, although significant challenges need to be met before this technology can reach clinical practice. This article discusses these advances and describes the impact that these advances may have on treating infertility. PMID:23664220

  5. Infections in solid organ transplant HIV-infected patients.

    PubMed

    Miro, J M; Agüero, F; Duclos-Vallée, J-C; Mueller, N J; Grossi, P; Moreno, A

    2014-09-01

    Solid organ transplantation (SOT) is an appropriate therapeutic option for HIV-infected patients with end-stage organ disease. Recent experience in North America and Europe indicates that 3- to 5-year survival in HIV/HCV-coinfected liver recipients is lower than that of HCV-monoinfected recipients. Conversely, 3- to 5-year survival of non-HCV-coinfected transplant patients (liver, kidney and heart) was similar to that of non-HIV-infected patients. Preliminary experience with lung transplantation and combined kidney and pancreas transplantation is also satisfactory. Infections in HIV-infected recipients during the post-transplant period are similar to those seen in non-HIV-infected patients, although the incidence rates of tuberculosis and fungal infections seem to be higher. HIV-infected patients who are being evaluated for SOT should follow the same recommendations as those used for non-HIV-infected patients in order to prevent infections during the pre-transplant period. After transplantation, HIV-infected SOT recipients must follow recommendations on post-SOT and anti-HIV immunization and on antimicrobial prophylaxis. The recommended antiretroviral regimen is one based on raltegravir or dolutegravir plus two nucleos(t)ide reverse transcriptase inhibitors (tenofovir + emtricitabine or abacavir + lamivudine), because it can prevent pharmacokinetic interactions between antiretroviral drugs, immunosuppressive drugs and some of the antimicrobial agents used to treat or prevent post-transplant infections. In this manuscript, we review current recommendations for preventing infections both before and after transplantation. We also analyse the incidence, aetiology and clinical characteristics of opportunistic and non-opportunistic bacterial, mycobacterial, fungal and viral infections in HIV-infected SOT recipients during the post-transplant period. PMID:25040016

  6. Sociocultural and epidemiological aspects of HIV/AIDS in Mozambique

    PubMed Central

    2010-01-01

    Background A legacy of colonial rule coupled with a devastating 16-year civil war through 1992 left Mozambique economically impoverished just as the human immunodeficiency virus (HIV) epidemic swept over southern Africa in the late 1980s. The crumbling Mozambican health care system was wholly inadequate to support the need for new chronic disease services for people with the acquired immunodeficiency syndrome (AIDS). Methods To review the unique challenges faced by Mozambique as they have attempted to stem the HIV epidemic, we undertook a systematic literature review through multiple search engines (PubMed, Google Scholar™, SSRN, AnthropologyPlus, AnthroSource) using Mozambique as a required keyword. We searched for any articles that included the required keyword as well as the terms 'HIV' and/or 'AIDS', 'prevalence', 'behaviors', 'knowledge', 'attitudes', 'perceptions', 'prevention', 'gender', drugs, alcohol, and/or 'health care infrastructure'. Results UNAIDS 2008 prevalence estimates ranked Mozambique as the 8th most HIV-afflicted nation globally. In 2007, measured HIV prevalence in 36 antenatal clinic sites ranged from 3% to 35%; the national estimate of was 16%. Evidence suggests that the Mozambican HIV epidemic is characterized by a preponderance of heterosexual infections, among the world's most severe health worker shortages, relatively poor knowledge of HIV/AIDS in the general population, and lagging access to HIV preventive and therapeutic services compared to counterpart nations in southern Africa. Poor education systems, high levels of poverty and gender inequality further exacerbate HIV incidence. Conclusions Recommendations to reduce HIV incidence and AIDS mortality rates in Mozambique include: health system strengthening, rural outreach to increase testing and linkage to care, education about risk reduction and drug adherence, and partnerships with traditional healers and midwives to effect a lessening of stigma. PMID:20529358

  7. Towards Combination HIV Prevention for Injection Drug Users: Addressing Addictophobia, Apathy and Inattention

    PubMed Central

    Strathdee, Steffanie A.; Shoptaw, Steven; Dyer, Typhanye Penniman; Quan, Vu Minh; Aramrattana, Apinun

    2013-01-01

    Purpose of the review Recent breakthroughs in HIV-prevention science led us to evaluate the current state of combination HIV-prevention for injection drug users (IDUs). We review the recent literature focusing on possible reasons why coverage of prevention interventions for HIV, HCV and tuberculosis among IDUs remains dismal. We make recommendations for future HIV research and policy. Recent findings IDUs disproportionately under-utilize VCT, primary care and ART, especially in countries that have the largest burden of HIV among IDUs. IDUs present later in the course of HIV infection and experience greater morbidity and mortality. Why are IDUs under-represented in HIV-prevention research, access to treatment for both HIV and addiction, and access to HIV combination prevention? Possible explanations include addictophobia, apathy, and inattention, which we describe in the context of recent literature and events. Summary This commentary discusses the current state of HIV-prevention interventions for IDUs including, VCT, NSP, OST, ART and PrEP, and discusses ways to work towards true combination HIV-prevention for IDU populations. Communities need to overcome tacit assumptions that IDUs can navigate through systems that are maintained as separate silos, and take a rights-based approach to HIV-prevention to ensure that IDUs have equitable access to life-saving prevention and treatments. PMID:22498479

  8. HIV and dentistry in Australia: clinical and legal issues impacting on dental care.

    PubMed

    McLean, A T; Wheeler, E K; Cameron, S; Baker, D

    2012-09-01

    The number of people in Australia living with HIV is growing. This reflects a consistent rate of new HIV infections combined with an increased life expectancy of people with HIV. Dentists are ideally positioned to identify, manage and treat HIV-associated oral manifestations and have a responsibility to themselves and to their patients to be up-to-date with the evolving area of HIV and related issues. Those issues include medico-legal implications associated with HIV diagnosis and treatment. This article provides a review of the current clinical and medico-legal aspects of HIV in Australia. The oral manifestations of HIV can be divided into five categories: microbiological infections (fungal, bacterial and viral); oral neoplasms; neurological conditions; other oral conditions that may be associated with HIV infection; and oral conditions associated with HIV treatment. Current treatment options in the scope of general dental practice are outlined. Medico-legal issues related to the management of patients with HIV are explored, including rights of the patient regarding disclosure of HIV status; an algorithm for the management of a patient with signs or symptoms indicating possible HIV infection, including referral pathways; and an algorithm for dealing with patient management and referral issues. PMID:22924347

  9. Antibodies: can they protect against HIV infection?

    PubMed

    Mc Cann, C M; Song, R J; Ruprecht, R M

    2005-06-01

    More than 20 million people have died since the discovery of human immunodeficiency virus (HIV), yet a broadly reactive AIDS vaccine remains elusive. Neutralizing antibody (nAb) response-based vaccine strategies were the first to be tested; however, when the difficulty in neutralizing primary HIV isolates was recognized, vaccine development focused instead on generating cytotoxic T-lymphocyte (CTL) responses. Recently, interest in anti-HIV nAbs has been revived by the impressive protection achieved in primates given passive immunization with neutralizing monoclonal antibodies (nmAbs) isolated from HIV clade B-infected individuals. The nmAbs used in these studies target conserved, functionally important epitopes in HIV gp120 and gp41. Regimens involving combinations of such human nmAbs or high-dose single-agent nmAb protected monkeys against intravenous (iv) and mucosal challenges with simian-human immunodeficiency virus (SHIV) strains encoding X4, X4R5 or R5 HIV env genes. In several such studies, sterilizing immunity was achieved, thus providing proof-of-concept that nAbs targeting conserved epitopes can be fully protective. The existence of these broadly reactive nmAbs suggests that it may be possible to design immunogens capable of inducing similar nAb responses by active vaccination. Unraveling the three-dimensional structures involved in the nmAb-HIV Env epitope interactions may facilitate the future development of a potent AIDS vaccine. This review is focused on the importance of nAbs in protecting against HIV infection or in containing viral spread, with particular emphasis on the successful use of nmAbs in passive immunization studies. The implications of the data from these studies on AIDS vaccine design in general are also discussed. PMID:15975016

  10. Increased α-Defensins 1-3 Production by Dendritic Cells in HIV-Infected Individuals Is Associated with Slower Disease Progression

    PubMed Central

    Rodríguez-García, Marta; Casanova, Víctor; Franco, Rafael; Leon, Agathe; Gatell, José M.; García, Felipe; Gallart, Teresa

    2010-01-01

    Background Defensins are natural endogenous antimicrobial peptides with potent anti-HIV activity and immuno-modulatory effects. We recently demonstrated that immature dendritic cells (DC) produce α-defensins1-3 and that α-defensins1-3 modulate DC generation and maturation. Since DC-HIV interaction plays a critical role during the first steps of HIV infection, we investigated the possible impact of α-defensins1-3 production by DC on disease progression. Methodology/Principal Findings Monocyte-derived DC (MDDC) were analyzed comparatively in healthy controls (HC) and HIV-infected patients, including untreated “elite” and “viremic” controllers, untreated viremic non-controllers and antiretroviral-treated patients. We found that production of α-defensins1-3 was significantly increased in MDDC from HIV-infected patients versus HC, and this increase was mainly due to that observed in controllers, while in non-controllers the increase was not statistically significant (controllers vs. HC, p<0.005; controllers vs. non-controllers p<0.05). Secreted α-defensins1-3 by immature MDDC positively correlated with CD4 T cell counts in controllers, but not in non-controllers. Moreover, independently of their clinical classification, HIV-infected patients with higher α-defensins1-3 secretion by immature MDDC showed slower disease progression, measured as no decrease in the number of CD4+ T-cells below 350 cell/mm3, lower increase of plasma viral load and no initiation of treatment over time. Plasma alpha-defensins1-3 levels lacked any relationship with immunologic and virologic parameters. Conclusions/Significance High production of α-defensins1-3 by immature DCs appears as a host protective factor against progression of HIV-1infection, suggesting potential diagnostic, therapeutic and preventive implications. This protective effect may arise from the activity of α-defensins1-3 to damage the virions prior and/or after their internalization by immature DC, and hence favoring a more efficient viral processing and presentation to HIV-specific CD4+ T cells, without or with a minor rate of transmission of infectious HIV-1 virions. PMID:20195543

  11. Relation of HIV-I in bronchoalveolar lavage cells to abnormalities of lung function and to the presence of Pneumocystis pneumonia in HIV-I seropositive patients.

    PubMed Central

    Clarke, J. R.; Taylor, I. K.; Fleming, J.; Williamson, J. D.; Mitchell, D. M.

    1993-01-01

    BACKGROUND--HIV is present in bronchoalveolar lavage cells of some but not all HIV seropositive patients. Abnormalities of lung function have been described in such patients in the absence of clinically overt pneumonia or other respiratory infections. It is possible that the presence of HIV in alveolar macrophages could account for these abnormalities. It is also possible that the presence of HIV in alveolar macrophages contributes to immunosuppression and an increased incidence of opportunistic infections. METHODS--This was a prospective study of 157 HIV seropositive patients requiring diagnostic bronchoscopy for investigation of new respiratory symptoms, chest radiograph abnormality, or pneumonic illness. Presence of HIV in bronchoalveolar lavage cells obtained at diagnostic bronchoscopy was determined by polymerase chain reaction to detect proviral DNA and in vitro cocultivation to detect productive virus infection. With these two techniques the presence or absence of HIV in bronchoalveolar lavage was compared with the presence of abnormalities of lung function or presence of Pneumocystis pneumonia. RESULTS--HIV was detected in bronchoalveolar lavage cells in 65% of patients by means of the polymerase chain reaction and 59% with cocultivation. With both methods of detection there was no association between the presence or absence of HIV and the presence of Pneumocystis pneumonia; nor was there a relation between the presence of HIV and abnormalities of lung function. CONCLUSION--The presence of HIV in bronchoalveolar lavage cells does not predispose to an increased incidence of Pneumocystis pneumonia; nor does it contribute to abnormalities of lung function. PMID:8303627

  12. Caspases as therapeutic targets

    PubMed Central

    Howley, B; Fearnhead, HO

    2008-01-01

    Abstract The development of small molecules to modulate caspase activity offers a novel therapeutic strategy in the treatment of apoptosis-related and inflammatory diseases. Caspases are key mediators of apoptosis and inflammation; deregulation of their activation or expression can lead to the development of conditions such as neurodegenerative and autoinflammatory disorders. This review details the different caspase-associated disorders while focusing on caspase-1 inhibition as a potential therapeutic strategy. Problems facing the development of effective and safe caspase therapeutics will also be addressed. PMID:18298652

  13. Molecular Characterization of Mexican HIV-1 Vif Sequences.

    PubMed

    Guerra-Palomares, Sandra E; Hernandez-Sanchez, Pedro G; Esparza-Perez, Mario A; Arguello, J Rafael; Noyola, Daniel E; Garcia-Sepulveda, Christian A

    2016-03-01

    The viral infectivity factor (Vif) is an HIV accessory protein that counteracts host antiviral proteins of the APOBEC3 family. Accumulating evidence highlights the pivotal role that accessory HIV proteins have on disease pathogenesis, a fact that has made them targets of interest for novel therapeutic and preventive strategies. Little is known about Vif sequence diversity outside of African or white populations. Mexico is home to Americas' third largest HIV-affected population and Mexican Hispanics represent an ever-increasing U.S. minority. This study provides a detailed analysis of the diversity seen in 77 Mexican Vif protein sequences. Phylogenetic analysis shows that most sequences cluster with HIV-1 subtype B, while less than 10% exhibit greater similarity to subtype D and A subtypes. Although most functional motifs are conserved among the Mexican sequences, substantial diversity was seen in some APOBEC binding sites, the nuclear localization inhibitory signal, and the CBFβ interaction sites. PMID:26529466

  14. Disruption of gut homeostasis by opioids accelerates HIV disease progression

    PubMed Central

    Meng, Jingjing; Sindberg, Gregory M.; Roy, Sabita

    2015-01-01

    Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. PMID:26167159

  15. Increased longevity in HIV: caring for older HIV-infected adults.

    PubMed

    Ball, Susan C

    2014-01-01

    The demographics of the HIV-infected population in the United States have shifted in a way that few would have predicted 30 years ago when the tide of sick and dying patients largely consisted of young men. Effective ART has allowed those infected to live long, productive lives and to grow old with their disease. With the increase in life expectancy afforded by HIV treatment, the cause of death among HIV-infected individuals is far more likely to be from an HIV-associated non-AIDS condition. Nonetheless, HIV seems to accelerate the aging process, and care providers involved in the treatment of older patients with HIV need to be aware that their patients are at increased risk of developing various common disorders, compared to uninfected same-age patients. Clinicians need to remain vigilant to the possibility of a new diagnosis of HIV among their older patients. Awareness of current or distant risk, frank discussions of sexual practices, and willingness to offer routine testing are crucial to making this diagnosis, with the recognition that longevity for patients with HIV is directly linked to how soon they enter care. HIV infection adds another challenge to the management of older patients; geriatricians and HIV specialists need to coordinate their efforts to provide patients with comprehensive multidisciplinary care. Older patients with HIV also have social and psychological needs that extend beyond the medical office. Maintaining independence, acknowledging limitations, reducing risk of adverse events such as falls or medication errors, and supporting self-acceptance and awareness are only a few of the many areas where care providers outside the medical office can be important for patients' ongoing well-being. Accessing family support, community outreach, church affiliation, or other outpatient support networks can be useful for patients. The remarkable change in prognosis brought about by effective ART in the mid-1990s has meant that HIV is now, for many, a manageable chronic illness. Clinicians and other care providers are changing their approach and goals of care as patients with HIV grow old. PMID:25118513

  16. Review of HIV Testing Efforts in Historically Black Churches

    PubMed Central

    Pichon, Latrice Crystal; Powell, Terrinieka Williams

    2015-01-01

    This paper aims to critically assess the state of HIV testing in African American churches. A comprehensive review of peer-reviewed publications on HIV testing in church-based settings was conducted by two independent coders. Twenty-six papers published between 1991 and 2015, representing 24 unique projects, were identified addressing at least one dimension of HIV testing. Thirteen faith-based projects have implemented HIV testing events or had clergy promote the importance of testing and knowing one’s HIV status, but empirical data and rigorous study designs were limited. Only eight papers reported onsite HIV testing in churches. Less than 5% of the studies reported the percentage of congregants who returned for their test results. Finally, no study has examined at baseline or post-intervention behavioral intentions to be screened for HIV. Future research is needed to evaluate the effectiveness of HIV testing in churches and to explore the possibilities of the role of the church and leadership structure in the promotion of HIV treatment and care. PMID:26030470

  17. Antiviral agents and HIV prevention: controversies, conflicts, and consensus

    PubMed Central

    Cohen, Myron S.; Muessig, Kathryn E.; Smith, M. Kumi; Powers, Kimberly A.; Kashuba, Angela D.M.

    2013-01-01

    Antiviral agents can be used to prevent HIV transmission before exposure as preexpo-sure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups – including intravenous drug users and MSM – has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation. PMID:22507927

  18. Review of HIV Testing Efforts in Historically Black Churches.

    PubMed

    Pichon, Latrice Crystal; Powell, Terrinieka Williams

    2015-06-01

    This paper aims to critically assess the state of HIV testing in African American churches. A comprehensive review of peer-reviewed publications on HIV testing in church-based settings was conducted by two independent coders. Twenty-six papers published between 1991 and 2015, representing 24 unique projects, were identified addressing at least one dimension of HIV testing. Thirteen faith-based projects have implemented HIV testing events or had clergy promote the importance of testing and knowing one's HIV status, but empirical data and rigorous study designs were limited. Only eight papers reported onsite HIV testing in churches. Less than 5% of the studies reported the percentage of congregants who returned for their test results. Finally, no study has examined at baseline or post-intervention behavioral intentions to be screened for HIV. Future research is needed to evaluate the effectiveness of HIV testing in churches and to explore the possibilities of the role of the church and leadership structure in the promotion of HIV treatment and care. PMID:26030470

  19. Can we treat our way out of HIV?

    PubMed

    Johnston, Rowena; Collins, Chris

    2010-01-01

    There is a range of settings in which antiretroviral therapy can decrease the incidence of HIV. Recently, it was revealed that the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC) plan to study a test and treat strategy to reduce the spread of HIV. A test and treat strategy presents numerous implementation, operational, structural, and policy issues that will require research to be effectively addressed. The timing of the interest in a test and treat strategy and this first foray into exploring its potential implementation come at a critical juncture in the history of HIV/AIDS in the United States, where recent data from the CDC indicate that the prevalence and incidence of HIV are considerably higher than had previously been thought, and the Obama administration is currently developing a National HIV/AIDS Strategy (NHAS) whose three primary goals are reducing HIV incidence, increasing access to care, and reducing HIV-related health disparities. Indeed, the test and treat strategy is possibly unique in its direct relevance to all three main goals of the NHAS. A strategic approach to research will define portfolios and allocate resources based on their ability to move toward accomplishing the three NHAS goals. A National HIV/AIDS Strategy that both informs and is informed by a strong research agenda is a long-awaited and much anticipated development in the battle against HIV/AIDS in the United States. PMID:20055588

  20. HIV/AIDS, conflict and security in Africa: rethinking relationships

    PubMed Central

    2008-01-01

    The effect of conflict on HIV transmission and regional and global security has been the subject of much recent discussion and debate. Many long held assumptions regarding these relationships are being reconsidered. Conflict has long been assumed to contribute significantly to the spread of HIV infection. However, new research is casting doubt on this assumption. Studies from Africa suggest that conflict does not necessarily predispose to HIV transmission and indeed, there is evidence to suggest that recovery in the "post-conflict" state is potentially dangerous from the standpoint of HIV transmission. As well, refugee populations have been previously considered as highly infected vectors of HIV transmission. But in light of new investigation this belief is also being reconsidered. There has additionally been concern that high rates of HIV infection among many of the militaries of sub-Saharan Africa poses a threat to regional security. However, data is lacking on both dramatically elevated prevalence amongst soldiers and a possible negative effect on regional security. Nevertheless, HIV/AIDS remain a serious threat to population health and economic well being in this region. These issues are of vital importance for HIV programming and health sector development in conflict and "post-conflict" societies and will constitute formidable challenges to the international community. Further research is required to better inform the discussion of HIV, conflict, and security in sub-Saharan Africa. PMID:19014653

  1. HIV, cancer, and aging.

    PubMed

    Grulich, Andrew E; Jin, Fengyi; Poynten, I Mary; Vajdic, Claire M

    2011-12-01

    As people with HIV age, they will experience increasing rates of all diseases of aging, including cancer. However, the pattern of higher cancer risk in people with HIV is mostly explained by the chronic effects of certain oncogenic infections, and is not consistent with a syndrome of accelerated aging. Many of those cancers that are most closely associated with aging do not occur at increased rates in people with HIV compared with the general population. The risk of many infection-associated cancers in people with HIV is closely related to the degree of immune deficiency, and for some types of cancer, it is also associated with ongoing HIV replication. Thus, if HIV therapy can provide durable HIV suppression and maintain near normal levels of immune function, the excess risk of cancer is likely to be minimised. While avoidance of profound immunity will greatly reduce cancer risk, it is unclear how close to normal immune function must be to minimise HIV-associated cancer risk. People with HIV are also at a high risk of cancer because they have high rates of lifestyle risks for cancer, in particular tobacco and alcohol exposure. For most cancers, it is appropriate to follow general population guidelines on cancer screening. The exception is cervical cancer, for which annual screening is recommended. In addition, active research is required to establish whether anal cancer screening would prevent the unacceptably high levels of morbidity caused by this disease in people with HIV, most particularly in gay men. PMID:22127038

  2. HIV/AIDS and Alcohol

    MedlinePlus

    ... Psychiatric Disorders Other Substance Abuse HIV/AIDS HIV/AIDS Human immunodeficiency virus (HIV) targets the body’s immune ... and often leads to acquired immune deficiency syndrome (AIDS). Each year in the United States, between 55, ...

  3. HIV, AIDS, and the Future

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues HIV / AIDS HIV, AIDS, and the Future Past Issues / Summer 2009 Table ... and your loved ones from HIV/AIDS. The AIDS Memorial Quilt In 1987, a total of 1, ...

  4. HIV / AIDS: An Unequal Burden

    MedlinePlus

    ... Navigation Bar Home Current Issue Past Issues HIV / AIDS HIV / AIDS: An Unequal Burden Past Issues / Summer 2009 Table ... Victoria Cargill talks to students about HIV and AIDS at the opening of a National Library of ...

  5. HIV/AIDS in Women

    MedlinePlus

    HIV, the human immunodeficiency virus, kills or damages cells of the body's immune system. The most advanced stage of infection with HIV is AIDS, which stands for acquired immunodeficiency syndrome. HIV often ...

  6. Interactive effects of cocaine on HIV infection: implication in HIV-associated neurocognitive disorder and neuroAIDS

    PubMed Central

    Dahal, Santosh; Chitti, Sai V. P.; Nair, Madhavan P. N.; Saxena, Shailendra K.

    2015-01-01

    Substantial epidemiological studies suggest that not only, being one of the reasons for the transmission of the human immunodeficiency virus (HIV), but drug abuse also serves its role in determining the disease progression and severity among the HIV infected population. This article focuses on the drug cocaine, and its role in facilitating entry of HIV into the CNS and mechanisms of development of neurologic complications in infected individuals. Cocaine is a powerfully addictive central nervous system stimulating drug, which increases the level of neurotransmitter dopamine (DA) in the brain, by blocking the dopamine transporters (DAT) which is critical for DA homeostasis and neurocognitive function. Tat protein of HIV acts as an allosteric modulator of DAT, where as cocaine acts as reuptake inhibitor. When macrophages in the CNS are exposed to DA, their number increases. These macrophages release inflammatory mediators and neurotoxins, causing chronic neuroinflammation. Cocaine abuse during HIV infection enhances the production of platelet monocyte complexes (PMCs), which may cross transendothelial barrier, and result in HIV-associated neurocognitive disorder (HAND). HAND is characterized by neuroinflammation, including astrogliosis, multinucleated giant cells, and neuronal apoptosis that is linked to progressive virus infection and immune deterioration. Cocaine and viral proteins are capable of eliciting signaling transduction pathways in neurons, involving in mitochondrial membrane potential loss, oxidative stress, activation of JNK, p38, and ERK/MAPK pathways, and results in downstream activation of NF-κB that leads to HAND. Tat-induced inflammation provokes permeability of the blood brain barrier (BBB) in the platelet dependent manner, which can potentially be the reason for progression to HAND during HIV infection. A better understanding on the role of cocaine in HIV infection can give a clue in developing novel therapeutic strategies against HIV-1 infection in cocaine using HIV infected population. PMID:26441868

  7. [The obese patient's therapeutic course].

    PubMed

    Giusti, V

    2006-03-29

    Obesity as a chronic disease needs a global approach taking into account, not only usual anthropometrical measurements allowing to define severity and the type of obesity (BMI and waist circumference) but also others parameters to evaluate the patient's morbid conscience and his level of motivation towards a potential treatment. Obese patient's possible therapeutic course is developed in this article according to three important parameters: eating disorders, motivation and capacity of introspection. The aim is to give tools to the generalist to select patients needing a multidisciplinary follow up in a specialized centre and those who can be treated in the office. PMID:16646369

  8. A lymphomagenic role for HIV beyond immune suppression?

    PubMed

    Dolcetti, Riccardo; Gloghini, Annunziata; Caruso, Arnaldo; Carbone, Antonino

    2016-03-17

    Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting. PMID:26773045

  9. A lymphomagenic role for HIV beyond immune suppression?

    PubMed Central

    Dolcetti, Riccardo; Gloghini, Annunziata; Caruso, Arnaldo

    2016-01-01

    Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting. PMID:26773045

  10. Salk's HIV immunogen: an immune-based therapy in human trials since 1988.

    PubMed

    Jonas Salk, the developer of the first polio vaccine, has created a therapeutic vaccine for HIV which helps the immune system fight disease progression. Salk uses inactivated HIV-1 virus combined with Incomplete Freund's Adjuvant (IFA) in the vaccine preparation. The resulting HIV-1 immunogen was first studied in 1987, and since then, 235 seropositive individuals have received inoculations without serious adverse effects. Data from the first 25 subjects indicate that immunization with the HIV-1 immunogen results in improvement of cell-mediated response against the virus, a slower increase in the amount of virus present, and a reduced rate of clinical progression. Subsequent studies also show that higher doses of immunogen may produce stronger cell-mediated responses and high HIV-DTH (delayed-type hypersensitivity responsiveness immunogen) is associated with better outcome. Additional trials of HIV-1 immunogen are awaiting Food and Drug Administration approval. PMID:11362152

  11. HIV-induced alteration in gut microbiota: driving factors, consequences, and effects of antiretroviral therapy.

    PubMed

    Lozupone, Catherine A; Rhodes, Matthew E; Neff, Charles P; Fontenot, Andrew P; Campbell, Thomas B; Palmer, Brent E

    2014-07-01

    Consistent with an important role for adaptive immunity in modulating interactions between intestinal bacteria and host, dramatic alteration in the composition of gut microbes during chronic HIV infection was recently reported by ourselves and independently by four other research groups. Here we evaluate our results in the context of these other studies and delve into the effects of antiretroviral therapy (ART). Although gut microbiota of HIV-positive individuals on ART usually does not resemble that of HIV-negative individuals, the degree to which ART restores health-associated prevalence varies across bacterial taxa. Finally, we discuss potential drivers and health consequences of gut microbiota alterations. We propose that understanding the mechanism of HIV-associated gut microbiota changes will elucidate the role of adaptive immunity in shaping gut microbiota composition, and lay the foundation for therapeutics targeting the microbiota to attenuate HIV disease progression and reduce the risk of gut-linked disease in people with HIV. PMID:25078714

  12. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection.

    PubMed

    Shankar, Esaki M; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-02-12

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis. PMID:25674514

  13. Gene Therapy Strategies for HIV/AIDS: Preclinical Modeling in Humanized Mice

    PubMed Central

    Bennett, Michael S.; Akkina, Ramesh

    2013-01-01

    In the absence of an effective vaccine and lack of a complete cure, gene therapy approaches to control HIV infection offer feasible alternatives. Due to the chronic nature of infection, a wide window of opportunity exists to gene modify the HIV susceptible cells that continuously arise from the bone marrow source. To evaluate promising gene therapy approaches that employ various anti-HIV therapeutic molecules, an ideal animal model is necessary to generate important efficacy and preclinical data. In this regard, the humanized mouse models that harbor human hematopoietic cells susceptible to HIV infection provide a suitable in vivo system. This review summarizes the currently used humanized mouse models and different anti-HIV molecules utilized for conferring HIV resistance. Humanized mouse models are compared for their utility in this context and provide perspectives for new directions. PMID:24351796

  14. Mechanistic insights on immunosenescence and chronic immune activation in HIV-tuberculosis co-infection

    PubMed Central

    Shankar, Esaki M; Velu, Vijayakumar; Kamarulzaman, Adeeba; Larsson, Marie

    2015-01-01

    Immunosenescence is marked by accelerated degradation of host immune responses leading to the onset of opportunistic infections, where senescent T cells show remarkably higher ontogenic defects as compared to healthy T cells. The mechanistic association between T-cell immunosenescence and human immunodeficiency virus (HIV) disease progression, and functional T-cell responses in HIV-tuberculosis (HIV-TB) co-infection remains to be elaborately discussed. Here, we discussed the association of immunosenescence and chronic immune activation in HIV-TB co-infection and reviewed the role played by mediators of immune deterioration in HIV-TB co-infection necessitating the importance of designing therapeutic strategies against HIV disease progression and pathogenesis. PMID:25674514

  15. Interleukin-7 promotes HIV persistence during antiretroviral therapy.

    PubMed

    Vandergeeten, Claire; Fromentin, Rémi; DaFonseca, Sandrina; Lawani, Mariam B; Sereti, Irini; Lederman, Michael M; Ramgopal, Moti; Routy, Jean-Pierre; Sékaly, Rafick-Pierre; Chomont, Nicolas

    2013-05-23

    HIV persists in latently infected memory CD4(+) T cells during antiretroviral therapy (ART). When administered to HIV-infected subjects receiving suppressive ART, interleukin-7 (IL-7) increases the number of CD4(+) T cells by promoting their survival and proliferation. However, little is known about the impact of IL-7 on HIV persistence during ART. By isolating large numbers of CD4(+) T cells from HIV-infected subjects, we demonstrate that IL-7 enhances viral production in productively infected cells but does not disrupt viral latency in latently infected cells. When administered to virally suppressed subjects, IL-7 led to the rapid proliferation of memory CD4(+) T cells, which resulted in a 70% increase in the absolute number of circulating CD4(+) T cells harboring integrated HIV DNA 4 weeks after therapy. The genetic diversity of the viral reservoir increased transiently in the majority of the subjects studied before returning to baseline values. Altogether, our results indicate that IL-7 promotes the mechanisms of HIV persistence during ART by enhancing residual levels of viral production and inducing proliferation of latently infected cells, and suggest that IL-7 does not represent a suitable candidate therapeutic strategy for HIV eradication. This trial was registered at www.clinicaltrials.gov as #NCT00099671 (AIDS Clinical Trials Group protocol 5214). PMID:23589672

  16. Interleukin-7 promotes HIV persistence during antiretroviral therapy

    PubMed Central

    Vandergeeten, Claire; Fromentin, Rémi; DaFonseca, Sandrina; Lawani, Mariam B.; Sereti, Irini; Lederman, Michael M.; Ramgopal, Moti; Routy, Jean-Pierre; Sékaly, Rafick-Pierre

    2013-01-01

    HIV persists in latently infected memory CD4+ T cells during antiretroviral therapy (ART). When administered to HIV-infected subjects receiving suppressive ART, interleukin-7 (IL-7) increases the number of CD4+ T cells by promoting their survival and proliferation. However, little is known about the impact of IL-7 on HIV persistence during ART. By isolating large numbers of CD4+ T cells from HIV-infected subjects, we demonstrate that IL-7 enhances viral production in productively infected cells but does not disrupt viral latency in latently infected cells. When administered to virally suppressed subjects, IL-7 led to the rapid proliferation of memory CD4+ T cells, which resulted in a 70% increase in the absolute number of circulating CD4+ T cells harboring integrated HIV DNA 4 weeks after therapy. The genetic diversity of the viral reservoir increased transiently in the majority of the subjects studied before returning to baseline values. Altogether, our results indicate that IL-7 promotes the mechanisms of HIV persistence during ART by enhancing residual levels of viral production and inducing proliferation of latently infected cells, and suggest that IL-7 does not represent a suitable candidate therapeutic strategy for HIV eradication. This trial was registered at www.clinicaltrials.gov as #NCT00099671 (AIDS Clinical Trials Group protocol 5214). PMID:23589672

  17. Molecular Mechanisms of Liver Fibrosis in HIV/HCV Coinfection

    PubMed Central

    Mastroianni, Claudio M.; Lichtner, Miriam; Mascia, Claudia; Zuccal, Paola; Vullo, Vincenzo

    2014-01-01

    Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV. PMID:24865485

  18. Serum suppressive activity of HIV seropositive patients.

    PubMed Central

    Israel-Biet, D; Ekwalanga, M; Venet, A; Even, P; Andrieu, J M

    1988-01-01

    The mechanisms by which HIV induces immunosuppression are still poorly understood so far. Several pathways of CD4 cell destruction are known, including cytolysis with or without syncitium formation and killing by cytotoxic effectors of HIV infected or non-infected CD4 cells. However, a discrepancy exists between the small number of actually infected cells in vivo and the extent of HIV-related immunodeficiency. Among other possible immunosuppressive factors, serum blocking factors have been reported, but only in AIDS-related opportunistic infections (OI), i.e. in a quite specific type of full-blown HIV disease. The purpose of this work was to determine whether serum blocking activity was unique to this group of patients, or if it was also expressed in other clinical presentations and, moreover, at earlier stages of the disease. We also attempted to delineate the nature of these seric factors. In order to do so, we assessed serum suppressive activity of 50 HIV seropositive patients, seven with OI, eight with Kaposi's sarcoma (KS), and 35 with no clinical AIDS. Our results confirm the existence of serum inhibiting factors in AIDS, and demonstrate their presence at earlier stages of the disease. They also highlight the fact that the level of serum suppression does not correlate with patients clinical status, but increases with the severity of the disease. The lower the CD4 count, the higher the suppression exerted. Furthermore, we showed that the suppression was at least partly mediated by small size molecules, which are not complement-mediated or directly lymphocytotoxic. On the other hand, this activity does not correlate with the serum level of p24 HIV core protein. The possible relation with other viral components is discussed. The relevance of these data to prognosis and pathogenesis of HIV disease deserves further investigation. PMID:2975974

  19. Therapeutic Drug Monitoring

    MedlinePlus

    ... Also known as: TDM Formal name: Therapeutic Drug Monitoring Related tests: Emergency and Overdose Drug Testing ; BUN ; Creatinine ; Liver ... tests such as BUN , creatinine , and liver function tests , monitoring can help identify decreases in the efficiency of ...

  20. Oral lesions of HIV disease and HAART in industrialized countries.

    PubMed

    Hodgson, T A; Greenspan, D; Greenspan, J S

    2006-01-01

    The epidemiology of HIV-related oral disease in industrialized nations has evolved following the initial manifestations described in 1982. Studies from both the Americas and Europe report a decreased frequency of HIV-related oral manifestations of 10-50% following the introduction of HAART (highly active antiretroviral therapy). Evidence suggests that HAART plays an important role in controlling the occurrence of oral candidosis. The effect of HAART on reducing the incidence of oral lesions, other than oral candidosis, does not appear as significant, possibly as a result of low lesion prevalence in industrialized countries. In contrast to other oral manifestations of HIV, an increased prevalence of oral warts in patients on HAART has been reported from the USA and the UK. HIV-related salivary gland disease may show a trend of rising prevalence in the USA and Europe. The re-emergence of HIV-related oral disease may be indicative of failing therapy. A range of orofacial iatrogenic consequences of HAART has been reported, and it is often difficult to distinguish between true HIV-related oral disease manifestations and the adverse effects of HAART. A possible association between an increased risk of oral squamous cell carcinoma and HIV infection has been suggested by at least three epidemiological studies, with reference to the lip and tongue. These substantial and intensive research efforts directed toward enhancing knowledge regarding the orofacial consequences of HIV infection in the industrialized nations require dissemination in the wider health care environment. PMID:16672551

  1. The treatment of non-HIV-related conditions in newborns at risk for HIV: a survey of neonatologists.

    PubMed Central

    Levin, B W; Krantz, D H; Driscoll, J M; Fleischman, A R

    1995-01-01

    OBJECTIVES. The purpose of this study was to examine attitudes of neonatologists about treatment of conditions unrelated to the human immunodeficiency virus (HIV) for critically ill newborns at risk for HIV. METHODS. Questionnaires were mailed to the 1508 members of the Section on Perinatal Medicine of the American Academy of Pediatrics; 63% completed the survey (n = 951). The survey included structured questions about treatment for hypothetical cases and open-ended questions eliciting reasons for decisions. RESULTS. Differences in recommendations for treatment by both maternal and infant HIV status were substantial and statistically reliable. For example, 98% of respondents recommended life-saving cardiac surgery for a neonate with no risk for HIV, but only 93% recommended such surgery for a child of an HIV-positive mother; only 50% recommended the same surgery for a newborn known to be infected. The corresponding figures for chronic dialysis were 91%, 61%, and 26%. Most expected diminished quality of life for both infected and uninfected children of HIV-positive mothers. CONCLUSIONS. Recommendations about life-sustaining treatment for non-HIV-related conditions varied by HIV status. These data on physician attitudes raise the possibility that infants labeled as HIV positive, whether infected or not, may suffer discrimination. PMID:7485662

  2. Cuba's response to the HIV epidemic.

    PubMed Central

    Pérez-Stable, E J

    1991-01-01

    BACKGROUND: Cuba's response to the human immunodeficiency virus (HIV) epidemic has been to conduct mass testing of the population to ascertain seroprevalence, to enforce mandatory relative quarantine of persons testing positive, and to implement educational interventions using media and school-based programs. METHODS: Interview with the Vice-Minister of Health and review of available data. RESULTS: Reports to date show a very low seroprevalence rate without evidence of a widespread epidemic. Sexual contact with foreign-born persons is the primary risk factor. Possible advantages of Cuba's policy include rapid reduction in the risk of HIV transmission by infected blood products, an opportunity for focused education and secondary prevention, and limitation of new infections. Possible disadvantages include the restriction of individual freedom in those who are not guilty of any illegal act, quarantine of persons with false positive HIV tests, and ongoing transmission because of the incomplete nature of the quarantine. The policy is expensive and may displace other public health priorities. The content of the media-based educational interventions has emphasized rational medical information in unimaginative formats with a limited focus on prevention. CONCLUSIONS: The issue of personal responsibility for behavioral change versus government imposed regulations is at the core of Cuba's HIV policy. The quarantine policy may paradoxically permit most Cubans to feel that they are personally invulnerable to the HIV epidemic. PMID:2014854

  3. What is new in HIV infection?

    PubMed

    Sherin, Kevin; Klekamp, Benjamin G; Beal, Jeffery; Martin, Nicolle

    2014-02-15

    Human immunodeficiency virus (HIV) prevention and treatment updates include screening recommendations, fourth-generation testing, preexposure prophylaxis, and a paradigm shift; treatment is prevention. The U.S. Preventive Services Task Force recommends routine HIV screening in persons 15 to 65 years of age, regardless of risk. Fourth-generation testing is replacing the Western blot and can identify those with acute HIV infection. The U.S. Food and Drug Administration approved the OraQuick In-Home HIV Test; however, there are concerns about reduced sensitivity, possible misinterpretation of results, potential for less effective counseling, and possible cost barriers. Preexposure prophylaxis (effective in select high-risk adult populations) is the combination of safer sex practices and continuous primary care prevention services, plus combination antiretroviral therapy. Concerns for preexposure prophylaxis include the necessity of strict medication adherence, limited use among high-risk populations, and community misconceptions of appropriate use. Evidence supports combination antiretroviral therapy as prevention for acute HIV infection, thus lowering community viral loads. Evidence has increased supporting combination antiretroviral therapy for treatment at any CD4 cell count. Resistance testing should guide therapy in all patients on entry into care. Within two weeks of diagnosis of most opportunistic infections, combination antiretroviral therapy should be started; patients with tuberculosis and cryptococcal meningitis require special considerations. PMID:24695446

  4. Bioengineering Beige Adipose Tissue Therapeutics

    PubMed Central

    Tharp, Kevin M.; Stahl, Andreas

    2015-01-01

    Unlocking the therapeutic potential of brown/beige adipose tissue requires technological advancements that enable the controlled expansion of this uniquely thermogenic tissue. Transplantation of brown fat in small animal model systems has confirmed the expectation that brown fat expansion could possibly provide a novel therapeutic to combat obesity and related disorders. Expansion and/or stimulation of uncoupling protein-1 (UCP1)-positive adipose tissues have repeatedly demonstrated physiologically beneficial reductions in circulating glucose and lipids. The recent discovery that brown adipose tissue (BAT)-derived secreted factors positively alter whole body metabolism further expands potential benefits of brown or beige/brite adipose expansion. Unfortunately, there are no sources of transplantable BATs for human therapeutic purposes at this time. Recent developments in bioengineering, including novel hyaluronic acid-based hydrogels, have enabled non-immunogenic, functional tissue allografts that can be used to generate large quantities of UCP1-positive adipose tissue. These sophisticated tissue-engineering systems have provided the methodology to develop metabolically active brown or beige/brite adipose tissue implants with the potential to be used as a metabolic therapy. Unlike the pharmacological browning of white adipose depots, implantation of bioengineered UCP1-positive adipose tissues offers a spatially controlled therapeutic. Moving forward, new insights into the mechanisms by which extracellular cues govern stem-cell differentiation and progenitor cell recruitment may enable cell-free matrix implant approaches, which generate a niche sufficient to recruit white adipose tissue-derived stem cells and support their differentiation into functional beige/brite adipose tissues. This review summarizes clinically relevant discoveries in tissue-engineering and biology leading toward the recent development of biomaterial supported beige adipose tissue implants and their potential for the metabolic therapies. PMID:26539163

  5. HIV infection and subfertility.

    PubMed

    Waters, Laura; Gilling-Smith, Carole; Boag, Fiona

    2007-01-01

    With the improvements in life expectancy and quality of life for HIV-infected individuals in the developed world, and the increasing rates of HIV transmission among heterosexuals, reproductive issues are becoming increasingly important. We discuss the management of conception and pregnancy in HIV-infected couples. Couples where one or both partners are HIV infected may also experience subfertility and in this article we review the methods available to treat subfertility in this population and the current guidelines for the use of these techniques. HIV-infected couples can enjoy normal, healthy lives and should have access to the same investigation and treatment as their HIV-negative counterparts. Current inequities in the treatment available must be addressed. PMID:17326853

  6. Comparison of the Cepheid GeneXpert and Abbott M2000 HIV-1 real time molecular assays for monitoring HIV-1 viral load and detecting HIV-1 infection.

    PubMed

    Ceffa, Susanna; Luhanga, Richard; Andreotti, Mauro; Brambilla, Davide; Erba, Fulvio; Jere, Haswel; Mancinelli, Sandro; Giuliano, Marina; Palombi, Leonardo; Marazzi, Maria Cristina

    2016-03-01

    Assessing treatment efficacy and early infant diagnosis (EID) are critical issues in HIV disease management. Point-of-care assays may greatly increase the possibility to access laboratory monitoring also in rural areas. Recently two new laboratory tests have been developed by Cepheid (Sunnyvale, California) the Xpert HIV-1 Viral Load for viral load determination and the Xpert HIV-1 Qualitative for early infant diagnosis. We conducted a study in Blantyre, Malawi, comparing the 2 methods versus the Abbott real time quantitative and qualitative assays, for viral load and EID respectively. We tested 300 plasma samples for viral load determination and 200 samples for infant diagnosis. HIV-1 RNA values of the 274 samples quantified by both assays were highly correlated (Pearson r=0.95, R(2)=0.90). In 90.9% of the cases the two methods were concordant in defining the HIV-1 RNA levels as detectable or undetectable. For EID, the Xpert HIV-1 Qualitative assay yielded the same identical results as the Abbott assay. Both the quantitative and the qualitative Xpert assays are promising tools to monitor treatment efficacy in HIV patients receiving treatment and for early diagnosis in HIV-exposed infants. PMID:26709099

  7. ORTHOPEDIC COMPLICATIONS IN HIV PATIENTS.

    PubMed

    Lima, Ana Lúcia Lei Munhoz; Godoy, Alexandre Leme; Oliveira, Priscila Rosalba Domingos; Gobbi, Ricardo Gomes; de Almeida Silva, Camila; Martino, Patricia Bernardelli; Gutierrez, Eliana Bataggia; Gianna, Maria Clara; Camanho, Gilberto Luis

    2009-01-01

    The considerable increase of the life expectancy of HIV-infected patients in the age of highly-powerful antiretroviral treatment results in important metabolic and bone-joint changes resulting from a long-lasting viral infection time and from this treatment. The most common orthopaedic complications are bone mineralization changes, osteonecrosis, carpal tunnel syndrome and gleno-humeral adhesive capsulitis, with different clinical presentation features, natural disease progression and therapeutic response compared to the overall population. Literature reports are initial, and the experience of the multidisciplinary service of the University of Sao Paulo's Institute of Orthopaedics and Traumatology enables us a more indepth knowledge about the various pathologies involved and the development of treatment protocols that are appropriate to these diagnoses. PMID:27004170

  8. ORTHOPEDIC COMPLICATIONS IN HIV PATIENTS

    PubMed Central

    Lima, Ana Lúcia Lei Munhoz; Godoy, Alexandre Leme; Oliveira, Priscila Rosalba Domingos; Gobbi, Ricardo Gomes; de Almeida Silva, Camila; Martino, Patricia Bernardelli; Gutierrez, Eliana Bataggia; Gianna, Maria Clara; Camanho, Gilberto Luis

    2015-01-01

    The considerable increase of the life expectancy of HIV-infected patients in the age of highly-powerful antiretroviral treatment results in important metabolic and bone-joint changes resulting from a long-lasting viral infection time and from this treatment. The most common orthopaedic complications are bone mineralization changes, osteonecrosis, carpal tunnel syndrome and gleno-humeral adhesive capsulitis, with different clinical presentation features, natural disease progression and therapeutic response compared to the overall population. Literature reports are initial, and the experience of the multidisciplinary service of the University of Sao Paulo's Institute of Orthopaedics and Traumatology enables us a more indepth knowledge about the various pathologies involved and the development of treatment protocols that are appropriate to these diagnoses. PMID:27004170

  9. HIV-1 transcription and latency: an update

    PubMed Central

    2013-01-01

    Combination antiretroviral therapy, despite being potent and life-prolonging, is not curative and does not eradicate HIV-1 infection since interruption of treatment inevitably results in a rapid rebound of viremia. Reactivation of latently infected cells harboring transcriptionally silent but replication-competent proviruses is a potential source of persistent residual viremia in cART-treated patients. Although multiple reservoirs may exist, the persistence of resting CD4+ T cells carrying a latent infection represents a major barrier to eradication. In this review, we will discuss the latest reports on the molecular mechanisms that may regulate HIV-1 latency at the transcriptional level, including transcriptional interference, the role of cellular factors, chromatin organization and epigenetic modifications, the viral Tat trans-activator and its cellular cofactors. Since latency mechanisms may also operate at the post-transcriptional level, we will consider inhibition of nuclear RNA export and inhibition of translation by microRNAs as potential barriers to HIV-1 gene expression. Finally, we will review the therapeutic approaches and clinical studies aimed at achieving either a sterilizing cure or a functional cure of HIV-1 infection, with a special emphasis on the most recent pharmacological strategies to reactivate the latent viruses and decrease the pool of viral reservoirs. PMID:23803414

  10. [Therapeutic equivalence of the new oral anticoagulants].

    PubMed

    Moreno Villar, A; Nacle López, I; Barbero Hernández, M J; Lizan Tudela, L

    2015-10-01

    In an attempt to minimize the economic impact due to the incorporation of innovative drugs, health authorities have promoted and supported the evaluation and market positioning of drugs, as equivalent therapeutic alternatives. This issue has recently gained importance, possibly due to the current economic crisis. The equivalent therapeutic alternatives are justified by the need to compete on price, and by the authorities recommendation to establish therapeutic equivalence, price and financing of medicinal products at the same time. The establishment of the new oral anticoagulants and the equivalent therapeutic alternatives is a problematic issue if it is based on the absence of direct comparisons between different drugs and the questionable methodology used in the current indirect comparisons. Currently, it is difficult to determine when a new oral anticoagulant is more recommendable than others, but efforts are being made in order to propose alternatives for the decision based on patient characteristics. PMID:26146035

  11. Primary HIV infection (image)

    MedlinePlus

    HIV (human immunodeficiency virus) is more frequently transmitted through unprotected sex or sharing contaminated needles. Transmission from mother to fetus or through blood products has significantly declined in ...

  12. Maternal HIV disclosure to HIV-uninfected children in rural South Africa: a pilot study of a family-based intervention

    PubMed Central

    2013-01-01

    Background As access to treatment increases, large numbers of HIV-positive parents are raising HIV-negative children. Maternal HIV disclosure has been shown to have benefits for mothers and children, however, disclosure rates remain low with between 30-45% of mothers reporting HIV disclosure to their children in both observational and intervention studies. Disclosure of HIV status by parent to an HIV-uninfected child is a complex and challenging psychological and social process. No intervention studies have been designed and tested in Southern Africa to support HIV-positive parents to disclose their status, despite this region being one of the most heavily affected by the HIV epidemic. Method This paper describes the development of a family-centred, structured intervention to support mothers to disclose their HIV status to their HIV-negative school-aged children in rural South Africa, an area with high HIV prevalence. The intervention package includes printed materials, therapeutic tools and child-friendly activities and games to support age-appropriate maternal HIV disclosure, and has three main aims: (1) to benefit family relationships by increasing maternal HIV disclosure; (2) to increase children’s knowledge about HIV and health; (3) to improve the quality of custody planning for children with HIV-positive mothers. We provide the theoretical framework for the intervention design and report the results of a small pilot study undertaken to test its acceptability in the local context. Results The intervention was piloted with 24 Zulu families, all mothers were HIV-positive and had an HIV-negative child aged 6–9 years. Lay counsellors delivered the six session intervention over a six to eight week period. Qualitative data were collected on the acceptability, feasibility and the effectiveness of the intervention in increasing disclosure, health promotion and custody planning. All mothers disclosed something to their children: 11/24 disclosed fully using the words "HIV" while 13/24 disclosed partially using the word "virus". Conclusion The pilot study found the intervention was feasible and acceptable to mothers and counsellors, and provides preliminary evidence that participation in the intervention encouraged disclosure and health promotion. The pilot methodology and small sample size has limitations and further research is required to test the potential of this intervention. A larger demonstration project with 300 families is currently underway. PMID:23418933

  13. Risk factors for HIV-2 infection in The Gambia.

    PubMed

    Wilkins, A; Hayes, R; Alonso, P; Baldeh, S; Berry, N; Cham, K; Hughes, A; Jaiteh, K; Oelman, B; Tedder, R

    1991-09-01

    A serosurvey was carried out to assess the prevalence of HIV infection in The Gambia and the importance of possible risk factors. The overall prevalence of HIV-2 infection among the 4228 adults studied was 1.7% while that of HIV-1 was 0.1%. The prevalence of HIV-2 was similar in both sexes but higher among those greater than 25 years of age and those who lived in two small towns along a main transport route. Among men, multivariate analysis showed prevalence of HIV-2 infection was significantly greater among those in the more affluent occupations, those without a secondary education and those with a history of urethral discharge. Among women, infection was more frequent in divorcees and widows and those who had been married several times. The prevalence was also higher in individuals born in Guinea-Bissau and in an ethnic group which originated there. PMID:1930776

  14. An immunomodulating dipeptide, SCV-07, is a potential therapeutic for recurrent genital herpes simplex virus type 2 (HSV-2).

    PubMed

    Rose, William A; Tuthill, Cynthia; Pyles, Richard B

    2008-09-01

    Herpes simplex virus type 2 (HSV-2) infections produce a recurrent disease state associated with susceptibility to other pathogens, including human immunodeficiency virus (HIV), and cannot be cured by current therapeutic treatments. The HSV-2 epidemic must therefore be addressed by therapeutic strategies that reduce recurrent lesions and ideally lack the possibility for development of drug resistance. To this end, the therapeutic potential of SCV-07 (gamma-D-glutamyl-L-tryptophan), a synthetic dipeptide with potent immunomodulatory and antimicrobial activity, was studied in the guinea pig model of recurrent genital HSV-2. Initial evaluations showed that when delivered orally, but not subcutaneously, SCV-07 significantly reduced recurrent lesions. Oral dose ranging studies indicated that, of the tested amounts, 5microg/kg was optimal when delivered after an overnight fast. Interestingly, fasting induced a significant increase in recurrent lesions in vehicle-treated guinea pigs relative to non-fasted animals. Despite this increase, SCV-07 significantly reduced lesion formation in treated animals but showed no durability following cessation of treatment. In fact, this regimen of SCV-07 treatment produced statistically indistinguishable outcomes compared with those provided by topical aciclovir. These data illustrate that SCV-07 may provide an easily administered alternative or supplemental treatment option for genital HSV-2 recurrent disease. PMID:18619817

  15. Cataloguing the HIV type 1 human protein interaction network.

    PubMed

    Ptak, Roger G; Fu, William; Sanders-Beer, Brigitte E; Dickerson, Jonathan E; Pinney, John W; Robertson, David L; Rozanov, Mikhail N; Katz, Kenneth S; Maglott, Donna R; Pruitt, Kim D; Dieffenbach, Carl W

    2008-12-01

    Although many interactions between HIV-1 and human proteins have been reported in the scientific literature, no publicly accessible source for efficiently reviewing this information was available. Therefore, a project was initiated in an attempt to catalogue all published interactions between HIV-1 and human proteins. HIV-related articles in PubMed were used to develop a database containing names, Entrez GeneIDs, and RefSeq protein accession numbers of interacting proteins. Furthermore, brief descriptions of the interactions, PubMed identification numbers of articles describing the interactions, and keywords for searching the interactions were incorporated. Over 100,000 articles were reviewed, resulting in the identification of 1448 human proteins that interact with HIV-1 comprising 2589 unique HIV-1-to-human protein interactions. Preliminary analysis of the extracted data indicates 32% were direct physical interactions (e.g., binding) and 68% were indirect interactions (e.g., upregulation through activation of signaling pathways). Interestingly, 37% of human proteins in the database were found to interact with more than one HIV-1 protein. For example, the signaling protein mitogen-activated protein kinase 1 has a surprising range of interactions with 10 different HIV-1 proteins. Moreover, large numbers of interactions were published for the HIV-1 regulatory protein Tat and envelope proteins: 30% and 33% of total interactions identified, respectively. The database is accessible at http://www.ncbi.nlm.nih.gov/RefSeq/HIVInteractions/ and is cross-linked to other National Center for Biotechnology Information databases and programs via Entrez Gene. This database represents a unique and continuously updated scientific resource for understanding HIV-1 replication and pathogenesis to assist in accelerating the development of effective therapeutic and vaccine interventions. PMID:19025396

  16. Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection

    PubMed Central

    Hanauske-Abel, Hartmut M.; Saxena, Deepti; Palumbo, Paul E.; Hanauske, Axel-Rainer; Luchessi, Augusto D.; Cambiaghi, Tavane D.; Hoque, Mainul; Spino, Michael; Gandolfi, Darlene D'Alliessi; Heller, Debra S.; Singh, Sukhwinder; Park, Myung Hee; Cracchiolo, Bernadette M.; Tricta, Fernando; Connelly, John; Popowicz, Anthony M.; Cone, Richard A.; Holland, Bart; Pe’ery, Tsafi; Mathews, Michael B.

    2013-01-01

    HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients. PMID:24086341

  17. The lost hope of elimination of Kala-azar (visceral leishmaniasis) by 2010 and cyclic occurrence of its outbreak in India, blame falls on vector control practices or co-infection with human immunodeficiency virus or therapeutic modalities?

    PubMed Central

    Muniaraj, Mayilsamy

    2014-01-01

    The Kala-azar/visceral leishmaniasis (VL) turns epidemic form once in every 15 years in the endemic regions of Indian subcontinent. The goal of elimination of Kala-azar from India by 2010 was lost despite paramount efforts taken by the Government of India and World Health Organization and Regional Office for South East Asia. The main objective of this review was to elucidate the possible reason for the failure of Kala-azar elimination program and to suggest possible remedial measures to achieve the goal in future. The annual numbers of VL cases and deaths recorded in India since 1977 were plotted on a graph, to see if the temporal trends could be associated with changes in the vector control practices or co-infection with human immunodeficiency virus (HIV) or therapeutic modalities used against VL. The VL cases flares up whenever the effect of dichlorodiphenyltrichloroethane (DDT) diminished after the withdrawal of spray. The fading effectiveness was clearly correlated with an increasing number of VL cases. Therapeutic modalities were found to be highly correlating with VL mortality not with VL morbidity. The diminishing efficacy of first and second line drugs and the introduction of new drugs and drugs combination were responsible for ups and downs in the VL mortality. The VL mortality is constantly declining since 1993, but cases started increasing from 2003 to 2007 and then recently again from 2010 to 2011. This shows a serious lacuna in the vector control practices applied. The extent of HIV co-infection did not show any correlation with number/trend of VL cases or death over the study period. It is concluded that, by strict vector control practices, the VL cases can be reduced and by applying proper therapeutic strategies, the VL mortality can be reduced. HIV-VL co-infection does not seem to be in a worried stage. PMID:24754021

  18. The church and paediatric HIV care in rural South Africa: a qualitative study.

    PubMed

    Norder, Wilma A J; Peters, Remco P H; Kok, Maarten O; van Elsland, Sabine L; Struthers, Helen E; Tutu, Mpho A; van Furth, A Marceline

    2015-01-01

    Religion has substantial - positive and negative - influence on South Africa's HIV context. This qualitative study explored possibilities for positive church engagement in paediatric HIV care in a rural district in Limpopo Province, South Africa. Opinions, attitudes and experiences of various stakeholders including religious leaders, healthcare workers and people infected/affected with/by HIV were investigated through participant observation, semi-structured interviews and focus group discussions. During the research the original focus on paediatric HIV care shifted to HIV care in general in reaction to participant responses. Participants identified three main barriers to positive church engagement in HIV care: (a) stigma and disclosure; (b) sexual associations with HIV and (c) religious beliefs and practices. All participant groups appreciated the opportunity and relevance of strengthening church involvement in HIV care. Opportunities for positive church engagement in HIV care that participants identified included: (a) comprehensive and holistic HIV care when churches and clinics collaborate; (b) the wide social reach of churches and (c) the safety and acceptance in churches. Findings indicate that despite barriers great potential exists for increased positive church engagement in HIV care in rural South Africa. Recommendations include increased medical knowledge and dialogue on HIV/AIDS within church settings, and increased collaboration between churches and the medical sector. PMID:26679269

  19. Education in HIV risk screening, counseling, testing, and referral: survey of U.S. dental schools.

    PubMed

    Patton, Lauren L; Santos, V Allen; McKaig, Rosemary G; Shugars, Diane C; Strauss, Ronald P

    2002-10-01

    According to Centers for Disease Control and Prevention estimates, thousands of Americans are infected with HIV but are unaware of their infection status. National disease prevention goals to identify and treat these individuals will benefit from HIV risk screening, counseling, testing, and referral services conducted in nontraditional settings and the use of alternative diagnostic methods such as oral fluid-based HIV antibody testing. Using a mail survey of the fifty-four U.S. dental schools (85 percent response rate), this study assessed the teaching and practice of HIV risk screening, as well as the opinions of dental educators regarding HIV counseling and testing and a possible role for oral fluid-based HIV antibody testing in dental offices. All responding dental schools have curriculum and clinical education training regarding HIV behavioral risks, medical history, and use of oral manifestations as indicators of HIV Educators felt risk screening and referral for HIV counseling and testing was part of a dentist's professional role. One-third of respondents indicated they might include HIV counseling and testing using a rapid oral fluid-based HIV antibody test in their clinics. However, these respondents lacked confidence that graduating dentists have the skills and willingness to conduct HIV counseling and testing in dental practice. Lack of training in prevention counseling was seen as a primary barrier. PMID:12449212

  20. HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates.

    PubMed

    Jones, R Brad; Garrison, Keith E; Mujib, Shariq; Mihajlovic, Vesna; Aidarus, Nasra; Hunter, Diana V; Martin, Eric; John, Vivek M; Zhan, Wei; Faruk, Nabil F; Gyenes, Gabor; Sheppard, Neil C; Priumboom-Brees, Ingrid M; Goodwin, David A; Chen, Lianchun; Rieger, Melanie; Muscat-King, Sophie; Loudon, Peter T; Stanley, Cole; Holditch, Sara J; Wong, Jessica C; Clayton, Kiera; Duan, Erick; Song, Haihan; Xu, Yang; SenGupta, Devi; Tandon, Ravi; Sacha, Jonah B; Brockman, Mark A; Benko, Erika; Kovacs, Colin; Nixon, Douglas F; Ostrowski, Mario A

    2012-12-01

    The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics. PMID:23143309