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.
Wallace, David R.
The goal of a therapeutic HIV vaccine is to attenuate HIV disease progression in those already infected. Our objective was to establish comparative efficacy and cost-effectiveness thresholds at which a therapeutic vaccine would make a valuable contribution to HIV care. Using an HIV computer simulation model, we compared therapeutic vaccination with HIV standard of care without vaccination. Input data were
Rochelle P. Walensky; A. David Paltiel; Sue J. Goldie; Rajesh T. Gandhi; Milton C. Weinstein; George R. Seage; Heather E. Smith; Hong Zhang; Kenneth A. Freedberg
The emerging role of immune activation and inflammation in the pathogenesis of human immunodeficiency virus (HIV) disease has stimulated the search for new approaches for managing HIV infection. Recent evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) might contribute to HIV-associated pathology by inducing remodelling of the extracellular matrix. Here, we discuss the evidence and the potential mechanisms for altered MMP or TIMP function in HIV infection and disease. Furthermore, we outline the possible medical implications for the use of compounds that target MMP activity, and we propose that antiretroviral drugs, particularly HIV protease inhibitors (PIs), and compounds with anti-inflammatory properties, such as statins, natural omega-3 fatty acids and tetracyclines, which inhibit MMP function, might represent useful therapeutic approaches to mitigate potential MMP-related damage during HIV infection. PMID:18029231
Mastroianni, Claudio M; Liuzzi, Grazia M
Fragment screening has proven to be a powerful alternative to traditional methods for drug discovery. Biophysical methods, such as X-ray crystallography, NMR spectroscopy, and surface plasmon resonance, are used to screen a diverse library of small molecule compounds. Although compounds identified via this approach have relatively weak affinity, they provide a good platform for lead development and are highly efficient binders with respect to their size. Fragment screening has been utilized for a wide-range of targets, including HIV-1 proteins. Here, we review the fragment screening studies targeting HIV-1 proteins using X-ray crystallography or surface plasmon resonance. These studies have successfully detected binding of novel fragments to either previously established or new sites on HIV-1 protease and reverse transcriptase. In addition, fragment screening against HIV-1 reverse transcriptase has been used as a tool to better understand the complex nature of ligand binding to a flexible target.
Bauman, Joseph D.; Patel, Disha; Arnold, Eddy
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 ?-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.
Essack, Magbubah; Bajic, Vladimir B.; Archer, John A. C.
Acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) are frequent, but not obligatory psychological sequelae following trauma. A major subgroup of patients face a chronic course of illness associated with an increased psychiatric comorbidity and significant impairments in psychosocial adaptation. The typical psychopathological symptoms of ASD and PTSD are best described within a multifactorial model integrating both neurobiological and psychosocial influences. The complex etiopathogenesis of acute and posttraumatic stress disorder favours multimodal approaches in the treatment. Differential psychotherapeutic and pharmacological strategies are available. In a critical survey on empirical studies, psychological debriefing cannot be considered as a positive approach to be recommended as general preventive measure during the immediate posttraumatic phase. Positive effects of cognitive-behavioral interventions can be established for ASD. Psychodynamic psychotherapy, cognitive-behavioral therapy and EMDR show promising results in the treatment of PTSD. Major clinical restrictions of patient sampling within special research facilities, however, do not allow an unconditional generalization of these data to psychiatric routine care. In an empirical analysis the SSRIs are the most and best studied medications for ASD and PTSD. In comparison to tricyclic antidepressants SSRIs demonstrate a broader spectrum of therapeutic effects and are better tolerated. The substance classes of SSNRI, DAS, SARI and NaSSA are to be considered as drugs of second choice. They promise a therapeutic efficacy equivalent to the SSRIs, being investigated so far only in open studies. MAO-inhibitors may dispose of a positive therapeutic potential, their profile of side effects must be respected, however. Mood stabilizers and atypical neuroleptics may be used first and foremost in add-on strategies. Benzodiazepines should be used only with increased caution for a short time in states of acute crisis. In early interventions, substances blocking the norepinephric hyperactivity seem to be promising alternatives. Stress doses of hydrocortisone may be considered as an experimental pharmacological strategy so far. PMID:19011595
An unprecedented number of investigational drugs are in the development pipeline for the treatment of tuberculosis. Among patients with tuberculosis, co-infection with HIV is common, and concurrent treatment of tuberculosis and HIV is now the standard of care. To ensure that combinations of anti-tuberculosis drugs and antiretrovirals are safe and are tested at doses most likely to be effective, selected pharmacokinetic studies based on knowledge of their metabolic pathways and their capacity to induce or inhibit metabolizing enzymes of companion drugs must be conducted. Drug interaction studies should be followed up by evaluations in larger populations to evaluate safety and pharmacodynamics more fully. Involving patients with HIV in trials of TB drugs early in development enhances the knowledge gained from the trials and will ensure that promising new tuberculosis treatments are available to patients with HIV as early as possible. In this review, we summarize current and planned pharmacokinetic and drug interaction studies involving investigational and licensed tuberculosis drugs and antiretrovirals and suggest priorities for tuberculosis-HIV pharmacokinetic, pharmacodynamic, and drug-drug interaction studies for the future. Priority studies for children and pregnant women with HIV and tuberculosis co-infection are briefly discussed.
Dooley, Kelly E.; Kim, Peter S.; Williams, Sharon D.; Hafner, Richard
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.
Since the human immunodeficiency virus (HIV-1) pandemic began, few prophylactic vaccines have reached phase III trials. Only one has shown partial efficacy in preventing HIV-1 infection. The introduction of antiretroviral therapy (ART) has had considerable success in controlling infection and reducing transmission but in so doing has changed the nature of HIV-1 infection for those with access to ART. Access, compliance, and toxicity alongside the emergence of serious non-AIDS morbidity and the sometimes poor immune reconstitution in ART-treated patients have emphasized the need for additional therapies. Such therapy is intended to contribute to control of HIV-1 infection, permit structured treatment interruptions, or even establish a functional cure of permanently suppressed and controlled infection. Both immunotherapy and therapeutic vaccination have the potential to reach these goals. In this review, the latest developments in immunotherapy and therapeutic vaccination are discussed.
Tanner, Helen; Dalgleish, Angus
The emergence of drug-resistant human immunodeficiency virus type I (HIV-1) strains presents a challenge for the design of new drugs. Anti-HIV compounds currently in use are the subject of advanced clinical trials using either HIV-1 reverse-transcriptase, viral protease, or integrase inhibitors. Recent studies show an increase in the number of HIV-1 variants resistant to anti-retroviral agents in newly infected individuals. Targeting host cell factors involved in the regulation of HIV-1 replication might be one way to combat HIV-1 resistance to the currently available anti-viral agents. A specific inhibition of HIV-1 gene expression could be expected from the development of compounds targeting host cell factors that participate in the activation of the HIV-1 LTR promoter. Here we will discuss how targeting the host can be accomplished either by using small molecules to alter the function of the host’s proteins such as p53 or cdk9, or by utilizing new advances in siRNA therapies to knock down essential host factors such as CCR5 and CXCR4. Finally, we will discuss how the viral protein interactomes should be performed to better design therapeutics against HIV-1.
Coley, William; Kehn-Hall, Kylene; Van Duyne, Rachel; Kashanchi, Fatah
Three-dimensional molecular structures can provide detailed information on biological mechanisms and, for cases in which the molecular function affects human health, can significantly aid in the development of therapeutic interventions. For almost 25 years, key components of the lentivirus HIV-1, including the envelope glycoproteins, the capsid and the replication enzymes reverse transcriptase, integrase and protease, have been scrutinized to near
Alan Engelman; Peter Cherepanov
Host–virus interactions permeate every aspect of both virus life cycle and host response and involve host cell macromolecular\\u000a machinery and viral elements. It is these intimate interactions that mandate the outcomes of the infection and pathogenesis.\\u000a It is also these intimate interactions that lay the foundation for the development of pharmaceutical interventions. HIV-1\\u000a is no exception in these regards. In
Johnny J. He
Community-based therapeutic care (CTC) is a community-based model for delivering care to malnourished people. CTC aims to treat the majority of severely malnourished people at home, rather than in therapeutic feeding centres. This paper describes the potential of the CTC approach to provide effective care and support for people living with HIV and AIDS (PLWHA). CTC includes many of the components of a home-based care model for PLWHA. It provides outpatient treatment for common complications of HIV and AIDS, such as acute malnutrition and simple infections, and an energy-dense ready-to-use food that could be made with the appropriate balance of micronutrients for the HIV-infected patient. Through the de-centralisation of outpatient treatment sites, CTC improves accessibility by moving treatment closer to people's homes and helps to promote the sustainability of care by building on the capacity of existing health infrastructure and staff. The CTC model contains many features that are appropriate for the care and support of HIV-affected people and, in its present form, can provide effective physical care for many HIV-affected individuals. We are currently working to adapt the CTC model to make it more suitable for the support of PLWHA in the longer term. PMID:16216293
Sadler, Kate; Bahwere, Paluku; Guerrero, Saul; Collins, Steve
Fournier's gangrene is a life-threatening necrotising infection of the perineal and genital regions. The case presented here refers to an HIV-positive 42-year-old man, admitted in emergency to our department with clinical signs and symptoms of sepsis related to gangrene of the perineum and scrotum. An early wide surgical necrosectomy was performed under epidural anaesthesia. Treatment was completed by intensive care, broad-spectrum antibiotics and hyperbaric oxygen therapy. The wound was managed with advanced dressing (AQUACEL Hydrofiber) until complete healing was obtained, and the scrotum was reconstructed with skin flaps. The disease did not involve the testes, spermatic cord or anorectal canal. The satisfactory aesthetic and functional outcome prompts the authors to stress a number of features of the therapeutic approach adopted: (i) the advantages of epidural anaesthesia with an indwelling catheter that allows further necrosectomy and wound dressing to be performed totally painlessly; (ii) the possibility of avoiding faecal diversion by means of synthetic opioid drugs which are useful to reduce the frequency of defecation; and (iii) the positive impact of advanced dressing on the wound healing process in relation to patient satisfaction and cost management. PMID:18837266
Licheri, Sergio; Erdas, Enrico; Pisano, Giuseppe; Garau, Annalisa; Barbarossa, Michela; Tusconi, Anna; Pomata, Mariano
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.
Engelman, Alan; Cherepanov, Peter
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.
Nissapatorn, Veeranoot; Sawangjaroen, Nongyao
Purpose of review One of the potential barriers to current HIV cure strategies is the persistence of elevated levels of immune activation despite otherwise effective antiretroviral therapy (ART). The purpose of this review is to examine the relationship between immune activation and HIV persistence, and to review novel therapeutic interventions that are currently being pursued to target immune activation in treated HIV disease. Recent findings Multiple groups have consistently observed that elevated levels of inflammation, immune activation, and immune dysfunction persist in ART-treated individuals, despite successful suppression of plasma viremia. Increased immune activation may lead to viral persistence through multiple mechanisms. Several novel interventions aimed at decreasing persistent immune activation are being pursued and include studies aimed at decreasing low-level viral replication, approaches aimed at decreasing microbial translocation, interventions to treat co-infections, and therapies that directly target immune activation. Summary There appears to be a clear and consistent relationship between immune activation and viral persistence in treated HIV disease. Whether this relationship is causal or mediated through other mechanisms is still unknown. Small-scale, pathogenesis-oriented interventional studies are necessary to further evaluate this relationship and the effect of potential interventions.
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 ?-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.
Oppenheimer, Steven B.; Alvarez, Maribel; Nnoli, Jennifer
The acquisition of affect regulation skills is often impaired or delayed in youth with mental health problems but the relationship between affect dysregulation and risk behaviors has not been well studied. Baseline data from adolescents (N =418; ages 13–19) recruited from therapeutic school settings examined the relationship between affect dysregulation, substance use, self-cutting, and sexual risk behavior. Analyses of covariance demonstrated that adolescents who did not use condoms at last sex, ever self-cut, attempted suicide, used alcohol and other drugs and reported less condom use self-efficacy when emotionally aroused were significantly more likely (p < .01) to report greater difficulty with affect regulation than peers who did not exhibit these behaviors. General patterns of difficulty with affect regulation may be linked to HIV risk behavior, including condom use at last sex. HIV prevention strategies for youth in mental health treatment should target affect regulation in relation to multiple risk behaviors.
Brown, Larry K.; Houck, Christopher; Lescano, Celia; Donenberg, Geri; Tolou-Shams, Marina; Mello, Justin
INTRODUCTION. Tuberous sclerosis complex (TSC) is frequently accompanied by difficult-to-treat epilepsy, which conditions these patients' quality of life and cognitive level. AIM. To dscribe the epidemiological and clinical characteristics, as well as the treatment of patients affected by TSC with epilepsy. PATIENTS AND METHODS. A retrospective review was carried out of the medical records of 30 patients aged under 18 registered in our database, who had been diagnosed with TSC and epilepsy. RESULTS. The age at onset of epilepsy in the patients with TSC in our series ranged from one month to four years. All of them began with partial crises. Two presented West's syndrome and four others had infantile spasms without hypsarrhythmia. In 19 of the patients, the epilepsy was medication resistant. As regards treatment with antiepileptic drugs, 11 are in monotherapy, 10 in bitherapy, seven in tritherapy and one with four drugs. Two were given ACTH, two carry an implanted vagal nerve stimulator, four receive treatment with everolimus and eight have undergone surgery. CONCLUSIONS. Epilepsy is a very common problem and begins in the early years of life in TSC. There are currently a large number of therapeutic options available, although 63.3% of patients have non-controlled epilepsy and most of them present crises on a daily basis. Poor control of their crises is correlated with mental retardation and autism spectrum disorder. The positive response obtained with other therapeutic possibilities, such as mTOR pathway inhibitors, surgery and vagal nerve stimulator, should be noted. PMID:24915028
Puertas-Martin, V; Carreras-Saez, I; Marana, A; Ruiz-Falco Rojas, M L; Cantarin-Extremera, V; Calleja-Gero, M L
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.
Silva, Diana F.; Selfridge, J. Eva; Lu, Jianghua; Lezi, E; Cardoso, Sandra M.; Swerdlow, Russell H.
Human immunodeficiency virus type 1 (HIV) infection presently affects more that 40 million people worldwide, and is associated with central nervous system (CNS) disruption in at least 30% of infected individuals. The use of highly active antiretroviral therapy has lessened the incidence, but not the prevalence of mild impairment of higher cognitive and cortical functions (HIV-associated neurocognitive disorders) as well as substantially reduced a more severe form dementia (HIV-associated dementia). Furthermore, improving neurological outcomes will require novel, adjunctive therapies that are targeted towards mechanisms of HIV-induced neurodegeneration. Identifying such molecular and pharmacological targets requires an understanding of the events preceding irreversible neuronal damage in the CNS, such as actions of neurotoxins (HIV proteins and cellular factors), disruption of ion channel properties, synaptic damage, and loss of adult neurogenesis. By considering the specific mechanisms and consequences of HIV neuropathogenesis, unified approaches for neuroprotection will likely emerge using a tailored, combined, and non-invasive approach.
Lindl, Kathryn A.; Marks, David R.; Kolson, Dennis L.
Human Immunodeficiency Virus type 1 Reverse Transcriptase (HIV-1 RT) is one of the most important targets for treatment of Acquired Immune Deficiency Syndrome (AIDS). It catalyzes the reverse transcription of HIV-RNA into a double stranded DNA, and the knowledge of its substrate specificity and catalytic mechanism has guided the development of several inhibitors widely used on current HIV/AIDS therapy. However, mutations in HIV-1 RT structure can lead to the emergence of drug-resistant virus strains. The goal of this review is to summarize relevant structural features of HIV-1 RT and its inhibitors in such a way that this cost-effective target in the development of new antiretroviral drugs is particularly highlighted. PMID:16475939
Castro, H C; Loureiro, N I V; Pujol-Luz, M; Souza, A M T; Albuquerque, M G; Santos, D O; Cabral, L M; Frugulhetti, I C; Rodrigues, C R
The breakdown of human retinal pigment epithelial (HRPE) barrier is considered as the etiology of retinopathy, which affects the quality of life of HIV/AIDS patients. Here we demonstrate that HIV-1 could directly impair HRPE barrier function, which leads to the translocation of HIV-1 and bacteria. HRPE cells (D407) were grown to form polarized, confluent monolayers and treated with different HIV-1 infectious clones. A significant increase of monolayer permeability, as measured by trans-epithelial electrical resistance (TEER) and apical-basolateral movements of sodium fluorescein, was observed. Disrupted tightness of HRPE barrier was associated with the downregulation of several tight junction proteins in D407 cells, including ZO-1, Occludin, Claudin-1, Claudin-2, Claudin-3, Claudin-4, and Claudin-5, after exposure to HIV-1, without affecting the viability of cells. HIV-1 gp120 was shown to participate in the alteration of barrier properties, as evidenced by decreased TEER and weakened expression of tight junction proteins in D407 monolayers after exposure to pseudotyped HIV-1, UV-inactivated HIV-1, and free gp120, but not to an envelope (Env)-defective mutant of HIV. Furthermore, exposure to HIV-1 particles could induce the release of pro-inflammatory cytokines in D407, including IL-6 and MCP-1, both of which downregulated the expression of ZO-1 in the HRPE barrier. Disrupted HRPE monolayer allowed translocation of HIV-1 and bacteria across the epithelium. Overall, these findings suggest that HIV-1 may exploit its Env glycoprotein to induce an inflammatory state in HRPE cells, which could result in impairment of HRPE monolayer integrity, allowing virus and bacteria existing in ocular fluids to cross the epithelium and penetrate the HRPE barrier. Our study highlights the role of HIV-1 in the pathogenesis of HIV/AIDS-related retinopathy and suggests potential therapeutic targets for this ocular complication. PMID:24840331
Tan, Suiyi; Duan, Heng; Xun, Tianrong; Ci, Wei; Qiu, Jiayin; Yu, Fei; Zhao, Xuyan; Wu, Linxuan; Li, Lin; Lu, Lu; Jiang, Shibo; Liu, Shuwen
Diacylglycerol kinase (DGK) is a lipid kinase converting diacylglycerol to phosphatidic acid, and regulates many enzymes including protein kinase C, phosphatidylinositol 4-phosphate 5-kinase, and mTOR. To date, ten mammalian DGK subtypes have been cloned and divided into five groups, and they show subtype-specific tissue distribution. Therefore, each DGK subtype is thought to be involved in respective cellular responses by regulating balance of the two lipid messengers, diacylglycerol and phosphatidic acid. Indeed, the recent researches using DGK knockout mice have clearly demonstrated the importance of DGK in the immune system and its pathophysiological roles in heart and insulin resistance in diabetes. Especially, most subtypes show high expression in brain with subtype specific regional distribution, suggesting that each subtype has important and unique functions in brain. Recently, neuronal functions of some DGK subtypes have accumulated. Here, we introduce DGKs with their structural motifs, summarize the enzymatic properties and neuronal functions, and discuss the possibility of DGKs as a therapeutic target of the neuronal diseases.
Despite decades of research, HIV remains a global health threat. Issues of multi-drug resistance and lack of an effective vaccine have recently led to the targeting of host factors for anti-viral drug development. While a few genome-wide screens for novel HIV co-factors have been reported, the promise of finding a therapeutic target has yet to be realized. Here, we report
Deborah G. Nguyen; Hong Yin; Yingyao Zhou; Karen C. Wolff; Kelli L. Kuhen; Jeremy S. Caldwell
From early in the HIV epidemic it was appreciated that many inflammatory markers such as neopterin and TNF-? were elevated in patients with AIDS. With the advent of modern technology able to measure a broad array of cytokines, we now know that from the earliest points of infection HIV induces a cytokine storm. This review will focus on how cytokines are disturbed in HIV infection and will explore potential therapeutic uses of cytokines. These factors can be used directly as therapy during HIV infection, either to suppress viral replication or prevent deleterious immune effects of infection, such as CD4+ T cell depletion. Cytokines also show great promise as adjuvants in the development of HIV vaccines, which would be critical for the eventual control of the epidemic.
Keating, Sheila M.; Jacobs, Evan S.; Norris, Philip J.
Vaccination is currently considered as an additional therapeutic approach to stimulate HIV-specific immune response in subjects that could not naturally control HIV. Ten chronically HIV infected individuals have been vaccinated with a modified vaccinia Ankara (MVA)-HIV-1LAI-nef vector in order to assess safety and immunogenicity. No significant adverse effects were observed during the course of vaccination indicating for the first time
Antonio Cosma; Rashmi Nagaraj; Silja Bühler; Jorma Hinkula; Dirk H. Busch; Gerd Sutter; Frank D. Goebel; Volker Erfle
Among the 3700 HIV-infected patients followed in our institution, 17 with regular clinical, immunological and virological follow-up and identified as being dually seropositive for HIV-1 and HIV-2 were included in this study. Antiretroviral therapy seemed to be as effective, in terms of virological and immunological response, as in patients infected by HIV-1 alone. Nevertheless, the observed selection of HIV-2 protease resistance mutations in two cases underlines the importance of selecting drugs that are active on both viruses. PMID:19114866
Landman, Roland; Damond, Florence; Gerbe, Juliette; Brun-Vezinet, Francoise; Yeni, Patrick; Matheron, Sophie
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy. PMID:21170360
Blair, Wade S; Pickford, Chris; Irving, Stephen L; Brown, David G; Anderson, Marie; Bazin, Richard; Cao, Joan; Ciaramella, Giuseppe; Isaacson, Jason; Jackson, Lynn; Hunt, Rachael; Kjerrstrom, Anne; Nieman, James A; Patick, Amy K; Perros, Manos; Scott, Andrew D; Whitby, Kevin; Wu, Hua; Butler, Scott L
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy.
Irving, Stephen L.; Brown, David G.; Anderson, Marie; Bazin, Richard; Cao, Joan; Ciaramella, Giuseppe; Isaacson, Jason; Jackson, Lynn; Hunt, Rachael; Kjerrstrom, Anne; Nieman, James A.; Patick, Amy K.; Perros, Manos; Scott, Andrew D.; Whitby, Kevin; Wu, Hua; Butler, Scott L.
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
Rubinstein, Paul G; Aboulafia, David M; Zloza, Andrew
Hepatitis C virus (HCV) is the cause of more than three-quarters of liver-related deaths in HIV-seropositive individuals and it is remarkable that today approximately one-quarter of HIV-infected individuals in Europe and the USA have a HCV coinfection. HIV/HCV coinfected patients were more likely to develop cirrhosis, had an increased risk of developing AIDS, of HIV-related disease and of overall mortality. How HCV may affect the course of HIV infection is not well known even if it was suggested that HCV co-infection is able to increase immune activation and to sensitize CD4+ T-cells towards apoptosis in the absence of HIV therapy. There are many evidences that the simultaneous presence of HIV infection accelerates the liver damage from HCV favouring the evolution to cirrhosis in co-infected patients. HIV increasing of TNF alpha liver production and of HCV replication in peripheral blood lymphomonocytes are the mechanisms at the basis of this phenomenon. HAART had a positive effect on HIV/HCV co-infection, otherwise it does not appear to fully correct the adverse effect of HIV infection on HCV-related outcomes. Traditional treatment with pegilated Interferon plus ribavirin have low rates of sustained virological response in co-infected patients especially if infected with HCV genotype 1, and better results were often obtained in patients in which the use of antiretroviral treatment was avoided to reduce the occurrence of adverse effects. The recent preliminary results on the use of anti-HCV protease inhibitor drugs, boceprevir and telapravir, in co-infected people seems to demonstrate an enhanced antiviral efficacy in the HIV/HCV co-infected population of triple anti-HCV treatment even is some important limitation as interactions with antiretroviral agents and selection of HCV drug resistance, lead to consider the need for further studies designed to assess the best therapeutic strategies. PMID:23111959
Andreoni, M; Giacometti, A; Maida, I; Meraviglia, P; Ripamonti, D; Sarmati, L
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.
Santa-Marta, Mariana; de Brito, Paula Matos; Godinho-Santos, Ana; Goncalves, Joao
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
Bozó, Tamás; Pál, Szilárd; Dévay, Attila
Despite decades of research, HIV remains a global health threat. Issues of multi-drug resistance and lack of an effective vaccine have recently led to the targeting of host factors for anti-viral drug development. While a few genome-wide screens for novel HIV co-factors have been reported, the promise of finding a therapeutic target has yet to be realized. Here, we report a screen of a cDNA library representing 15,000 unique genes in an infectious HIV system, and show that genomic screening can lead to the identification of novel proviral host factors. Mixed lineage kinase 3 (MLK3/MAP3K11) was identified as one of the strongest enhancers of infection and mutant studies show that its activity is dependent on its kinase function. Consistent with its known role in the activation of the AP-1 pathway through JNK kinase, MLK3 was able to enhance Tat-dependent HIV transcription in vitro thus leading to an increase in infection signal. RNA interference studies confirm the involvement of endogenous MLK3 in HIV infection, further implicating this kinase as a potential therapeutic target. PMID:17257639
Nguyen, Deborah G; Yin, Hong; Zhou, Yingyao; Wolff, Karen C; Kuhen, Kelli L; Caldwell, Jeremy S
HIV-1 is a lentivirus capable of infecting CD4(+) T-lymphocytes and CD4-expressing innate immune cells. Infection with HIV-1 leads to rapid and early depletion of mucosal CD4(+) T-cells, and to the establishment of viral reservoirs that are resistant to the most potent antiretroviral therapy currently available. Commonly observed virus-induced adaptive immune defects consist of weak-to-absent HIV-specific CD4 T-cell responses and of inappropriate or inefficient CD8(+) cytotoxic T-lymphocyte activity. Moreover, the virus establishes early and long-lasting deficits in innate immunity characterized by reduced numbers or/and disrupted functions of antigen-presenting cells, natural killer cells and natural-kiiller T-lymphocytes. Therapeutic approaches have long been oriented toward restoration of adaptive immunity in HIV-1 patients. This is exemplified by the use, in antiretrovial treated subjects, of interleukin-2 to increase and expand CD4(+) lymphocytes, and of structured treatment interruptions or therapeutic vaccination to restore HIV-specific responses. More recently, approaches aimed at correcting the deficits in innate immune responses have been explored. The most advanced of these strategies include synthetic immunomodulators targeting antigen presentation and human recombinant cytokines capable of regulating the functions of natural-killer cells. Today, in addition to the combined use of different classes of antiretrovirals, a highly active immune therapy, with components targeting both innate and adaptive responses, appears to be absolutely necessary to formulate immune control of the virus. Current and future clinical protocols will eventually define the timing, composition and formulations of combined HIV-specific and nonspecific immunotherapy that could be safely administered to HIV patients to restore immune homeostasis. PMID:20477596
Bahr, George M
Monocyte-derived macrophages (MDM) are widely distributed in all tissues and organs, including the central nervous system, where they represent the main part of HIV-infected cells. In contrast to activated CD4+ T lymphocytes, MDM are resistant to cytopathic effects and survive HIV infection for a long period of time. The molecular mechanisms of how HIV is able to persist in macrophages are not fully elucidated yet. In this context, we have studied the effect of in vitro HIV-1 infection on telomerase activity (TA), telomere length, and DNA damage. Infection resulted in a significant induction of TA. This increase was directly proportional to the efficacy of HIV infection and was found in both nuclear and cytoplasmic extracts, while neither UV light-inactivated HIV nor exogenous addition of the viral protein Tat or gp120 affected TA. Furthermore, TA was not modified during monocyte-macrophage differentiation, MDM activation, or infection with vaccinia virus. HIV infection did not affect telomere length. However, HIV-infected MDM showed less DNA damage after oxidative stress than noninfected MDM, and this resistance was also increased by overexpressing telomerase alone. Taken together, our results suggest that HIV induces TA in MDM and that this induction might contribute to cellular protection against oxidative stress, which could be considered a viral strategy to make macrophages better suited as longer-lived, more resistant viral reservoirs. In the light of the clinical development of telomerase inhibitors as anticancer therapeutics, inhibition of TA in HIV-infected macrophages might also represent a novel therapeutic target against viral reservoirs.
Reynoso, Rita; Wieser, Matthias; Ojeda, Diego; Bonisch, Maximilian; Kuhnel, Harald; Bolcic, Federico; Quendler, Heribert; Grillari, Johannes
Monocyte-derived macrophages (MDM) are widely distributed in all tissues and organs, including the central nervous system, where they represent the main part of HIV-infected cells. In contrast to activated CD4(+) T lymphocytes, MDM are resistant to cytopathic effects and survive HIV infection for a long period of time. The molecular mechanisms of how HIV is able to persist in macrophages are not fully elucidated yet. In this context, we have studied the effect of in vitro HIV-1 infection on telomerase activity (TA), telomere length, and DNA damage. Infection resulted in a significant induction of TA. This increase was directly proportional to the efficacy of HIV infection and was found in both nuclear and cytoplasmic extracts, while neither UV light-inactivated HIV nor exogenous addition of the viral protein Tat or gp120 affected TA. Furthermore, TA was not modified during monocyte-macrophage differentiation, MDM activation, or infection with vaccinia virus. HIV infection did not affect telomere length. However, HIV-infected MDM showed less DNA damage after oxidative stress than noninfected MDM, and this resistance was also increased by overexpressing telomerase alone. Taken together, our results suggest that HIV induces TA in MDM and that this induction might contribute to cellular protection against oxidative stress, which could be considered a viral strategy to make macrophages better suited as longer-lived, more resistant viral reservoirs. In the light of the clinical development of telomerase inhibitors as anticancer therapeutics, inhibition of TA in HIV-infected macrophages might also represent a novel therapeutic target against viral reservoirs. PMID:22787205
Reynoso, Rita; Wieser, Matthias; Ojeda, Diego; Bönisch, Maximilian; Kühnel, Harald; Bolcic, Federico; Quendler, Heribert; Grillari, Johannes; Grillari-Voglauer, Regina; Quarleri, Jorge
Schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future. PMID:17166669
Pae, Chi-Un; Lee, Chul; Paik, In-Ho
More than twenty-five years after its discovery, HIV-1 remains one of the world’s most formidable and destructive pathogens. Several classes of anti-HIV-1 agents are currently in widespread clinical use in developed nations; however, viral resistance to these drugs limits their effectiveness in a growing number of patients. It is therefore imperative that novel drugs be developed. Recent advances in the fields of HIV-1 molecular virology and cell biology have revealed possible new targets for drug discovery. The current status of antiretroviral therapy and some of the promising new targets against which novel antiviral agents could be developed are discussed.
Adamson, Catherine S.; Freed, Eric O.
Restriction factors are natural cellular proteins that defend individual cells from viral infection. These factors include the APOBEC3 family of DNA cytidine deaminases, which restrict the infectivity of HIV-1 by hypermutating viral cDNA and inhibiting reverse transcription and integration. HIV-1 thwarts this restriction activity through its accessory protein virion infectivity factor (Vif), which uses multiple mechanisms to prevent APOBEC3 proteins such as APOBEC3G and APOBEC3F from entering viral particles. Here, we review the basic biology of the interactions between human APOBEC3 proteins and HIV-1 Vif. We also summarize, for the first time, current clinical data on the in vivo effects of APOBEC3 proteins and survey strategies and progress toward developing therapeutics aimed at the APOBEC3-Vif axis.
Albin, John S.; Harris, Reuben S.
Homocysteine (Hcy) is metabolized through two pathways, requiring folates and B6-12 vitamins as cofactors. Increased Hcy concentration is responsible for early atherosclerosis with possible acute cardiovascular events. Ample evidence has demonstrated that Hcy lowering with folic acid and B vitamin supplementation, even if reduces Hcy serum levels, is unable to lower cardiovascular risk. On the contrary, omega-3 fatty acids and some nutraceuticals, such as N-acetyl cysteine, taurine, or S-adenosyl-methionine, reduce both Hcy serum concentration and cardiovascular risk. Instead, antiplatelet drugs, such as aspirin and clopidogrel or ticlopidine and statins only antagonize vascular derangements. Finally, metformin, some lipid-lowering drugs, and some diuretics should be avoided because they can increase Hcy levels. PMID:23135377
The development of a preventive vaccine to neutralize the highly variable and antigenically diverse human immunodeficiency virus type 1 (HIV-1) has been an indomitable goal. The recent discovery of a number of cross-neutralizing and potent monoclonal antibodies from elite neutralizers has provided important insights in this field. Neutralizing antibodies (NAbs) are useful in identifying neutralizing epitopes of vaccine utility and for understanding the mechanism of potent and broad cross-neutralization thus providing a modality of preventive and therapeutic value. In this article we review the current understanding on the potential use of broadly neutralizing antibodies (bNAbs) in their full-length IgG structure, engineered domain antibody or bispecific versions towards preventive and therapeutic applications. The potential implications of NAbs are discussed in the light of the recent developments as key components in vaccination against HIV-1. The development of a vaccine immunogen which elicits bNAbs and confers protective immunity remains a real challenge.
HIV-1-specific monoclonal antibodies (mAbs) with extraordinary potency and breadth have recently been described. In humanized mice, combinations of mAbs have been shown to suppress viremia, but the therapeutic potential of these mAbs has not yet been evaluated in primates with an intact immune system. Here we show that administration of a cocktail of HIV-1-specific mAbs, as well as the single glycan-dependent mAb PGT121, resulted in a rapid and precipitous decline of plasma viremia to undetectable levels in rhesus monkeys chronically infected with the pathogenic virus SHIV-SF162P3. A single mAb infusion afforded up to a 3.1 log decline of plasma viral RNA in 7 days and also reduced proviral DNA in peripheral blood, gastrointestinal mucosa, and lymph nodes without the development of viral resistance. Moreover, following mAb administration, host Gag-specific T lymphocyte responses exhibited improved functionality. Virus rebounded in the majority of animals after a median of 56 days when serum mAb titers had declined to undetectable levels, although a subset of animals maintained long-term virologic control in the absence of further mAb infusions. These data demonstrate a profound therapeutic effect of potent neutralizing HIV-1-specific mAbs in SHIV-infected rhesus monkeys as well as an impact on host immune responses. Our findings strongly encourage the investigation of mAb therapy for HIV-1 in humans.
Barouch, Dan H.; Whitney, James B.; Moldt, Brian; Klein, Florian; Oliveira, Thiago Y.; Liu, Jinyan; Stephenson, Kathryn E.; Chang, Hui-Wen; Shekhar, Karthik; Gupta, Sanjana; Nkolola, Joseph P.; Seaman, Michael S.; Smith, Kaitlin M.; Borducchi, Erica N.; Cabral, Crystal; Smith, Jeffrey Y.; Blackmore, Stephen; Sanisetty, Srisowmya; Perry, James R.; Beck, Matthew; Lewis, Mark G.; Rinaldi, William; Chakraborty, Arup K.; Poignard, Pascal; Nussenzweig, Michel C.; Burton, Dennis R.
The problem of prevention of lymphatic complications in surgery is extremely important if we think about the frequency of both early complications such as lymphorrhea, lymphocele, wound dehiscence and infections and late complications such as lymphangitis and lymphedema. Nowadays, it is possible to identify risk patients and prevent these lesions or treat them at an early stage. This report helps to demonstrate how it is important to integrate diagnostic and clinical findings to better understand how to properly identify risk patients for lymphatic injuries and, therefore, when it is useful and proper to do prevention. Authors report their experiences in the prevention and treatment of lymphatic injuries after surgical operations and trauma. After an accurate diagnostic approach, prevention is based on different technical procedures among which microsurgical procedures. It is very important to follow-up the patient not only clinically but also by lymphoscintigraphy. A protocol of prevention of secondary limb lymphedema was proposed and it includes, from the diagnostic point of view, lymphoscintigraphy and, as concerns therapy, it recognizes also a role to early microsurgery. It is necessary to accurately follow-up the patient who has undergone an operation at risk for the appearance of lymphatic complications and, even better, to assess clinically and by lymphoscintigraphy the patient before surgical operation. PMID:22821181
Boccardo, Francesco; Campisi, Corrado Cesare; Molinari, Lidia; Dessalvi, Sara; Santi, Pier Luigi; Campisi, Corradino
Objective To evaluate the effectiveness of Safe Thinking and Affect Regulation (STAR), a 14-session HIV-prevention program for adolescents at alternative/therapeutic schools. Because these youth frequently have difficulties with emotions and cognitions, it was designed to improve sexuality specific affect management and cognitive monitoring, as well as HIV-related knowledge and attitudes. It was hypothesized that STAR would lead to a decrease in sexual risk and improved HIV knowledge and attitudes. Method Fourteen schools were randomly assigned by year either to the STAR intervention or a brief educational program. Schools received the alternate intervention the following year. 185 adolescents in 29 cohorts (groups) participated in the interventions. Assessment of sexual behavior, knowledge and attitudes with audio computer-assisted self-interviews occurred at three, six and nine months post intervention. Results Hierarchical Linear Model (HLM) analyses found that adolescents in the STAR intervention reported a significantly greater decrease (p < .05) in the Sexual Risk Index than youth in the control group over the six months post intervention and similar improvements in the HIV Knowledge Scale and the Condom Use Self Efficacy Scale. There were no group differences between six and nine months post intervention. Conclusions This STAR intervention for youth in alternative schools was associated with decreased sexual risk for six months after the intervention. These data suggest that intervention strategies that target cognitions and affect within a sexual context might be usefully applied to improving sexual behavior but may need to be reinforced over time.
Brown, Larry K.; Nugent, Nicole R.; Houck, Christopher D.; Lescano, Celia M.; Whiteley, Laura B.; Barker, David; Viau, Lisa; Zlotnick, Caron
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
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.
Battistini, Angela; Sgarbanti, Marco
The role of volunteer recruitment in HIV vaccine trials has recently been considered particularly with respect to critical issues, such as motivation, psychological assessment and social impact. The preventative and therapeutic phase I trials based on the recombinant biologically active Tat vaccine candidate, sponsored in Italy by the Istituto Superiore di Sanità, included a specific centralised procedure (SCP) developed to
Anna Maria Luzi; Pietro Gallo; Anna Colucci; Simone Marcotullio; Stefania Bellino; Olimpia Longo; Barbara Ensoli
Chagasdisease is a zoonosis caused by the parasite Trypanosoma cruzi, a haematic protozoan, transmitted by insects from the Reduviidae family. This constitutes a relevant health and socio-economic problem in the Americas, with 11 - 18 million people infected, and approximately 100 million people at risk. The therapeutic possibilities rely into two drugs, nifurtimox® and benznidazole ®, that were discovered more
Ariel Mariano Silber; Walter Colli; Henning Ulrich; Maria Julia Manso Alves; Claudio Alejandro Pereira
Background Mitochondrial dysfunction (MD) has been associated with both HIV infection and exposure to antiretroviral therapies. MD has not been widely studied in HIV-infected children. Methods Children with perinatal HIV infection enrolled in a prospective cohort, Pediatric AIDS Clinical Trials Group 219/ 219C, between 1993 and 2004 were included. Two clinical case definitions of MD, the Enquête Périnatale Française criteria and the Mitochondrial Disease Classification, were used to classify signs and symptoms consistent with possible MD. Adjusted odds ratios of the associations between single and dual nucleoside reverse transcriptase inhibitor (NRTI) use and possible MD were estimated using logistic regression. Results Overall, 982/2931 children (33.5%) met one or both case definitions of possible MD. Mortality was highest among the 96 children meeting both case definitions (20%). After adjusting for confounders, children using d4T regardless of other exposures (OR 3.44, 95% CI 1.91, 6.20) or d4T/ddI combination therapy (OR 2.23, 95% CI 1.19, 4.21) had a higher risk of possible MD. 3TC and 3TC/d4T exposures also were associated with increased MD. Conclusions NRTIs, especially d4T and 3TC, were associated with possible MD in children with perinatal HIV. Further studies are warranted to elucidate potential mechanisms of NRTI toxicities.
Crain, Marilyn J.; Chernoff, Miriam C.; Oleske, James M.; Brogly, Susan B.; Malee, Kathleen M.; Borum, Peggy R.; Meyer, William A.; Mitchell, Wendy G.; Moye, John H.; Ford-Chatterton, Heather M.; Van Dyke, Russell B.; Seage, George R.
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
Morton, R S; Rashid, S
Chronic HIV infection is associated with persistent immune activation and inflammation even among patients virologically suppressed on antiretroviral therapy for years. Chronic immune activation has been associated with poor outcomes--both AIDS-defining and non-AIDS-defining clinical events--and persistent CD4 T-cell depletion. The cause of chronic immune activation in well-controlled HIV infection is unknown. Proposed drivers include residual viral replication, microbial translocation, and coinfecting pathogens. Therapeutic interventions targeting immune activation are emerging, from approaches that interfere directly with activation and inflammatory pathways to those that prevent microbial translocation or decrease the availability of host target cells for the virus. In the context of the disappointing results of the interleukin-2 trials, the main challenges to developing these disease-modifying therapies include identifying an adequate target population and choosing surrogate endpoints that will provide positive proof-of-concept that the interventions will translate into long-term clinical benefit before embarking on large clinical endpoint trials. PMID:21792065
Butler, Scott L; Valdez, Hernan; Westby, Michael; Perros, Manos; June, Carl H; Jacobson, Jeffrey M; Levy, Yves; Cooper, David A; Douek, Daniel; Lederman, Michael M; Tebas, Pablo
Chronic generalized immune activation represents one of the most critical features determining progression to AIDS. This may result in the manifestation of malignancy, with lymphoma and Karposi's sarcoma being the first to be recognised. In this regard, the manifestation of lymphoma is very similar to that seen in transplant patients and those with graft versus host disease (GVHD) where both chronic immune activation and immune suppression are present. Unlike the latter conditions which involve HLA mismatch, the source of this phenomenon during HIV infection remains elusive. Despite a lifecycle adapted to the host and possessing a plethora of survival strategies, HIV promotes disease progression in a manner that is consistently associated with the HLA repertoire suggesting pathogenic features relating to immunological incompatibility may be at the root of disease. Here we review the influence of immune activation on progression to AIDS with particular reference to molecular mimicry and autoimmune phenomenon and highlight the therapeutic potential of non-neutralizing antibodies and strategies designed to diffuse immune activation. PMID:19055948
Cadogan, Martin; Dalgleish, Angus G
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 ?200 cells\\/mm3 and CD4 cell count decline were studied in a multicenter cohort study of 56 individuals who participated in a phase II double-blind placebo-controlled trial with p24-VLP in 1993. Using Cox proportional hazard
Catharina E. A. Lindenburg; Ineke Stolte; Miranda W. Langendam; Frank Miedema; Ian G. Williams; Robert Colebunders; Jonathan N. Weber; Martin Fisher; Roel A. Coutinho
Treatment of HIV-infected patients with highly active antiretroviral therapy (HAART) usually results in diminished viral replication, increasing CD4+ cell counts, a reversal of most immunological disturbances, and a reduction in risk of morbidity and mortality. However, approximately 20% of all HIV-infected patients do not achieve optimal immune reconstitution despite suppression of viral replication. These patients are referred to as immunological nonresponders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoetic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Additional treatment to HAART that may improve immune reconstitution has been investigated, but results thus far have proved disappointing. The reason for immunological nonresponse is incompletely understood. This paper summarizes the known and unknown factors regarding the incomplete immune reconstitution in HIV infection, including mechanisms, relevance for clinical care, and possible solutions.
Gaardbo, Julie C.; Hartling, Hans J.; Gerstoft, Jan; Nielsen, Susanne D.
Cardiac surgery with cardiopulmonary bypass provokes a systemic inflammatory response syndrome caused by the surgical trauma itself, blood contact with the non-physiological surfaces of the extracorporeal circuit, endotoxemia, and ischemia. The role of endotoxin in the inflammatory response syndrome has been well investigated. In this report, we reviewed recent advances in the understanding of the pathophysiology of the endotoxin release during cardiopulmonary bypass and the possible therapeutic strategies aimed to reduce the endotoxin release or to counteract the inflammatory effects of endotoxin. Although many different strategies to detoxify endotoxins were evaluated, none of them were able to show statistically significant differences in clinical outcome. PMID:20663682
Kats, Suzanne; Schönberger, Jacques P A M; Brands, Ruud; Seinen, Willem; van Oeveren, Wim
Werner syndrome (WS) is a premature aging disorder that is widely used as a model for some aspects of the normal human aging process. Individuals with WS have several of the characteristics of normal aging, such as cataracts, hair graying, and skin aging, but manifest these at an early age. In addition, WS is associated with high levels of inflammatory diseases such as atherosclerosis and type II diabetes. Recent data have indicated that fibroblasts derived from individuals with WS have activated a major molecular pathway involved in inflammation. This observation ties in with the presence of high plasma levels of inflammatory cytokines in individuals with WS. In this paper, the authors discuss the possibility that WS is an example of "inflamm-aging," in that many of the phenotypic manifestations may result from an increased inflammatory state. Moreover, drugs that specifically block this inflammation pathway may be possible candidates for therapeutic intervention in WS. PMID:16859481
Davis, Terence; Kipling, David
Many conventional chemotherapeutic drugs exert their cytotoxic function by inducing DNA damage in the tumor cell. Therefore, a cell-inherent DNA repair pathway, which reverses the DNA-damaging effect of the cytotoxic drugs, can mediate therapeutic resistance to chemotherapy. The monofunctional DNA-alkylating agent temozolomide (TMZ) is a commonly used chemotherapeutic drug and the gold standard treatment for glioblastoma (GBM). Although the activity of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) has been described as the main modulator to determine the sensitivity of GBM to TMZ, a subset of GBM does not respond despite MGMT inactivation, suggesting that another DNA repair mechanism may also modulate the tolerance to TMZ. Considerable interest has focused on MGMT, mismatch repair (MMR), and the base excision repair (BER) pathway in the mechanism of mediating TMZ resistance, but emerging roles for the DNA strand-break repair pathway have been demonstrated. In the first part of this review article, we briefly review the significant role of MGMT, MMR, and the BER pathway in the tolerance to TMZ; in the last part, we review the recent publications that demonstrate possible roles of DNA strand-break repair pathways, such as single-strand break repair and double-strand break repair, as well as the Fanconi anemia pathway in the repair process after alkylating agent-based therapy. It is possible that all of these repair pathways have a potential to modulate the sensitivity to TMZ and aid in overcoming the therapeutic resistance in the clinic.
Yoshimoto, Koji; Mizoguchi, Masahiro; Hata, Nobuhiro; Murata, Hideki; Hatae, Ryusuke; Amano, Toshiyuki; Nakamizo, Akira; Sasaki, Tomio
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.
Mariottini, Gian Luigi; Pane, Luigi
Targeting canarypox (CP)-HIV vaccine to dendritic cells (DCs) elicits anti-HIV-1 immune responses in vitro. We conducted a phase I/II clinical trial to evaluate whether adding DC to a CP-HIV vaccine improved virologic control during analytic treatment interruption (ATI) in HIV-1-infected subjects. Twenty-nine subjects on suppressive antiretroviral therapy were randomized to vaccination with autologous DCs infected with CP-HIV+keyhole limpet hemocyanin (KLH) (arm A, n=14) or CP-HIV+KLH alone (arm B, n=15). The mean viral load (VL) setpoint during ATI did not differ between subjects in arms A and B. A higher percentage of subjects in the DC group had a VL setpoint < 5,000 c/mL during ATI (4/13 or 31% in arm A compared with 0/13 in arm B, p=0.096), but virologic control was transient. Subjects in arm A had a greater increase in KLH lymphoproliferative response than subjects in arm B; however, summed ELISPOT responses to HIV-1 antigens did not differ by treatment arm. We conclude that a DC-CP-HIV vaccine is well-tolerated in HIV-1-infected patients, but does not lower VL setpoint during ATI compared with CP-HIV alone. New methods to enhance the immunogenicity and antiviral efficacy of DC-based vaccines for HIV-1 infection are needed. PMID:19450647
Gandhi, Rajesh T; O'Neill, David; Bosch, Ronald J; Chan, Ellen S; Bucy, R Pat; Shopis, Janet; Baglyos, Lynn; Adams, Elizabeth; Fox, Lawrence; Purdue, Lynette; Marshak, Ann; Flynn, Theresa; Masih, Reena; Schock, Barbara; Mildvan, Donna; Schlesinger, Sarah J; Marovich, Mary A; Bhardwaj, Nina; Jacobson, Jeffrey M
Lipodystrophy (LD) is a common adverse effect of HIV treatment with highly active antiretroviral therapy, which comprises morphological and metabolic changes. The underlying mechanisms for LD are thought to be due to mitochondrial toxicity and insulin resistance, which results from derangements in levels of adipose tissue-derived proteins (adipocytokines) that are actively involved in energy homeostasis. Several management strategies for combating this syndrome are available, but they all have limitations. They include: switching from thymidine analogues to tenofovir or abacavir in lipoatrophy, or switching from protease inhibitors associated with hyperlipidaemia to a protease-sparing option; injection into the face with either biodegradable fillers such as poly-L-lactic acid and hyaluronic acid (a temporary measure requiring re-treatment) or permanent fillers such as bio-alcamid (with the risk of foreign body reaction or granuloma formation); and structured treatment interruption with the risk of loss of virological control and disease progression. There is therefore a need to explore alternative therapeutic options. Some new approaches including adipocytokines, uridine supplementation, glitazones, growth hormone (or growth hormone-releasing hormone analogues), metformin and statins (used alone or in combination) merit further investigation. PMID:18565973
Mallewa, Jane E; Wilkins, Edmund; Vilar, Javier; Mallewa, Macpherson; Doran, Dominic; Back, David; Pirmohamed, Munir
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 host’s 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.
Wagner, Marc C.E.
Persons with advanced human immunodeficiency virus type one (HIV-1) infection seek medical advice for a wide range of neurological disorders including, but not limited to, peripheral neuropathy, toxoplasmosis, cryptococcal meningitis, cytomegalovirus retinitis progressive multifocal leukoencephalopathy, lymphoma and dementia. The diagnosis of HIV-1-associated dementia (HAD) induced as a direct consequence of HIV infection of the brain comes commonly by exclusion. Diagnostic decisions can often be clouded by concomitant depression, motor impairments, and lethargy that follow debilitating immune suppression and weight loss. Indeed, cognitive, motor and behavior abnormalities underlie a variety of neurological dysfunctions associated with advanced HIV-1 infection. Thus, even combinations of clinical, laboratory and neuroimaging tests [for example, magnetic resonance imaging (MRI), computed tomography (CT), single photon emission computed tomography (SPECT) and positron emission tomography (PET)] often fail to provide conclusive diagnostic information. Nonetheless, the recent development of quantitative MR spectroscopic imaging has improved diagnostic possibilities for HAD. We are pleased to discuss these developments as well as taking a forward look into what will soon be made available to improve neuroimaging diagnostic precision. New MR and SPECT testing are being developed in our laboratories and elsewhere both for animal model systems and in humans with HIV-1 disease. Such tests can facilitate dynamic measures of HIV-1 neuropathogenesis providing information for disease events that even 2 years ago were unattainable. PMID:15053341
Boska, Michael D; Mosley, R Lee; Nawab, Mehmood; Nelson, Jay A; Zelivyanskaya, Marina; Poluektova, Larisa; Uberti, Mariano; Dou, Huanyu; Lewis, Travis B; Gendelman, Howard E
Clinical studies indicate that alcohol dependence has an additive effect on cognitive deficits associated with HIV-1 infection. Findings in humans and animal models suggest that alcohol, similar to HIV-1, induces inflammatory processes in the brain leading to neurodegeneration. The causes of HIV-1-associated neurotoxicity are comparable to those mediating alcohol-induced neuronal injury. This review aims to present the mechanisms of the combined effects of HIV-1 and alcohol abuse in the brain and to discuss neuroprotective therapies. Oxidative stress, overproduction of pro-inflammatory factors, impairment of blood brain barrier and glutamate associated neurotoxicity appear to play important roles in alcohol driven neurodegeneration. Diminution of neuroinflammation constitutes a logical approach for prevention of HIV-1 and alcohol mediated neurodegeneration. Agonists of cannabinoid receptor 2 (CB2) possess potent anti-inflammatory and neuroprotective properties. We address multifaceted beneficial effects of CB2 activation in the setting of HIV-1 brain infection and alcohol abuse.
Persidsky, Yuri; Ho, Wenzhe; Ramirez, Servio H.; Potula, Raghava; Abood, Mary E.; Unterwald, Ellen; Tuma, Ronald
Central nervous system (CNS) HIV-related disorders frequently have devastating consequences. Significant progress has been\\u000a made in the early diagnosis and treatment of the HIV-infected patient. As a result, the prevalence and natural history of\\u000a neurologic illnesses have changed. This paper reviews the epidemiology, clinical manifestations, and neuropathogenesis of\\u000a HIV-related CNS disorders. Advances in antiretroviral therapy, neuroprophylaxis, and neuroprotective strategies are
Abstract Objectives: The aim of this study was to develop a small interfering RNA (siRNA) against the expression of KIR3DL1 receptor on natural killer (NK) cells, in order to promote the ability of NK cells to destroy human immunodeficiency virus (HIV)-infected cells and thus prevent failure of siRNA therapy targeting human immunodeficiency virus type 1 (HIV-1) virus among HIV-1 infected patients in vitro. Methods: A siRNA targeting KIR3DL1 was synthesized and then modified with cholesterol, methylene, and sulfate. The inhibitory action of the siRNAs on primary cultured NK cells was detected. The amount of IFN-? and TNF-? secretions in NK cells was measured. The intended functions of NK cells in vitro were analyzed by CFSE and PI methods. Results: There were no significant differences in inhibiting the expression of KIR3DL1 on NK cells between the modified and unmodified siRNAs, while inhibition by each of them differed significantly from controls. The amount of IFN-? and TNF-? secretions in the NK cells was abundant due to unsuccessful expression of KIR3DL1 on NK cells, which further promoted function of the NK cells. Conclusion: The siRNA against KIR3DL1 could enhance the ability of the NK cells to kill the HIV-1 infected cells in vitro and successfully prevented the failure of siRNA therapy targeting the HIV-1 virus. Therefore, it can act as a potential gene therapeutic agent among HIV-1 infected people. PMID:24834927
Fu, Geng-Feng; Pan, Ji-Cheng; Lin, Nan; Hu, Hai-Yang; Tang, Wei-Ming; Xu, Jin-Shui; Wang, Xiao-Liang; Xu, Xiao-Qin; Qiu, Tao; Liu, Xiao-Yan; Chen, Guo-Hong; Mahapatra, Tanmay; Huan, Xi-Ping; Yang, Hai-Tao
Objectives: To assess the evolution of the HIV screening practices towards pregnant women between 1992 and 1996, in relation with the 1993 French mandatory obligation to offer prenatal HIV testing and recent therapeutic possibilities to reduce HIV vertical transmission. Study design: Three successive surveys (January 1992, May 1994 and May 1996) about HIV screening policies among medical chiefs of all
Dominique Rey; Yolande Obadia; Maria-Patrizia Carrieri; Jean-Paul Moatti
HIV-2 drug resistance in a case of dual HIV infection presents a formidable challenge to the treating physician. We report a patient with dual infection on highly active antiretroviral therapy (HAART) since March 2001 presented with clinical failure. Laboratory assays showed undetectable HIV-1 viral RNA copies, but with low CD4 count. Suspecting HIV-2 resistance, specific genotype assays were performed. Mutations at codons M184V and Q151M conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-1 infection were detected, as were mutations at codons V71I and L90M implying indinavir and nelfinavir resistance as well. Salvage therapy was initiated with good clinical response. PMID:17062187
Maniar, Janak K; Damond, Florence; Kamath, Ratnakar R; Mandalia, Sundhiya; Surjushe, Amar
With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing various alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were synthesized. The inhibitors possessing a 6-alkyl group exhibited superior antiviral activities when compared to 6-phenyl analogues. Antiviral efficacies were further improved upon introduction of a polar group (hydroxyl or amino)
J. V. N. Vara Prasad; Frederick E. Boyer; John M. Domagala; Edmund L. Ellsworth; Christopher Gajda; Harriet W. Hamilton; Susan E. Hagen; Larry J. Markoski; Bruce A. Steinbaugh; Bradley D. Tait; Christine Humblet; Elizabeth A. Lunney; Alexander Pavlovsky; John R. Rubin; Donna Ferguson; Neil Graham; Tod Holler; Donald Hupe; Carolyn Nouhan; Peter J. Tummino; A. Urumov; Eric Zeikus; Greg Zeikus; Stephen J. Gracheck; James M. Saunders; Steven VanderRoest; Joanne Brodfuehrer; K. Iyer; M. Sinz; Sergei V. Gulnik; John W. Erickson
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
Gillette, Devyn D; Tridandapani, Susheela; Butchar, Jonathan P
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.
Biswas, Archita; Gomes, Aparna; Sengupta, Jayeeta; Datta, Poulami; Singha, Santiswarup; Dasgupta, Anjan Kr; Gomes, Antony
1. The present study was designed to determine whether naftidrofuryl oxalate exerts a possible therapeutic effect on brain energy metabolism impaired by microsphere-induced cerebral embolism in vitro. 2. Injection of microspheres into the right carotid canal resulted in a decrease in tissue high-energy phosphates both in the right and left hemispheres, and an increase in tissue lactate in the right hemisphere, on the 3rd and the 5th day after the embolism. The embolism also induced a marked reduction in mitochondrial oxidative phosphorylation ability and succinate dehydrogenase activity. The results suggest that severe ischaemia was induced in the brain by the microsphere administration. 3. Treatment of microsphere-injected rats with naftidrofuryl oxalate (15 mg kg-1) for 3 or 5 days elicited a significant recovery of tissue high-energy phosphate and lactate levels. The recovery was associated with a significant restoration of mitochondrial succinate dehydrogenase activity on the both days and of mitochondrial oxidative phosphorylation rate on the 5th day. 4. The results suggest that naftidrofuryl oxalate is beneficial in the recovery of cerebral energy metabolism impaired by microsphere-induced cerebral ischaemia, presumably through a mechanism involving its direct effect on the cerebral mitochondrial enzyme activities.
Miyake, K.; Tanonaka, K.; Minematsu, R.; Inoue, K.; Takeo, S.
Objective To evaluate the effect of hysterosalpingo-contrast sonography (HyCoSy) on natural conception in the infertile patient. Methods We conducted a prospective observational study recruiting 180 patients admitted to Infertility Center of Ferrara University from January 2010 to February 2012. The essential inclusion criteria was the couple's desire to perform only diagnostic evaluation on infertility causes and to wait for natural conception before proceeding with further management. Couples were investigated with hormonal profile, semen analysis and HyCoSy. Expected time for spontaneous pregnancy was 180 days from HyCoSy. First datation sonography of pregnancy was used calculating time elapsed from HyCoSy at conception. Results Forty patients (22.2%) obtained spontaneous pregnancy within 6 months after HyCoSy. The mean of "conception time" was 75 days. The pregnancy rate was significantly higher in the first 30 days (45%) compared to other the months of observation (p<0.0005). Multiple linear regression analysis showed that maternal age and sterility duration proved independent variables in detecting the "conception time" after HyCoSy (t=3.742, p=0.001, t=2.371, p=0.02, respectively). Conclusion A possible beneficial effect of HyCoSy is feasible especially in the days following its execution. This temporal correlation supports its therapeutic use.
Cagnazzo, Elisa; Bazzan, Elisa; Patella, Alfredo; Marci, Roberto
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…
Lewis, Linwood J.; Mellins, Claude A.; Brackis-Cott, Elizabeth
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
Telan, Elizabeth Freda O; Samonte, Genesis May J; Palaypayon, Noel; Abellanosa-Tac-An, Ilya P; Leaño, Prisca Susan A; Tsuneki, Akeno; Kageyama, Seiji
HIV-1-associated neuroinflammation persists even with effective combined antiretroviral therapy, and it is associated with the presence of activated monocytes/macrophages within the CNS. To infiltrate the CNS, monocytes transmigrate across the selectively permeable blood-brain barrier, which is compromised during HIV-1 infection. Interestingly, platelet-derived excess soluble CD40 ligand found in the plasma and cerebrospinal fluid of HIV-1-infected individuals with cognitive impairment has previously been implicated in increased blood-brain barrier permeability. In this study we show that soluble CD40 ligand also promotes the formation of complexes between inflammatory monocytes and activated platelets (PMCs), which are detected by flow cytometry as monocytes that express excess of CD61, a platelet marker, and that these complexes are increased in individuals with HIV-1 infection. PMCs exhibit an enhanced ability to adhere to human brain microvascular endothelial cells as compared with monocytes alone, and they migrate across the transendothelial barrier. These complexes can be found marginalized in the lumen of postcapillary venules in postmortem brain tissue derived from cases of HIV-1-associated encephalitis. The extravasation of monocytes across the brain endothelium may exacerbate neuroinflammation, indicating that enhancing this event via platelet interaction may be a contributing factor in the development of cognitive impairment. Thus, dampening platelet activation, and in turn PMC formation, with antiplatelet agents may prove beneficial in developing adjunctive therapies for use in combination with combined antiretroviral therapy in an effort to reduce HIV-1-associated neurologic deficit. PMID:24729609
Singh, Meera V; Davidson, Donna C; Jackson, Joseph W; Singh, Vir B; Silva, Jharon; Ramirez, Servio H; Maggirwar, Sanjay B
Human immunodeficiency virus (HIV) patients have more aggressive presentation of colorectal cancer (CRC) and less favourable outcome. Bevacizumab is an antiangiogenic agent that has emerged as a major drug for metastatic CRC. However, few data are available on the safety of bevacizumab in HIV patients. In the light of a case study, we briefly draw intention on how angiogenesis inhibitors could interact with antiviral tri-therapy. PMID:24090564
Magné, Nicolas; Chargari, Cyrus; Levy, Antonin; Guy, Jean-Baptiste; Merrouche, Yacine; Spano, Jean-Philippe
Background The HIV integrase inhibitor, Dolutegravir (DTG), was recently approved by the Food and Drug Administration in the United States and is the only HIV drug that has not selected for resistance mutations in the clinic when used as part of first-line therapy. This has led to speculation that DTG might have a higher genetic barrier for the development of drug resistance than the other compounds that are used in therapy. Discussion In this Opinion article, we speculate that this is due to greatly diminished replication capacity on the part of viruses that might become resistant to DTG when the drug is used in initial therapy and that DTG might be able to be used in HIV prevention and eradication strategies. We also note that no compensatory mutation that might restore viral replication fitness to HIV in the aftermath of the appearance of a single drug resistance mutation has yet to be observed. Summary DTG is a valuable addition to the anti-HIV armamentarium of drugs and its long-term utility may potentially exceed its obvious use in treatment of HIV disease.
Protein misassembly into aggregate structures, including cross-?-sheet amyloid fibrils, is linked to diseases characterized by the degeneration of post-mitotic tissue. While amyloid fibril deposition in the extracellular space certainly disrupts cellular and tissue architecture late in the course of amyloid diseases, strong genetic, pathological and pharmacologic evidence suggests that the process of amyloid fibril formation itself, known as amyloidogenesis, likely causes these maladies. It seems that the formation of oligomeric aggregates during the amyloidogenesis process causes the proteotoxicity and cytotoxicity characteristic of these disorders. Herein, we review what is known about the genetics, biochemistry and pathology of familial amyloidosis of Finnish Type (FAF) or gelsolin amyloidosis. Briefly, autosomal dominant D187N or D187Y mutations compromise Ca2+ binding in domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations. When domain 2 is unfolded, gelsolin is subject to aberrant furin endoproteolysis as it passes through the Golgi on its way to the extracellular space. The resulting C-terminal 68kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin. These amyloidogenic fragments deposit systemically, causing a variety of symptoms, including corneal lattice dystrophy and neurodegeneration. The first murine model of the disease recapitulates the aberrant processing of mutant plasma gelsolin, amyloid deposition, and the degenerative phenotype. We use what we have learned from our biochemical studies, as well as insight from mouse and human pathology to propose therapeutic strategies that may halt the progression of FAF.
Solomon, James P.; Page, Lesley J.; Balch, William E.; Kelly, Jeffery W.
It is estimated that 4 to 5 million people are currently co-infected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). HIV/HCV co-infection is associated with unique health risks including increased hepatotoxicity of antiretrovirals, accelerated progression of HCV and liver diseases. The standard interferon-based therapy is effective only in about 50% of patients and often is associated with autoimmune and neuro-psychiatric complications. The treatment of co-infection (HIV/HCV) requires new strategic approaches. To this end, the formulations of an amphiphatic ?-helical peptide, a positively charged analog of C5A peptide derived from the HCV NS5A protein, with a reported virocidal activity were prepared by electrostatic coupling with anionic poly(amino acid)-based block copolymers. The self-assembled antiviral peptide nanocomplexes (APN) were ca. 35 nm in size, stable at physiological pH and ionic strength, and retained in vitro antiviral activity against HCV and HIV. Moreover, incorporation of the peptide into APN attenuated its cytotoxicity associated with the positive charge. In vivo APN were able to decrease the viral load in mice transplanted with human lymphocytes and HIV-1-infected. Overall, these findings indicate the potential of these formulations for stabilization and delivery of antiviral peptides while maintaining their functional activity. PMID:23403120
Zhang, Jinjin; Mulvenon, Andrea; Makarov, Edward; Wagoner, Jill; Knibbe, Jaclyn; Kim, Jong Oh; Osna, Natalia; Bronich, Tatiana K; Poluektova, Larisa Y
It is estimated that 4 to 5 million people are currently co-infected with Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). HIV/HCV co-infection is associated with unique health risks including increased hepatotoxicity of antiretrovirals, accelerated progression of HCV and liver diseases. The standard interferon-based therapy is effective only in about 50% of patients and often is associated with autoimmune and neuro-psychiatric complications. The treatment of co-infection (HIV/HCV) requires new strategic approaches. To this end, the formulations of an amphiphatic ?-helical peptide, a positively charged analog of C5A peptide derived from the HCV NS5A protein, with a reported virocidal activity were prepared by electrostatic coupling with anionic poly(amino acid)-based block copolymers. The self-assembled antiviral peptide nanocomplexes (APN) were ca. 35 nm in size, stable at physiological pH and ionic strength, and retained in vitro antiviral activity against HCV and HIV. Moreover, incorporation of the peptide into APN attenuated its cytotoxicity associated with the positive charge. In vivo APN were able to decrease the viral load in mice transplanted with human lymphocytes and HIV-1-infected. Overall, these findings indicate the potential of these formulations for stabilization and delivery of antiviral peptides while maintaining their functional activity.
Zhang, Jingjin; Mulvenon, Andrea; Makarov, Edward; Wagoner, Jill; Knibbe, Jaclyn; Kim, Jong Oh; Osna, Natalia
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.
Adams, Vera J; Markus, Miles B; Kwitshana, Zilungile L; Dhansay, Muhammad A; van der Merwe, Lize; Walzl, Gerhard; Fincham, John E
This paper presents a number of deterministic models for theoretically assessing the potential impact of an imperfect prophylactic HIV-1 vaccine that has five biological modes of action, namely “take,” “degree,” “duration,” “infectiousness,” and “progression,” and can lead to increased risky behavior. The models, which are of the form of systems of nonlinear differential equations, are constructed via a progressive refinement
Elamin H. Elbasha; Abba B. Gumel
Abstract Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1+ vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56neg cell subpopulation, while levels of the NK CD56dim and NK CD56bright cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients. Taken together, these results suggest that this vaccine might enhance innate immunity by amplifying the inflammatory and cytolytic capacity.
Frias, Mario; Castro-Orgaz, Laura; Gonzalez, Rafael; Garcia, Felipe; Gallart, Teresa; Gatell, Jose Maria; Plana, Montserrat
Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1(+) vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56(neg) cell subpopulation, while levels of the NK CD56(dim) and NK CD56(bright) cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients. Taken together, these results suggest that this vaccine might enhance innate immunity by amplifying the inflammatory and cytolytic capacity. PMID:22233253
Peña, José; Frías, Mario; Castro-Orgaz, Laura; González, Rafael; García, Felipe; Gallart, Teresa; Gatell, Jose María; Plana, Montserrat
With regard to hair growth induced by therapeutics, we have to consider various aspects of the activity of the hair follicle. This means that a study on the efficacy of hair growth therapeutics requires a selective investigation of different kinds of follicular activity. The decision which of the non-invasive, semi-invasive or invasive techniques available should be applied in a specific case depends on the reliability of the method in relation to the technical requirement, on the one hand, and the acceptance by the volunteer as well as the clinical type and degree of hair loss, on the other. Trichorhizogram results as the only means of evaluating the efficacy of hair growth therapeutics seem problematical, since an increase of the anagen rate does not absolutely correlate with a prolongation of the anagen phase. PMID:2087834
CTL are by far the most important defence mechanisms against viral infections, and many attempts have been undertaken to induce protective CTL in vivo. In order to identify CTL epitopes for their possible use as peptide-vaccine candidates, HIV proteins were screened for peptide sequences which (i) fulfil the binding motif of the HLA-A2.1 molecule, and (ii) are involved in the natural immune response to HIV. From 73 nonameric peptides satisfying the binding motif, 20 peptides were synthesized and their binding to HLA-A2.1 was monitored by measuring the expression of HLA-A2.1 molecules on the cell surface of the mutant cell line T2. To evaluate the involvement in natural HIV infection, strongly binding peptides were used in cytotoxicity assays to assess their capacity to generate a peptide-specific CTL response in vitro. From 20 nonameric peptides synthesized, only five showed strong binding to HLA-A2.1. All five binding peptides had the secondary anchor residues, recently proposed by Ruppert et al.  to be required for binding to HLA-A2.1. The discrimination between bound and unbound peptides confirmed the importance of these secondary anchor residues which, beside the known binding motif, may dictate if a peptide can bind to HLA-A2.1 or not. In HIV- donors, no CTL activity against any of the HIV-derived peptides was detectable after a 12-day in vitro stimulation. In contrast, HIV-infected persons showed a cytotoxic response against peptide-labelled target cells, suggesting that they had developed upon HIV infection a cytotoxic immune response against the identified CTL epitopes.
Brander, C; Pichler, W J; Corradin, G
Recently, several reports have indicated that individuals living with HIV\\/AIDS undergo a condition of chronic oxidative stress with a resultant decline in nutritional antioxidants and other micronutrients. It has also been reported that these micronutrient deficiencies interfere with immune functions, weaken epithelial integrity, contribute to oxidative stress and enhance HIV disease progression. Reports from observational studies have led to an
O. O. Oguntibeju; A. J. Esterhuyse; E. J. Truter
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
Desmond, Christopher; Bruce, Faikah; Tomlinson, M; Marlow, Marguerite B; Aber, J Lawrence; Ouifki, Rachid; Welte, Alex
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.
Pirooznia, Sheila K.; Elefant, Felice
Abstract 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.
Chane, Tanea; Patel, Manish; Chen, Shuo; Xue, Wenqiong; Easley, Kirk A.
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
Delva, Wim; Abdool Karim, Quarraisha
Thrombogenic and inflammatory activity are two distinct aspects of platelet biology, which are sustained by the ability of activated platelets to interact with each other (homotypic aggregation) and to adhere to circulating leucocytes (heterotypic aggregation). These two events are regulated by distinct biomolecular mechanisms that are selectively activated in different pathophysiological settings. They can occur simultaneously, for example, as part of a pro-thrombotic/pro-inflammatory response induced by vascular damage, or independently, as in certain clinical conditions in which abnormal heterotypic aggregation has been observed in the absence of intravascular thrombosis. Current antiplatelet drugs have been developed to target specific molecular signalling pathways mainly implicated in thrombus formation, and their ever increasing clinical use has resulted in clear benefits in the treatment and prevention of arterial thrombotic events. However, the efficacy of currently available antiplatelet drugs remains suboptimal, most likely because their therapeutic action is limited to only few of the signalling pathways involved in platelet homotypic aggregation. In this context, modulation of heterotypic aggregation, which is believed to contribute importantly to acute thrombotic events, as well to the pathophysiology of atherosclerosis itself, may offer benefits over and above the classical antiplatelet approach. This review will focus on the distinct biomolecular pathways that, following platelet activation, underlie homotypic and heterotypic aggregation, aiming potentially to identify novel therapeutic targets.
Passacquale, Gabriella; Ferro, Albert
Spinal cord injury (SCI) often results in significant dysfunction and disability. A series of treatments have been proposed to prevent and overcome the formation of the glial scar and inhibitory factors to axon regrowth. In the last decade, cell therapy has emerged as a new tool for several diseases of the nervous system. Stem cells act as minipumps providing trophic and immunomodulatory factors to enhance axonal growth, to modulate the environment, and to reduce neuroinflammation. This capability can be boosted by genetical manipulation to deliver trophic molecules. Different types of stem cells have been tested, according to their properties and the therapeutic aims. They differ from each other for origin, developmental stage, stage of differentiation, and fate lineage. Related to this, stem cells differentiating into neurons could be used for cell replacement, even though the feasibility that stem cells after transplantation in the adult lesioned spinal cord can differentiate into neurons, integrate within neural circuits, and emit axons reaching the muscle is quite remote. The timing of cell therapy has been variable, and may be summarized in the acute and chronic phases of disease, when stem cells interact with a completely different environment. Even though further experimental studies are needed to elucidate the mechanisms of action, the therapeutic, and the side effects of cell therapy, several clinical protocols have been tested or are under trial. Here, we report the state-of-the-art of cell therapy in SCI, in terms of feasibility, outcome, and side effects. PMID:22539011
Garbossa, D; Boido, M; Fontanella, M; Fronda, C; Ducati, A; Vercelli, A
Stimulation of vascular growth to treat limb ischemia is promising, and early results obtained from uncontrolled clinical trials using angiogenic agents, e.g., vascular endothelial growth factor, led to high expectations. However, negative results from recent placebo-controlled trials warrant further research. Here, current insights into mechanisms of vascular growth in the adult, in particular the role of angiogenic factors, the immune system, and bone marrow, were reviewed, together with modes of its therapeutic stimulation and results from recent clinical trials. Three concepts of vascular growth have been described to date-angiogenesis, vasculogenesis, and arteriogenesis (collateral artery growth)-which represent different aspects of an integrated process. Stimulation of arteriogenesis seems clinically most relevant and has most recently been attempted using autologous bone marrow transplantation with some beneficial results, although the mechanism of action is not completely understood. Better understanding of the highly complex molecular and cellular mechanisms of vascular growth may yet lead to meaningful clinical applications. PMID:18504100
van Weel, V; van Tongeren, R B; van Hinsbergh, V W M; van Bockel, J H; Quax, P H A
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
Crowder, Stephen A; Merritte, Kristin
Apoptosis plays a role in pemphigus IgG-dependent acantholysis; theoretically, the blockade of the caspase pathway could prevent the blistering that is caused by pemphigus autoantibodies. Using this strategy, we attempted to block the pathogenic effect of pemphigus IgG in Balb/c mice by using the caspase inhibitor Ac-DEVD-CMK. This inhibitor was administrated before the injection of pemphigus IgG into neonatal mice. The main results of the present investigation are as follows: (1) pemphigus IgG induces intraepidermal blisters in Balb/c neonatal mice; (2) keratinocytes around the blister and acantholytic cells undergo apoptosis; (3) the caspases inhibitor Ac-DEVD-CMK prevents apoptosis; (4) the inhibition of the caspase pathway prevents blister formation. In conclusion, inhibition of the caspase pathway may be a promising therapeutic tool that can help in the treatment of pemphigus flare ups. PMID:21403857
Pacheco-Tovar, Deyanira; López-Luna, Argelia; Herrera-Esparza, Rafael; Avalos-Díaz, Esperanza
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.
Srinivasan, Venkatramanujam; Kaur, Charanjit; Pandi-Perumal, Seithikurippu; Brown, Gregory M.; Cardinali, Daniel P.
Sonic hedgehog (Shh) signaling controls many aspects of human development, regulates cell growth and differentiation in adult tissues, and is activated in a number of malignancies. Rheumatoid arthritis (RA) is characterized by chronic synovitis and pannus formation associated with activation of fibroblast-like synoviocytes (FLS). We investigated whether Shh signaling plays a role in the proliferation of FLS in RA. Expression of Shh signaling related components (Shh, Ptch1, Smo, and Gli1) in RA synovial tissues was examined by immunohistochemistry (IHC) and in FLS by IHC, immunofluorescence (IF), quantitative RT-PCR, and western blotting. Expression of Shh, Smo, and Gli1 in RA synovial tissue was higher than that in control tissue (P < 0.05). Cyclopamine (a specific inhibitor of Shh signaling) decreased mRNA expression of Shh, Ptch1, Smo, and Gli1 in cultured RA FLS, Shh, and Smo protein expression, and significantly decreased FLS proliferation. Flow cytometry analysis suggested that cyclopamine treatment resulted in cell cycle arrest of FLS in G1 phase. Our data show that Shh signaling is activated in synovium of RA patients in vivo and in cultured FLS form RA patients in vitro, suggesting a role in the proliferation of FLS in RA. It may therefore be a novel therapeutic target in RA.
Wang, Mingxia; Zhu, Shangling; Peng, Weixiang; Li, Qiuxia; Li, Zhaoxia; Luo, Minqi; Feng, Xiaoxue; Lin, Zhuofeng; Huang, Jianlin
The advanced liver fibrosis and cirrhosis had been regarded irreversible until quite lately. However, experimental and clinical studies confirmed possibility of stopping or even decreasing the stage of liver fibrosis through causal factor elimination and application of pharmacological preparation of potential antifibrotic activity. The morphological examination of liver bioptate is a "gold standard" in assessment of liver fibrosis stage. However it is an invasive procedure and has several limitation such as "sampling error". Therefore several biochemical blood tests for liver fibrosis have been evaluated which are less invasive and give possibility of long-term monitoring of the course of disease and possible changes caused by treatment. The non-invasive markers of liver fibrosis include extracellular matrix components (ECM) as well as non-ECM biochemical panels (FibroTest, Forns index, APRI). Significant progress in diagnostics and treatment confirmed the reversibility of liver fibrosis. However, reversibility of cirrhosis still becomes controversial. Further investigations of antifibrotic drugs and settlement of proper biochemical blood panel for better monitoring of possible disease regression are needed. PMID:16190564
Lebensztejn, Dariusz Marek
Pityriasis rubra pilaris (PRP) is a rare skin disorder with versatile clinical presentations. A 62-year-old Caucasian woman with progressive erythroderma and classic adult (type I) PRP is presented. Treatment with systemic steroids and methotrexate produced no improvement. Clinical remission was achieved after systemic therapy with penicillin (both intravenous and intramuscular) and vitamin A. The therapy of PRP is reviewed, focusing on a possible infectious genesis of PRP as well as the role of antibiotics in its management. PMID:19912462
Popova, Ludmila; Darlenski, Razvigor; Tsankov, Nikolai
Nutritional, psychological, and psychoanalytic studies of toddler eating have focussed on food intake and the possible links to childhood and adolescent eating disorders, generally based on mothers' self-reports. The present study was based on video recordings of snack time at a psychoanalytic toddler group. The qualitative methodology employed involved line-by-line thematic extraction based on Interpretative Phenomenological Analysis. Extracts of observations
The pathogenesis of the HIV associated Kaposi's sarcoma is still unclear, but it appears to be a multifactorial process. Different investigations have shown, that cytokines and growth factors influence the development of KS. Several cases with tumor manifestation after irritation of the skin are demonstrated. Therefore a mechanism of development comparable with the Koebner Phenomenon can be postulated. PMID:2399758
Plettenberg, A; Engelmann, L; Meigel, W
Potassium channels are ion channels in the cell membrane which are especially important for regulation of the membrane potential and the cell's excitability. Potassium channel openers are drugs that interfere with these channels, and several such substances have been developed. Existing substances show highest affinity to vascular smooth muscle. The clinical effect is relaxation of blood vessels resulting in lower blood pressure. However, current efforts are concentrated on finding substances which are selective for other cell types. Possible areas of application are treatment of hypertension, angina pectoris, arrhythmias, asthma and urinary bladder instability. PMID:8009483
Drottning, P; Christensen, H; Storstein, L
We report the case of an HIV-2-infected patient with severe immunosupression despite undetectable plasma HIV-2 RNA. This immunovirological discordance was due to failure of the viral load assay and infection by an unknown HIV-2 subtype. Treatment was probably suboptimal, leading to the selection of several resistance mutations and treatment failure. PMID:16293278
Fonquernie, Laurent; Eholié, Serge P; Damond, Florence; Lacombe, Karine; Girard, Pierre-Marie
We have studied interaction of well known antioxidant L-ascorbic acid with magnetic nanoparticles containing insoluble Fe(III) in their core. In analogy with ferritin, mobilization of iron in the form of water soluble Fe(II) was observed, especially pronounced at higher temperatures. In the presence of hydrogen peroxide cytotoxic hydroxyl radicals are produced. These results suggest possible harmful effects of widely used magnetic nanoparticles as a MRI contrast agents in combination with overload of organism with ascorbic acid in some specific conditions, like fever of patient. On the other hand combination of magnetic nanoparticles and ascorbic acid may be used for a cancer therapy using alternating magnetic field for the release of Fe(II) via Néel relaxation of magnetic moment of used nanoparticles. We have further found that lipoic acid is an efficient antioxidant scavenging hydroxyl radicals produced by Fenton reaction from Fe(II). PMID:23479451
Durdík, Stefan; Vrbovská, Hanka; Olas, Adam; Babincová, Melánia
The clinical manifestations of supraorbital neuralgia are apparently only incompletely known. The lack of awareness of this head pain may possibly be due to its rarity and problems with making the diagnosis. In the present work, the long-term result of minor, decompressive surgery of the supraorbital nerve in five patients is reported. The immediate improvement was good and, after a mean observation time of more than 6 years, an improvement of 50% to 100% was observed (mean, circa 85%). In the two patients with the longest postoperative observation time, approximately 8 years, pain has not recurred. The pain was severe, leading to suicidal thoughts in several patients. The long-term course was intermittent or continuous. The pain was generally unilateral, but was bilateral in one patient. Generally, there was lack of, or only minor benefit from drug treatment, including carbamazepine and indomethacin. There was clearly tenderness over the supraorbital nerve, especially at its outlet, and in some subjects occasionally, a slight local loss of sensation. Definite trigger zones were not present. Supraorbital nerve blockade generally provided instant and considerable pain relief. The persistence of protracted unilateral forehead/ocular pain, tenderness over the nerve, and repeated blockade effect strongly suggests the diagnosis. PMID:15613215
Sjaastad, O; Stolt-Nielsen, A; Pareja, J A; Fredriksen, T A; Vincent, M
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
Galin, F Shawn; Chrisman, Cheryl L; Cook, James R; Xu, Likang; Jackson, Patricia L; Noerager, Brett D; Weathington, Nathaniel M; Blalock, J Edwin
Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S-nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent.
Ishima, Yu; Kragh-Hansen, Ulrich; Maruyama, Toru; Otagiri, Masaki
HIV-associated neurologic disease continues to be a significant complication in the era of highly active antiretroviral therapy. A substantial subset of the HIV-infected population shows impaired neuropsychological performance as a result of HIV-mediated neuroinflammation and eventual central nervous system (CNS) injury. CNS compartmentalization of HIV, coupled with the evolution of genetically isolated populations in the CNS, is responsible for poor prognosis in patients with AIDS, warranting further investigation and possible additions to the current therapeutic strategy. This chapter reviews key advances in the field of neuropathogenesis and studies that have highlighted how molecular diversity within the HIV genome may impact HIV-associated neurologic disease. We also discuss the possible functional implications of genetic variation within the viral promoter and possibly other regions of the viral genome, especially in the cells of monocyte–macrophage lineage, which are arguably key cellular players in HIV-associated CNS disease.
Nonnemacher, Michael R.; Wigdahl, Brian
Stability of enalapril maleate formulations can be affected when the product is exposed to higher temperature and humidity, with the formation of two main degradation products: enalaprilat and a diketopiperazine derivative. In this work, stability and drug release profiles of 20 mg enalapril maleate tablets (reference, generic and similar products) were evaluated. After 180 days of the accelerated stability testing, most products did not exhibit the specified amount of drug. Additionally, drug release profiles were markedly different from that of the reference product, mainly due to drug degradation. Changes in drug concentration and drug release profile of enalapril formulations are strong indicators of a compromised bioavailability, with possible interferences on the therapeutic response for this drug. PMID:18472382
Lima, Dione Marçal; dos Santos, Leandro Dias; Lima, Eliana Martins
The progression of HIV infection has been associated with an increase in the plasma levels of total IgE. The mechanisms responsible for the increased IgE have not been elucidated. The type-1 and type-2 cytokine imbalance associated with HIV infection has been proposed as a possible mechanism for elevated IgE. The current study was undertaken to investigate the relationship between total
Sandeep K Agarwal; Gailen D Marshall
The global AIDS pandemic continues to expand and in some regions of the world, such as southern Africa, the prevalence of HIV-1 infection exceeds 20%. The devastating spread of the virus in young women in these countries appears disproportional to overall risk of infection. Regions with high prevalence of HIV-1 are often also highly endemic for other pathogenic viruses including HSV, CMV and HTLV. We propose that acquisition by HIV-1 of the envelope glycoproteins of other viruses, in a process we call “natural pseudotyping,” expands the cellular tropism of HIV-1, enabling it to infect female genital epithelial cells directly and thereby dramatically increasing risk of infection during sexual intercourse. In this proof-of-concept study, we demonstrate that when HIV-1 co-infects T cells along with the gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), progeny HIV-1 particles are produced capable of infecting primary vaginal, ectocervical and endocervical epithelial cells. These cell types are normally resistant to HIV-1 infection. Infection of primary genital cells was neutralized by antisera against the XMRV glycoprotein, confirming that infection was mediated by the XMRV glycoprotein acquired through pseudotyping of HIV. Inhibition by AZT showed that active replication of HIV-1 occurred in these cells and ruled out non-specific endocytic uptake of the virus. These results demonstrate that natural pseudotyping can expand the tropism of HIV-1 to include genital epithelial cells and have potential implications for sexual transmission of the virus.
Tang, Yuyang; George, Alvin; Nouvet, Franklin; Sweet, Stephanie; Emeagwali, Nkiruka; Taylor, Harry E.; Simmons, Glenn; Hildreth, James E. K.
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
Lori, Franco; De Forni, Davide; Katabira, Elly; Baev, Denis; Maserati, Renato; Calarota, Sandra A.; Cahn, Pedro; Testori, Marco; Rakhmanova, Aza; Stevens, Michael R.
Summary Work from our laboratories has validated mixed lineage kinase type 3 (MLK3) as an enzyme pathologically activated in the CNS\\u000a by human immunodeficiency virus 1 (HIV-1) neurotoxins. In this review, we discuss MLK3 activation in the context of the neuropathogenesis\\u000a of HIV-1 associated neurocognitive deficits (HAND). We use findings from the literature to substantiate the neuropathologic\\u000a relevance of MLK3 to
Harris A. Gelbard; Stephen Dewhurst; Sanjay B. Maggirwar; Michelle Kiebala; Oksana Polesskaya; Howard E. Gendelman
Subjects Twenty vertically HIV-infected children, 6–16 years of age, with stable viral load control and CD4+ values above 400 cells/mm3. Intervention Ten subjects continued their ongoing antiretroviral treatment (ART, Group A) and 10 were immunized with a HIV-DNA vaccine in addition to their previous therapy (ART and vaccine, Group B). The genetic vaccine represented HIV-1 subtypes A, B and C, encoded Env, Rev, Gag and RT and had no additional adjuvant. Immunizations took place at weeks 0, 4 and 12, with a boosting dose at week 36. Monitoring was performed until week 60 and extended to week 96. Results Safety data showed good tolerance of the vaccine. Adherence to ART remained high and persistent during the study and did not differ significantly between controls and vaccinees. Neither group experienced either virological failure or a decline of CD4+ counts from baseline. Higher HIV-specific cellular immune responses were noted transiently to Gag but not to other components of the vaccine. Lymphoproliferative responses to a virion antigen HIV-1 MN were higher in the vaccinees than in the controls (p?=?0.047), whereas differences in reactivity to clade-specific Gag p24, RT or Env did not reach significance. Compared to baseline, the percentage of HIV-specific CD8+ lymphocytes releasing perforin in the Group B was higher after the vaccination schedule had been completed (p?=?0.031). No increased CD8+ perforin levels were observed in control Group A. Conclusions The present study demonstrates the feasibility, safety and moderate immunogenicity of genetic vaccination in vertically HIV-infected children, paving the way for amplified immunotherapeutic approaches in the pediatric population. Trial registration clinicaltrialsregister.eu _2007-002359-18IT
Palma, Paolo; Romiti, Maria Luisa; Montesano, Carla; Santilli, Veronica; Mora, Nadia; Aquilani, Angela; Dispinseri, Stefania; Tchidjou, Hyppolite K.; Montano, Marco; Eriksson, Lars E.; Baldassari, Stefania; Bernardi, Stefania; Scarlatti, Gabriella
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
Marech, Ilaria; Gadaleta, Cosmo Damiano; Ranieri, Girolamo
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.
Richman, Douglas D.
Work from our laboratories has validated mixed lineage kinase type 3 (MLK3) as an enzyme pathologically activated in the CNS by human immunodeficiency virus 1 (HIV-1) neurotoxins. In this review, we discuss MLK3 activation in the context of the neuropathogenesis of HIV-1 associated neurocognitive deficits (HAND). We use findings from the literature to substantiate the neuropathologic relevance of MLK3 to neurodegenerative disease, with an emphasis on Parkinson's disease that shares a number of important phenotypic and neuropathologic characteristics with HAND. We discuss signal transduction pathways downstream from MLK3 activation, with an emphasis on their involvement in microglia and neurons in preclinical models of HAND. Finally, we make a case for pharmacologic intervention targeted at inhibition of MLK3 as a strategy to reverse HAND, in light of the fact that combination antiretroviral therapy, despite successfully managing systemic infection of HIV-1, has been largely unsuccessful in eradicating HAND. PMID:20880503
Gelbard, Harris A; Dewhurst, Stephen; Maggirwar, Sanjay B; Kiebala, Michelle; Polesskaya, Oksana; Gendelman, Howard E
Levels of interleukin 8 (IL-8), gamma interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1b (MIP-1b) 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-1b in vitro, which was partly inhibited by anti-tumor necrosis
NICOLE P. JUFFERMANS; ANNELIES VERBON; Deventer van S. J. H; HENK VAN DEUTEKOM; JOHN T. BELISLE; MICHAEL E. ELLIS; F. Speelman; TOM VAN DER POLL
No data are available for the kinetics of anti-Hepatitis C Virus (HCV) antibodies in HIV/HCV co-infected patients after sustained virological response (SVR). We present a case of a HIV/HCV co-infected patient, showing a significant anti-HCV antibodies decrease during therapy, who achieved a HCV seroreversion 3 years after SVR. Among them, antibodies to core protein, the most strongly antigenic protein showed significant decrease. Our results indicate an absence of antigenic stimulation suggesting a total clearance of HCV. PMID:24613600
Maylin, Sarah; de Verdière, Nathalie Colin; Salmona, Maud; Simon, François; Delaugerre, Constance
An anti-HIV effect of soy products (emulsion, flour) has been revealed in vitro experiment. The unique properties of biologically active components of soy products made from the whole soybeans justify their usage in HIV/AIDS treatment as an additional treatment and prophylactic nutrition. PMID:19663020
Rybalko, S L; Anisimova, Iu N; Maksimenok, E V
Highly active antiretroviral therapy has dramatically improved the morbidity and mortality of HIV-1-infected individuals. A total of 25 licensed drugs provide the basis for an optimized virus-suppressive treatment of nearly each subject. The promises of immune reconstitution and normal life expectancy, however, fall short for a number of patients, either through inadequate recovery of CD4+ T-cell counts or the occurrence of non-AIDS defining malignancies. In this respect, the prevalence of Epstein-Barr virus-associated Hodgkin lymphoma and human papillomavirus-related anal neoplasia is rising in aging HIV-1-infected individuals despite antiretroviral therapy. An important cause appears to be the HIV-1-induced chronic immune activation, propagated by inappropriate release of proinflammatory cytokines and type I interferons. This immune dysregulation can be reduced in vitro by inhibitors blocking the endosomal acidification. Recent data suggest that this concept is also of relevance in vivo, which opens the door for adjuvant immunomodulatory therapies in HIV-1 infection.
Ries, Moritz; Pritschet, Kathrin; Schmidt, Barbara
The aim of this study was to assess the therapeutic potential of telaprevir (TPV)/boceprevir (BOC)-based triple-therapy in a complete cohort of HIV/chronic hepatitis C co-infected patients (HIV/HCV). Moreover, a case series of four HIV/HCV genotype (HCV-GT)1 patients with rapid virologic response (RVR), who received only 28 weeks of BOC-based triple-therapy (BOCW28), was reported. 290/440 HIV-positive patients with positive HCV serology had at least one visit during the past 2 years, 142/290 had target detectable HCV-RNA with 64% (82/142) carrying HCV-GT1. While 18 HIV/HCV-GT1 displayed contraindications, 45% (64/142) of HIV/HCV were eligible for triple-therapy. Insufficiently controlled HIV-infection despite combined antiretroviral therapy (cART) (HIV-RNA <50 copies/mL: 73% vs. 22%; p<0.001) and liver cirrhosis (31% vs. 8%; p=0.025) were overrepresented among patients with contraindications for triple-therapy. Low treatment uptake rates (39% (25/64)) during the first 2 years of triple-therapy availability suggest that its benefit in HIV/HCV co-infected patients might fall short of expectations. Modification of cART or TPV dose adjustment would have been necessary in 61% and 84% of HIV/HCV-GT1 on cART eligible for triple-therapy using TPV and BOC, respectively, suggesting that drug-drug interactions with cART complicate management in the majority of patients. All four BOCW28 patients achieved a sustained virologic response. Prospective studies are necessary to validate our observations on the shortening of treatment duration in HIV/HCV-GT1 with RVR. PMID:24796757
Mandorfer, Mattias; Payer, Berit A; Niederecker, Alexander; Lang, Gerold; Aichelburg, Maximilian C; Strassl, Robert; Boesecke, Christoph; Rieger, Armin; Trauner, Michael; Peck-Radosavljevic, Markus; Reiberger, Thomas
Understanding family dynamics and relationship is an important facet of care, therapeutic education and psychosocial support. As part of a therapeutic education program organized within a pediatric service in Cotonou, Benin, we have experimented with the genogram at the time of diagnosis and tested it as an educational tool. This study evaluates the usefulness of the genogram for therapeutic patient education, and its capacity to serve as an aid to better understand family structure and dynamics. The study was conducted in 2007 with 29 parents of children living with HIV / AIDS. Six professionals observed the conditions for the development and application of the genograms their effects on the production of information of an educational nature. The results indicate that it can provide families and caregivers benchmarks essential for understanding the role of the family and community in which the child-patient is situated and how they function. It facilitates the identification of key resource persons for the child and selfcare to be mobilized and fostered within the family. PMID:20441620
Juré, Estelle; Iguenane, Jacqueline; Toudonou, Annicette; Azondekon, Alain; Gagnayre, Rémi
We have studied zinc deficiency in hepatitis C patients (complete responder [C,R] 22, nonresponder [NR] 25) with relation\\u000a to the therapeutic effect of interferon-? (IFN-?). Circadian variations in serum zinc levels were high in the morning (basal\\u000a level) and then gradually decreased during the day in both chronic hepatitis C patients and healthy controls. Basal zinc levels\\u000a in serum were
Takeaki Nagamine; Hitoshi Takagi; Yoshiaki Hashimoto; Hisashi Takayama; Ryuya Shimoda; Naruo Nomura; Keiji Suzuki; Masatomo Mori; Katsuyuki Nakajima
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 ...
W. K. Keener
BACKGROUND: In Malawi and other high HIV prevalence countries, studies suggest that more than 30% of all severely malnourished children admitted to inpatient nutrition rehabilitation units are HIV-infected. However, clinical algorithms designed to diagnose paediatric HIV are neither sensitive nor specific in severely malnourished children. The present study was conducted to assess : i) whether HIV testing can be integrated
Paluku Bahwere; Ellen Piwoz; Marthias C Joshua; Kate Sadler; Caroline H Grobler-Tanner; Saul Guerrero; Steve Collins
In the gastrointestinal tract, interstitial cells of Cajal (ICCs) act as pacemaker cells to generate slow wave activity. Interstitial cells that resemble ICCs in the gastrointestinal tract have been identified by their morphological characteristics in the bladder. KIT is used as an identification marker of ICCs. ICCs in the bladder may be involved in signal transmission between smooth muscle bundles, from efferent nerves to smooth muscles, and from the urothelium to afferent nerves. Recent research has suggested that not only the disturbance of spontaneous contractility caused by altered detrusor ICC signal transduction between nerves and smooth muscle cells but also the disturbance of signal transduction between urothelial cells and sensory nerves via suburothelial ICC may induce overactive bladder (OAB). Recent reports have suggested that KIT is not only a detection marker of these cells, but also may play a crucial role in the control of bladder function. Research into the effect of a c-kit receptor inhibitor, imatinib mesylate, on bladder function implies that KIT-positive ICCs may be therapeutic target cells to reduce bladder overactivity and that the blockage of c-kit receptor may offer a new therapeutic strategy for OAB treatment, although further study will be needed.
Kubota, Yasue; Kojima, Yoshiyuki; Shibata, Yasuhiro; Imura, Makoto; Sasaki, Shoichi; Kohri, Kenjiro
Purpose We aimed to establish a novel screening system for identifying potential therapeutic agents for treating proliferative vitreoretinal diseases (PVDs). In this study, we focused on vitreous explants from chicken embryos and evaluated the usefulness of quantitatively analyzing the effects of potential candidates on cell-mediated vitreous contraction, which leads to blindness in PVDs. Methods Vitreous explants were extracted from 19-day-old embryonic chickens and then incubated with retinal Müller cells or endothelial cells to permit cell adhesion. After cell adhesion occurred, we examined the effect of the attached cells on the wet weight of vitreous explants as an index of vitreous contraction. We also performed hematoxylin and eosin staining to characterize the cell morphology on the vitreous surface. Results Contraction of the vitreous explants was observed after cell adhesion of not only retinal Müller cells but also endothelial cells. We confirmed the adhesion of these cells on vitreous explants and estimated the number of adherent cells with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. The cells on the vitreous surface presented an elongated fibroblast-like phenotype. Integrin was found to be a receptor involved in cell adhesion on the vitreous surface. Discussion Our results suggest that vitreous explants from chicken embryos may be novel useful tools for screening antiadhesion therapeutic agents in PVDs. This preliminary study must be validated with human vitreous and human retinal pigment epithelial cells.
Oki, Keitaro; Shimada, Arata; Nagase, Terumasa; Katsura, Yoshiya; Kosano, Hiroshi
In the gastrointestinal tract, interstitial cells of Cajal (ICCs) act as pacemaker cells to generate slow wave activity. Interstitial cells that resemble ICCs in the gastrointestinal tract have been identified by their morphological characteristics in the bladder. KIT is used as an identification marker of ICCs. ICCs in the bladder may be involved in signal transmission between smooth muscle bundles, from efferent nerves to smooth muscles, and from the urothelium to afferent nerves. Recent research has suggested that not only the disturbance of spontaneous contractility caused by altered detrusor ICC signal transduction between nerves and smooth muscle cells but also the disturbance of signal transduction between urothelial cells and sensory nerves via suburothelial ICC may induce overactive bladder (OAB). Recent reports have suggested that KIT is not only a detection marker of these cells, but also may play a crucial role in the control of bladder function. Research into the effect of a c-kit receptor inhibitor, imatinib mesylate, on bladder function implies that KIT-positive ICCs may be therapeutic target cells to reduce bladder overactivity and that the blockage of c-kit receptor may offer a new therapeutic strategy for OAB treatment, although further study will be needed. PMID:21785586
Kubota, Yasue; Kojima, Yoshiyuki; Shibata, Yasuhiro; Imura, Makoto; Sasaki, Shoichi; Kohri, Kenjiro
HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4+ T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing antibodies (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer, and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fc? receptor (Fc?R)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here, we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.
Su, Bin; Moog, Christiane
The adherence profile of HIV-infected patients predicts the therapeutic outcome, in particular during the early phase of antiretroviral therapy (ART). We conducted a prospective observational multicenter trial monitoring adherence and virological and immunological parameters over the initial 6 months of treatment. Thirty-five subjects were starting a treatment regimen including atazanavir, ritonavir, and emtricitabine-tenofovir. Adherence was assessed using self-completed questionnaires, announced pill counts, and the medication event monitoring system (MEMS) for each drug. Three MEMS measures were defined: the percentages of doses taken, days with the correct dosing, and doses taken on time (±3 h). Dynamic virological suppression (DVS) was defined as a reduction in the plasma HIV-RNA level of >1 log10 per month or <40 copies/ml. The cumulative treatment time was 5,526 days. A high level of adherence was observed. The MEMS-defined adherence for correct dosing (?0.68% per 4-week period, P < 0.03) and timing compliance (?1.60% per 4-week period, P < 0.003) decreased significantly over time. The MEMS-defined adherence data were concordant with the pill counts during the trial but not with the data from the questionnaires. The median [range] percentages of doses taken (100% [50 to 102]), days with the correct dosing (95% [41 to 100]), and doses taken on time (86% [32 to 100]) were significantly associated with DVS in separate models. Among these three measures, the percentage of doses taken on time had the greatest ability to predict DVS. Timing compliance should be supported to optimize DVS during the early phase of treatment by once-daily boosted protease inhibitor-based ART. (This study has been registered at ClinicalTrials.gov under registration no. NCT00528060.)
Barrail-Tran, Aurelie; Duval, Xavier; Nembot, Georges; Descamps, Diane; Vigan, Marie; Vrijens, Bernard; Panhard, Xaviere; Taburet, Anne-Marie; Mentre, France; Goujard, Cecile
Acetylcholine (Ach), one of the most important examples of a neurotransmitter, represents a phylogenetically old molecule, widely distributed from bacteria to humans. The finding that neuronal Ach receptors (nAChRs) are present in non-neuronal cells raised some interesting issues related to their specific activity. In humans, different studies have showed that many lung cancer cells expressed nAchRs and that low concentrations of nicotine blocked the induction of apoptosis in these cells. A recent study presents data that SCLC express a cholinergic autocrine loop that can regulate cell growth. Such work demonstrates that SCLC cells have a cholinergic phenotype and that ACh exerts as an autocrine growth factor in human lung tumors. Recently it has been shown that human malignant pleural mesothelioma express a cholinergic system, involved in cell growth regulation. Hence, mesothelioma cell growth as well as normal mesothelial cells growth is modulated by the cholinergic system in which agonists (i.e. nicotine) has a proliferative effect and antagonists (i.e. curare) has an inhibitory effect. Furthermore apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of NF-kappaB complexes and phosphorilation of Bad at Serine(112), curare proapoptotic via G(0)-G(1) arrest p21(waf-1)-dependent, but p53-independent). The involvement of the non-neuronal cholinergic system in lung cancer and mesothelioma appears reasonable and open up new therapeutic strategies. PMID:15579018
Trombino, Sonya; Bisio, Alessandra; Catassi, Alessia; Cesario, Alfredo; Falugi, Carla; Russo, Patrizia
Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. Trial registration ClinicalTrials.gov NCT00751595
Ensoli, Barbara; Bellino, Stefania; Tripiciano, Antonella; Longo, Olimpia; Francavilla, Vittorio; Marcotullio, Simone; Cafaro, Aurelio; Picconi, Orietta; Paniccia, Giovanni; Scoglio, Arianna; Arancio, Angela; Ariola, Cristina; Ruiz Alvarez, Maria J.; Campagna, Massimo; Scaramuzzi, Donato; Iori, Cristina; Esposito, Roberto; Mussini, Cristina; Ghinelli, Florio; Sighinolfi, Laura; Palamara, Guido; Latini, Alessandra; Angarano, Gioacchino; Ladisa, Nicoletta; Soscia, Fabrizio; Mercurio, Vito S.; Lazzarin, Adriano; Tambussi, Giuseppe; Visintini, Raffaele; Mazzotta, Francesco; Di Pietro, Massimo; Galli, Massimo; Rusconi, Stefano; Carosi, Giampiero; Torti, Carlo; Di Perri, Giovanni; Bonora, Stefano; Ensoli, Fabrizio; Garaci, Enrico
Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a non-linear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics was best described by a one compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance (CL/F) and volume of distribution (Vd/F) and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir CL/F and Vd/F were 21.3 L/h/70kg (30%) and 90.7 L/70kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration > 0.1 mg/L was >99% for 600/100 mg and >98% for 400/100 mg, twice daily, in patients 40–80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (>10.0 mg/L), increased from 1% to 10% with 600/100 mg, compared to <1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients <50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity.
Cressey, Tim R.; Urien, Saik; Hirt, Deborah; Halue, Guttiga; Techapornroong, Malee; Bowonwatanuwong, Chureeratana; Leenasirimakul, Prattana; Treluyer, Jean-Marc; Jourdain, Gonzague; Lallemant, Marc
Sensory nerves regulate central and local reflexes such as airway plasma leakage, and cough and their function may be enhanced during inflammation. Evidence suggests that dopamine receptor agonists may inhibit sensory nerve-mediated responses. In this study dopamine inhibited vagal sensory nerve induced microvascular leakage in the rat. In order to characterize the receptor involved rat vagus preparations were utilized. Quinagolide (D(2/3) agonist), ropinirole (D(2/3/4) agonist), SKF 38393 (D(1/5) agonist), AR-C68397AA (Viozan) (dual D(2)/B(2) agonist) and dopamine inhibited hypertonic saline induced depolarization by approximately 50%. Data suggests that AR-C68397AA and quinagolide also inhibited depolarization of the human vagus. The quinagolide response was blocked by sulpiride (D(2/3) antagonist) but not SCH 23390 (D(1/5) antagonist); ropinirole was partially blocked by sulpiride, totally blocked by spiperone (at a concentration that blocks all dopamine receptors) but not by SCH 23390. The response to SKF 38393 was not blocked by sulpiride but was by SCH 23390. The inhibition evoked by AR-C68397AA was only partially blocked by SCH 23390 but not by sulpiride or spiperone whereas dopamine was blocked by spiperone. The effect of dopamine was not stimulus-specific as it inhibited capsaicin-induced depolarization of the rat vagus in a spiperone sensitive manner. In conclusion, dopamine receptor ligands inhibit depolarization of the rat and human vagus. These data suggest that dopamine receptor agonists may be of therapeutic benefit in the treatment of symptoms such as cough and mucus secretion which are evident in respiratory diseases such as asthma and chronic obstructive pulmonary disease. PMID:12055141
Birrell, Mark A; Crispino, Natascia; Hele, David J; Patel, Hema J; Yacoub, Magdi H; Barnes, Peter J; Belvisi, Maria G
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
Alias, A G
Recently identified broadly neutralizing antibodies (bNAbs) that potently neutralize most HIV-1 strains are key to potential antibody-based therapeutic approaches to combat HIV/AIDS in the absence of an effective vaccine. Increasing bNAb potencies and resistance to common routes of HIV-1 escape through mutation would facilitate their use as therapeutics. We previously used structure-based design to create the bNAb NIH45-46G54W, which exhibits superior potency and/or breadth compared with other bNAbs. We report new, more effective NIH45-46G54W variants designed using analyses of the NIH45-46–gp120 complex structure and sequences of NIH45-46G54W–resistant HIV-1 strains. One variant, 45-46m2, neutralizes 96% of HIV-1 strains in a cross-clade panel and viruses isolated from an HIV-infected individual that are resistant to all other known bNAbs, making it the single most broad and potent anti–HIV-1 antibody to date. A description of its mechanism is presented based on a 45-46m2–gp120 crystal structure. A second variant, 45-46m7, designed to thwart HIV-1 resistance to NIH45-46G54W arising from mutations in a gp120 consensus sequence, targets a common route of HIV-1 escape. In combination, 45-46m2 and 45-46m7 reduce the possible routes for the evolution of fit viral escape mutants in HIV-1YU-2–infected humanized mice, with viremic control exhibited when a third antibody, 10–1074, was added to the combination.
Klein, Florian; Horwitz, Joshua A.; Halper-Stromberg, Ariel; Sather, D. Noah; Marcovecchio, Paola M.; Lee, Terri; West, Anthony P.; Gao, Han; Seaman, Michael S.; Stamatatos, Leonidas; Nussenzweig, Michel C.; Bjorkman, Pamela J.
Structured Treatment Interruptions (STI) during HIV drug therapy were thought to potentially reduce side effects and toxicity,\\u000a boost immune involvement, and possibly lower the viral set-point. Clinical trials of STI regimens, however, have had mixed\\u000a results. We use an established mathematical model of HAART to estimate possible therapeutic outcomes for STI and for other,\\u000a similar patterns in HIV combination therapy.
O. Krakovska; L. M. Wahl
Since HIV/AIDS was first recognized in 1981, an urgent need has existed for the development of novel therapeutic strategies to treat the disease. Due to the current antiretroviral therapy not being curative, human stem cell-based therapeutic intervention has emerged as an approach for its treatment. Genetically modified hematopoietic stem cells (HSCs) possess the potential to self-renew, reconstitute the immune system with HIV-resistant cells, and thus control, or even eliminate, viral replication. However, HSCs may be difficult to isolate in sufficient number from HIV-infected individuals for transplantation and/or re-infusion of autologous HSCs preparations would also include some contaminating HIV-infected cells. Furthermore, since genetic modification of HSCs is not completely efficient, the risk of providing unprotected immune cells to become new targets for HIV to infect could contribute to continued immune system failure. Therefore, induced pluripotent stem cells (iPSCs) should be considered a new potential source of cells to be engineered for HIV resistance and subsequently differentiated into clonal anti-HIV HSCs or hematopoietic progeny for transplant. In this article, we provide an overview of the current possible cellular therapies for treating HIV/AIDS. PMID:24509823
Armijo, Enrique; Soto, Claudio; Davis, Brian R
Background Genomic DNA amplification is a genetic factor involved in cancer, and some oncogenes, such as ERBB2, are highly amplified in gastric cancer. We searched for the possible amplification of other genes in gastric cancer. Methods and Results A genome-wide single nucleotide polymorphism microarray analysis was performed using three cell lines of differentiated gastric cancers, and 22 genes (including ERBB2) in five highly amplified chromosome regions (with a copy number of more than 6) were identified. Particular attention was paid to the CRKL gene, the product of which is an adaptor protein containing Src homology 2 and 3 (SH2/SH3) domains. An extremely high CRKL copy number was confirmed in the MKN74 gastric cancer cell line using fluorescence in situ hybridization (FISH), and a high level of CRKL expression was also observed in the cells. The RNA-interference-mediated knockdown of CRKL in MKN74 disclosed the ability of CRKL to upregulate gastric cell proliferation. An immunohistochemical analysis revealed that CRKL protein was overexpressed in 24.4% (88/360) of the primary gastric cancers that were analyzed. The CRKL copy number was also examined in 360 primary gastric cancers using a FISH analysis, and CRKL amplification was found to be associated with CRKL overexpression. Finally, we showed that MKN74 cells with CRKL amplification were responsive to the dual Src/BCR-ABL kinase inhibitor BMS354825, likely via the inhibition of CRKL phosphorylation, and that the proliferation of MKN74 cells was suppressed by treatment with a CRKL-targeting peptide. Conclusion These results suggested that CRKL protein is overexpressed in a subset of gastric cancers and is associated with CRKL amplification in gastric cancer. Furthermore, our results suggested that CRKL protein has the ability to regulate gastric cell proliferation and has the potential to serve as a molecular therapy target for gastric cancer.
The authors have analysed the findings obtained in a comprehensive examination followed by surgical management of eighty-five patients presenting with chronic obliterating diseases of lower limbs arteries (CODLLA). Studying the macrohaemodynamics and microcirculation of the ischaemic extremity was carried out according to the diagnostic programme for the disease concerned: i.e., rheovasography, photoplethysmography, transcutaneous oximetry, ultrasonographic duplex scanning of the lower-limb arteries, and angiography. All the patients were found to have signs of critical ischaemia of the lower extremities on the background of a concomitant lesion of the vessels of the femoropopliteal and crural segments. However, no reconstructive operations were performed owing to occlusion of the arteries of the feet and crura, and the patients were therefore subjected to surgical procedures aimed at indirect revascularization of the extremity involved. The patients were divided into two groups (Group One and Group Two, comprising 45 and 40 patients, respectively). The forty-five Group One patients were subjected to revascularizing osteotrephination (ROT) of the femur and cms in the sites with sufficient blood supply, as determined by duplex scanning. We managed to relieve the symptoms of critical ischaemia in 82.2% of the patients from this group. The manifestations of ischaemia were noted to be gradually increasing in seven (15.6%) patients during the postoperative period, and they all had to be subjected to a high amputation of the affected extremity. Whereas, the forty Group Two patients underwent ROT supplemented by ultrasonography-controlled lumbar chemical sympathectomy (LCS). A combination of LCS and revascularizing osteotrephination made it possible to stop ischaemia in 90% of the patients suffering from critical ischaemia of the lower limbs, and to reduce the rate of amputations by 5.6%. PMID:19791428
Sukovatykh, B S; Itinson, A I; Kniazev, V V; Magamedaliva, K S; Savchuk, O F
HIV-associated lymphoproliferative disorders represent a heterogeneous group of diseases, arising in the presence of HIV-associated immunodeficiency. The overall prevalence of HIV-associated lymphoma is significantly higher compared to that of the general population and it continues to be relevant even after the wide availability of highly active antiretroviral therapy (HAART) (1). Moreover, they still represent one of the most frequent cause of death in HIV-infected patients. Epstein–Barr virus (EBV), a ?-Herpesviruses, is involved in human lymphomagenesis, particularly in HIV immunocompromised patients. It has been largely implicated in the development of B-cell lymphoproliferative disorders as Burkitt lymphoma (BL), Hodgkin disease (HD), systemic non Hodgkin lymphoma (NHL), primary central nervous system lymphoma (PCNSL), nasopharyngeal carcinoma (NC). Virus-associated lymphomas are becoming of significant concern for the mortality of long-lived HIV immunocompromised patients, and therefore, research of advanced strategies for AIDS-related lymphomas is an important field in cancer chemotherapy. Detailed understanding of the EBV lifecycle and related cancers at the molecular level is required for novel strategies of molecular-targeted cancer chemotherapy The linkage of HIV-related lymphoma with EBV infection of the tumor clone has several pathogenetic, prognostic and possibly therapeutic implications which are reviewed herein.
Bibas, Michele; Antinori, Andrea
Therapeutic HIV vaccines represent promising strategy as an adjunct or alternative to current antiretroviral treatment options for HIV. Unlike prophylactic AIDS vaccines designed to prevent HIV infection, therapeutic vaccines are given to already infected individuals to help fight the disease by modulating their immune response. The first immunotherapeutic trial in AIDS patients was conducted in 1983. Since then several dozen conventional therapeutic vaccine trials have been carried out. Unfortunately, the results have consistently shown that while HIV-specific immune responses were evident as a result of vaccination, the clinical improvement has been seldom observed. The instances of the apparent clinical benefit were invariably associated with unconventional vaccines that acted in accord with the principles of alloimmunization and/or autologous vaccination. All such vaccines were derived from the blood of HIV carriers or a cell culture and thus they inherently contained allo- or self-antigens unrelated to HIV. This intriguing observation raises the issue whether this clinically successful approach has been unduly neglected. The current strategy biased toward vaccines, which have shown little evidence of clinical efficacy, needs to be diversified and supplemented with research on alternative vaccine approaches geared toward immune tolerance induction. PMID:16787245
Bourinbaiar, A S; Root-Bernstein, R S; Abulafia-Lapid, R; Rytik, P G; Kanev, A N; Jirathitikal, V; Orlovsky, V G
The HIV-1 virus can enter a dormant state and become inactive, which reduces accessibility by antiviral drugs. We approach this latency problem from an unconventional point of view, with the focus on understanding how intrinsic chemical noise (copy number fluctuations of the Tat protein) can be used to assist the activation process of the latent virus. Several phase diagrams have been constructed in order to visualize in which regions of the parameter space noise can drive the activation process. Essential to the study is the use of a hyperbolic coordinate system, which greatly facilitates quantification of how the various reaction rate combinations shape the noise behavior of the Tat protein feedback system. We have designed a mathematical manual of how to approach the problem of activation quantitatively, and introduce the notion of an “operating point” of the virus. For both noise-free and noise-based strategies we show how operating point off-sets induce changes in the number of Tat molecules. The major result of the analysis is that for every noise-free strategy there is a noise-based strategy that requires lower dosage, but achieves the same anti-latency effect. It appears that the noise-based activation is advantageous for every operating point.
We report a challenging case of HIV-associated neurocognitive disorder with superimposed Epstein-Barr virus (EBV) encephalitis. The patient presented with an abnormal MRI brain scan, and EBV DNA that was detected in the cerebrospinal fluid and brain biopsy, which also demonstrated histopathological findings consistent with the diagnosis. This occurred on the background of a 12-month period of gradual cognitive decrease secondary to HIV-associated dementia. Invasive testing was required to reach the diagnosis in this case, highlighting the importance of thorough investigation of neurological impairment in HIV-positive patients. Clinicopathological recovery was achieved through optimization of antiretroviral therapy and use of valganciclovir. PMID:23475078
Trevillyan, Janine M; Mahony, Andrew A; McLean, Catriona; Hoy, Jennifer F
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.
Luetkemeyer, Anne F.; Havlir, Diane V.; Currier, Judith S.
HIV/AIDS remains a chronic and incurable disease, in spite of the notable successes of highly active antiretroviral therapy. Gene therapy offers the prospect of creating genetic resistance to HIV that supplants the need for antiviral drugs. In sight of this goal, a variety of anti-HIV genes have reached clinical testing, including gene-editing enzymes, protein-based inhibitors, and RNA-based therapeutics. Combinations of therapeutic genes against viral and host targets are designed to improve the overall antiviral potency and reduce the likelihood of viral resistance. In cell-based therapies, therapeutic genes are expressed in gene modified T lymphocytes or in hematopoietic stem cells that generate an HIV-resistant immune system. Such strategies must promote the selective proliferation of the transplanted cells and the prolonged expression of therapeutic genes. This review focuses on the current advances and limitations in genetic therapies against HIV, including the status of several recent and ongoing clinical studies.
Burnett, John C.; Zaia, John A.; Rossi, John J.
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
Cargill, Victoria A; Stone, Valerie E
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.
Gomes-Neto, Mansueto; Conceicao, Cristiano Sena; Carvalho, Vitor Oliveira; Brites, Carlos
A study was conducted in an HIV/AIDS Zimbabwean cohort to assess possible associations of pharmacogenetic variants with common adverse drug reactions (ADRs) during anti-retroviral treatment (ART) and/or tuberculosis (TB) treatment. Genotype and allele frequencies for CYP2B6 G516T, CYP2B6 T983C, CYP2A6*17, ABCB1 rs10276036 C>T, NAT2*5 and NAT2*14 were similar to those reported in literature for other African populations. The CYP2B6 516TT genotype and male gender were significantly associated with occurrence of Efavirenz induced central nervous system disorders (OR 20.58, p=0.004) and the ABCB1 rs10276036TT genotype with Nevirapine induced skin hypersensitivity (OR 4.01, p=0.04). For Stavudine, time on treatment was the main factor in development of lipodystrophy (OR 1.06, p<0.0001). For isoniazid, increasing patient age was associated with peripheral neuropathy (OR 1.05, p=0.001). Although genetic polymorphisms may play a role in predicting occurrence of ADRs, this study also indicates that other factors (gender, age, treatment time) are crucial in predicting drug-induced adverse effects. PMID:24517233
Dhoro, Milcah; Ngara, Bernard; Kadzirange, Gerald; Nhachi, Charles; Masimirembwa, Collen
Factors that may influence engagement into a family—ecological psychosocial intervention and a nondirective psychosocial intervention designed for HIV+ asymptomatic women were examined. Participants were 136 HIV+ African American women. Participant characteristics and therapeutic alliance were examined as possible predictors of engagement. Both participant characteristics and therapeutic alliance had some power in predicting engagement. However, fewer participant characteristics than expected were statistically significant. Statistically significant results indicate that women who had more daily hassles, more distress, more social support, and more disagreements with their spouse were more likely to engage in the intervention. The strongest predictor of engagement was therapeutic alliance, indicating the importance of the alliance between the HIV+ participant and the interventionist. The importance of these findings is discussed.
Prado, Guillermo; Szapocznik, Jose; Mitrani, Victoria B.; Mauer, Magaly H.; Smith, Lila; Feaster, Daniel J.
To study the determinants of CD4% and CD4 counts among HIV-negative Ethiopians, and to identify factors susceptible to explain the low CD4 counts observed among Ethiopian subjects. Cohort studies among factory workers in Akaki and Wonji, Ethiopia. Clinical and laboratory examinations, including determination of HIV serological status and T-cell subsets, were performed during follow-up visits every six months. In addition,
C. Abuye; A. Tsegaye; C. E. West; P. Versloot; E. J. Sanders; D. Wolday; D. Hamann; T. F. Rinke De Wit; A. L. Fontanet
Human Immunodeficiency Virus-1 (HIV-1) infection leads to CD4+ T cell depletion primarily by apoptosis employing both intrinsic\\u000a and extrinsic pathways. Although extensive literature exists about the role of mitochondrial proteins in HIV induced T cell\\u000a apoptosis, there is little understanding about the role of different components of mitochondrial oxidative phosphorylation\\u000a (OXPHOS) system in apoptosis. The OXPHOS system comprises of five
Manoj Kumar Tripathy; Debashis Mitra
Cell surface receptors, such as the CCR5 chemokine receptors, represent key determinants of the human immunodeficiency virus type 1 (HIV-1) entry into target cells. The CC-chemokine, RANTES (regulated upon activation, normal T-cell expressed and secreted), a ligand for CCR5, have been targeted to the lumen of endocytoplasmic reticulum (ER) using a KDEL (ER-retention signal) fusion termed RANTES–KDEL and this construct
Li Sun; Ying Zhang; Chang-Xing Huang; Xiao-Li Qu; Ye Zhang; Jiu-Cong Zhang; Xin Wei; Yan Zhuang; Song Zhai; Mei-Juan Peng; Hong Jiang; Chun-Qiu Hao; Yan-Hong Li; Jiang Lu; Jian-Qi Lian; Yong-Tao Sun; Xue-Fan Bai
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/?l). 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/?l 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
Tau, Pamela; Mancon, Alessandro; Mileto, Davide; Di Nardo Stuppino, Silvia; Bottani, Giulia; Gismondo, Maria Rita; Galli, Massimo; Micheli, Valeria; Rusconi, Stefano
A Randomized Clinical Trial Evaluating Therapeutic Drug Monitoring (TDM) for Protease Inhibitor-Based Regimens in Antiretroviral-Experienced HIV-Infected Individuals: Week 48 Results of the A5146 Study
Background We devised an open-label, randomized trial to evaluate whether therapeutic drug monitoring (TDM) of protease inhibitors (PIs) and dose escalation based upon a normalized inhibitory quotient (NIQ), which integrates PI trough concentration and drug resistance, could improve virologic outcome in PI-experienced patients with treatment failure. Secondary analyses through 48 weeks are presented. Methods Eligible HIV-infected subjects with a screening viral load of ?1000 copies/mL initiated a new PI-based regimen at entry and had NIQ performed at week 2. Subjects with an NIQ ?1 were randomized at week 4 to a standard-of-care (SOC) arm or TDM arm featuring PI dose escalation. Results One hundred and eighty-three subjects were randomized. There was no significant treatment difference in change from randomization to week 48 in HIV-1 RNA [P = .13, median (25th, 75th percentile log10 copies/mL change): ?0.03 (?0.74, 0.62) with TDM and 0.11 (?2.3, 0.82) with SOC]. In subgroup analysis, patients with ?0.69 active PIs benefited from TDM compared to those with <0.69 active PIs (P = .05). Conclusions While the TDM strategy of PI dose escalation did not improve virologic response at week 48 overall, in subgroup analysis, TDM favorably impacted virologic outcome in subjects taking PI-based regimens with moderate antiviral activity.
Albrecht, Mary; Mukherjee, A. Lisa; Tierney, Camlin; Morse, Gene D.; Dykes, Carrie; Klingman, Karin L.; Demeter, Lisa M.
Background Triple infection (TI) with HIV-1, HCV, and HBV (TI) is highly prevalent in intravenous drug users (IDUs). These TI patients have a faster progression to AIDS, and even after antiretroviral therapy (ART) the prognosis of their disease is poor. The use of microRNA (miRNA) to silence genes holds potential applications for anti-HCV therapy. Methods We analyzed the role of human miRNAs (hsa-miRs) in TI by computational analyses for HCV, HIV-1, and HBV showing identity to these three viral genomes. Results We identified one unique miRNA, hsa-miR-3065-3p, that shares significant mutual identity to these three viral genomes (?61–83%). In addition, hsa-miR-99, hsa-miR-548, and hsa-miR-122 also showed mutual identity with these three viral genomes, albeit at a lower degree (?52–88%). Conclusion Here, we present evidence using essential components of bioinformatics tools, and hypothesize that utility of hsa-miR-3065-3p and perhaps miR-548 would be potential antiviral therapeutic agents in the treatment of TI patients because it shows near perfect alignment in the seed region for all three viruses. We also make an argument that current proposed therapy with hsa-miR-122 may not be the optimal choice for HCV patients since it lacks essential gene alignment and may be harmful for the patients.
Khokhar, Ambreen; Noorali, Samina; Sheraz, Muhammad; Mahalingham, Kuha; Pace, Donald G.; Khanani, Mohammad R.; Bagasra, Omar
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.
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
Background.?Individuals infected with human immunodeficiency virus (HIV) appear to age faster than the general population, possibly related to HIV infection, antiretroviral therapy, and/or social/environmental factors. We evaluated leukocyte telomere length (LTL), a marker of cellular aging, in HIV-infected and uninfected adults. Methods.?Clinical data and blood were collected from Children and women: AntiRetrovirals and the Mechanism of Aging (CARMA) cohort study participants. Variables found to be important in univariate analysis were multivariate model candidates. Results.?Of the 229 HIV-infected and 166 HIV-uninfected participants, 76% were women, and 71% were current/previous smokers. In a multivariate model of all participants, older age (P < .001), HIV infection (P = .04), active hepatitis C virus (HCV) infection (P = .02), and smoking (P < .003) were associated with shorter LTL. An interaction was detected, whereby smoking was associated with shorter LTL in HIV-uninfected subjects only. Among those, age and smoking (P ? .01) were related to shorter LTL. In 2 models of HIV-infected individuals, age (P ? .002) and either active HCV infection (P = .05) or peak HIV RNA ?100 000 copies/mL (P = .04) were associated with shorter LTL, whereas other HIV disease or treatment parameters were unrelated. Conclusions.?Our results suggest that acquisition of HIV and viral load are primarily responsible for the association between HIV-positive status and shorter LTL. The lack of association between LTL and time since HIV diagnosis, antiretroviral treatment, or degree of immune suppression would implicate HIV infection-related factors rather than disease progression or treatment. Smoking effects on LTL appear masked by HIV, and HCV infection may accelerate LTL shortening, particularly in coinfected individuals. The effect of early therapeutic intervention on LTL in HIV and HCV infections should be evaluated. PMID:24457340
Zanet, Deanna L; Thorne, Anona; Singer, Joel; Maan, Evelyn J; Sattha, Beheroze; Le Campion, Armelle; Soudeyns, Hugo; Pick, Neora; Murray, Melanie; Money, Deborah M; Côté, Hélène C F
Induced pluripotent stem cells (iPSCs) have radically advanced the field of regenerative medicine by making possible the production of patient-specific pluripotent stem cells from adult individuals. By developing iPSCs to treat HIV, there is the potential for generating a continuous supply of therapeutic cells for transplantation into HIV-infected patients. In this study, we have used human hematopoietic stem cells (HSCs) to generate anti-HIV gene expressing iPSCs for HIV gene therapy. HSCs were dedifferentiated into continuously growing iPSC lines with four reprogramming factors and a combination anti-HIV lentiviral vector containing a CCR5 short hairpin RNA (shRNA) and a human/rhesus chimeric TRIM5? gene. Upon directed differentiation of the anti-HIV iPSCs toward the hematopoietic lineage, a robust quantity of colony-forming CD133(+) HSCs were obtained. These cells were further differentiated into functional end-stage macrophages which displayed a normal phenotypic profile. Upon viral challenge, the anti-HIV iPSC-derived macrophages exhibited strong protection from HIV-1 infection. Here, we demonstrate the ability of iPSCs to develop into HIV-1 resistant immune cells and highlight the potential use of iPSCs for HIV gene and cellular therapies. PMID:21119622
Kambal, Amal; Mitchell, Gaela; Cary, Whitney; Gruenloh, William; Jung, Yunjoon; Kalomoiris, Stefanos; Nacey, Catherine; McGee, Jeannine; Lindsey, Matt; Fury, Brian; Bauer, Gerhard; Nolta, Jan A; Anderson, Joseph S
Induced pluripotent stem cells (iPSCs) have radically advanced the field of regenerative medicine by making possible the production of patient-specific pluripotent stem cells from adult individuals. By developing iPSCs to treat HIV, there is the potential for generating a continuous supply of therapeutic cells for transplantation into HIV-infected patients. In this study, we have used human hematopoietic stem cells (HSCs) to generate anti-HIV gene expressing iPSCs for HIV gene therapy. HSCs were dedifferentiated into continuously growing iPSC lines with four reprogramming factors and a combination anti-HIV lentiviral vector containing a CCR5 short hairpin RNA (shRNA) and a human/rhesus chimeric TRIM5? gene. Upon directed differentiation of the anti-HIV iPSCs toward the hematopoietic lineage, a robust quantity of colony-forming CD133+ HSCs were obtained. These cells were further differentiated into functional end-stage macrophages which displayed a normal phenotypic profile. Upon viral challenge, the anti-HIV iPSC-derived macrophages exhibited strong protection from HIV-1 infection. Here, we demonstrate the ability of iPSCs to develop into HIV-1 resistant immune cells and highlight the potential use of iPSCs for HIV gene and cellular therapies.
Kambal, Amal; Mitchell, Gaela; Cary, Whitney; Gruenloh, William; Jung, Yunjoon; Kalomoiris, Stefanos; Nacey, Catherine; McGee, Jeannine; Lindsey, Matt; Fury, Brian; Bauer, Gerhard; Nolta, Jan A; Anderson, Joseph S
Background The etiology of Bell's palsy can vary but anterograde axonal degeneration may delay spontaneous functional recovery leading the necessity of therapeutic interventions. Corticotherapy and/or complementary rehabilitation interventions have been employed. Thus the natural history of the disease reports to a neurotrophic resistance of adult facial motoneurons leading a favorable evolution however the related molecular mechanisms that might be therapeutically addressed in the resistant cases are not known. Fibroblast growth factor-2 (FGF-2) pathway signaling is a potential candidate for therapeutic development because its role on wound repair and autocrine/paracrine trophic mechanisms in the lesioned nervous system. Methods Adult rats received unilateral facial nerve crush, transection with amputation of nerve branches, or sham operation. Other group of unlesioned rats received a daily functional electrical stimulation in the levator labii superioris muscle (1 mA, 30 Hz, square wave) or systemic corticosterone (10 mgkg-1). Animals were sacrificed seven days later. Results Crush and transection lesions promoted no changes in the number of neurons but increased the neurofilament in the neuronal neuropil of axotomized facial nuclei. Axotomy also elevated the number of GFAP astrocytes (143% after crush; 277% after transection) and nuclear FGF-2 (57% after transection) in astrocytes (confirmed by two-color immunoperoxidase) in the ipsilateral facial nucleus. Image analysis reveled that a seven days functional electrical stimulation or corticosterone led to elevations of FGF-2 in the cytoplasm of neurons and in the nucleus of reactive astrocytes, respectively, without astrocytic reaction. Conclusion FGF-2 may exert paracrine/autocrine trophic actions in the facial nucleus and may be relevant as a therapeutic target to Bell's palsy.
Background & objectives: Information available on HIV-2 and dual infection (HIV-1/2) is limited. This study was carried out among HIV positive individuals in an urban referral clinic in Khar, Mumbai, India, to report on relative proportions of HIV-1, HIV-2 and HIV-1/2 and baseline characteristics, response to and outcomes on antiretroviral treatment (ART). Methods: Retrospective analysis of programme data (May 2006-May 2009) at Khar HIV/AIDS clinic at Mumbai, India was done. Three test algorithm was used to diagnose HIV-1 and -2 infection. Standard ART was given to infected individuals. Information was collected on standardized forms. Results: A total of 524 individuals (male=51%; median age=37 yr) were included in the analysis over a 3 year period (2006-2009) - 489 (93%) with HIV-1, 28 (6%) with HIV-2 and 7(1%) with dual HIV-1/2 infection. HIV-2 individuals were significantly older than HIV-1 individuals (P<0.001). A significantly higher proportion of HIV-2 patients and those with dual infections had CD4 counts <200 cells/µl compared to HIV-1. HIV-2 individuals were more likely to present in WHO Clinical Stage 4. Of the 443 patients who were started on ART, 358 (81%) were still alive and on ART, 38 (8.5%) died and 3 were transferred out. CD4 count recovery at 6 and 12 months was satisfactory for HIV-1 and HIV-2 patients on protease inhibitor based regimens while this was significantly lower in HIV-2 individuals receiving 3 nucleoside reverse transcriptase inhibitors. Interpretation & conclusions: In an urban HIV clinic in Mumbai, India, HIV-2 and dual infections are not uncommon. Adaptation of the current national diagnostic and management protocols to include discriminatory testing for HIV types and providing access to appropriate and effective ART regimens will prevent the development of viral resistance and preserve future therapeutic options.
Chiara, Montaldo; Rony, Zachariah; Homa, Mansoor; Bhanumati, Varghese; Ladomirska, Joanna; Manzi, M.; Wilson, N.; Alaka, Deshpande; Harries, A.D.
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…
Sacks, Joann Y.; Sacks, Stanley; Mckendrick, Karen; Banks, Steven; Schoeneberger, Marlies; Hamilton, Zachary; Stommel, Joseph; Shoemaker, Joanie
In this study, anti-convulsant effect of Sidr leaf extract was examined by using pentylenetetrazol (PTZ) model on male albino rat by evaluating the changes in norepinephrine (NE), dopamine (DA) and serotonin (5-HT) contents in different brain regions (cerebellum, brainstem, striatum, cerebral cortex, hypothalamus and hippocampus). The administration of subconvulsive dose of PTZ (40 mg/kg i.p.) every other day for 9 days caused a significant decrease in monoamine content in different brain areas, this is may be due to the increase in nitric oxide levels, although antagonized the GABAA receptors which led to neurotransmitter release so the content is decreased. Administration of PTZ after treatment with Sidr (50 mg/kg i.p.) leaf extract for 3 weeks as a protective group and administration of Sidr leaf extract for 3 weeks after treatment of PTZ as a therapeutic group caused significant increase in NE, DA, and 5-HT contents in all tested brain regions at most of the time intervals studied. This may be due to the presence of peptide and cyclopeptide alkaloids in the extract which inhibit neurotransmitter activity which led to the inhibition of neurotransmitter release. From these results, we can say that the Sidr leaf extract has neuroprotective and therapeutic roles against pentylenetetrazol convulsant effect. PMID:23961090
Waggas, Abeer M; Al-Hasani, Reem H
Viremic controllers (VC) and elite controllers/suppressors (ES) maintain control over HIV-1 replication. Some studies suggested that control is a result of infection with a defective viral strain while others suggested host immune factors play a key role. Here we document two HIV-1 transmission pairs: one consisting of a patient with progressive disease and an individual who became an ES, and the second consisting of a patient with progressive disease and a VC. In contrast to another ES transmission pair, virus isolated from all patients was fully replication competent. These data suggests that some VC and ES are infected with HIV-1 isolates that replicate vigorously in vitro and are able to cause progressive disease in vivo. These data suggest that host factors play a dominant role in control of HIV-1 infection, thus it may be possible to control fully pathogenic HIV-1 isolates with therapeutic vaccination.
Buckheit, Robert W.; Allen, Tracy G.; Alme, Angela; Salgado, Maria; O'Connell, Karen A.; Huculak, Sarah; Falade-Nwulia, Oluwaseun; Williams, Thomas M.; Gallant, Joel E.; Siliciano, Robert F.; Blankson, Joel N.
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
Gómara, María José; Haro, Isabel
Objectives Our goal in this study was to examine how Vitamin C interacts with antiretroviral therapy in individuals with HIV. We specifically evaluated how Vitamin C impacts highly active antiretroviral therapy (HAART) adherence and HAART effectiveness as adjudicated by HIV viral loads and CD4 cell counts. Women served as their own controls, comparing periods of Vitamin C usage with periods of non-usage. Design An intra-individual, cross-sectional comparative study ‘nested’ in the WIHS observational cohort study Subjects Women in the Women’s Interagency HIV Study (WIHS). Outcome Measures Adherence, CD4 count and Viral load. Results Our study population was drawn from 2,813 HIV+ participants who contributed 44,588 visits in WIHS from October, 1994 to April, 2009. Among them, there were 1,122 Vitamin C users with 4,954 total visits where use was reported. In the multivariate model adjusting for age, education, race, income, drug use, Vitamin C use order and depression score, there was a 44% increase in the odds of >=95% HAART adherence among participants during their period of Vitamin C use compared to when they were not using Vitamin C (OR=1.44; 95% CI=1.1–1.9; P-value=0.0179). There was an association with Vitamin C usage and CD4 counts on viral loads. Conclusion Vitamin C usage appears to be associated with improved adherence. Future Vitamin C studies should target specific HAART drugs, and prospective clinical outcomes.
Merenstein, Daniel; Wang, Cuiwei; Gandhi, Monica; Robison, Esther; Levine, Alexandra M.; Schwartz, Rebecca M.; Weber, Kathleen M.; Liu, Chenglong
Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-?, IFN-?, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infected patients had raised levels of both IP-10 and IFN-? compared with healthy controls (n = 19), with particularly high levels in advanced disease. HAART induced a marked decrease in levels of both IFN-?, neopterin and IP-10, though not to normal concentrations. In contrast, IFN-? levels were low throughout the study, and not different from controls. While neopterin and IP-10 remained significantly decreased compared with baseline levels throughout the study, IFN-? levels returned to baseline at the end of the study. Persistently high IP-10 and IFN-? levels were associated with immunological treatment failure and even high baseline levels of IFN-? appeared to predict immunological relapse. Furthermore, we found a markedly suppressive effect of exogenously added IFN-? on phytohaemagglutinin-stimulated lymphocyte proliferation in both patients and controls, and this suppressive effect seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-? in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART.
Stylianou, E; Aukrust, P; Bendtzen, K; Muller, F; Fr?land, S S
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
Zule, William A; Cross, Harry E; Stover, John; Pretorius, Carel
The aim of this work is to: (1) assess therapeutic drug monitoring of indinavir (IDV) during clinical routine practice in HIV-infected children, whose antiretroviral treatment includes IDV boosted with ritonavir (RTV), and (2) describe a possible relationship between IDV pharmacokinetics and MDR1 genotypes. In 21 ambulatory pediatric patients receiving IDV plus RTV, IDV plasma levels and MDR1 genotypes on exon
Verónica Curras; Christian Höcht; Andrea Mangano; Viviana Niselman; Eduardo Mariño Hernández; Paulo Cáceres Guido; Débora Mecikovsky; Carolina Bellusci; Rosa Bologna; Luisa Sen; Modesto C. Rubio; Guillermo F. Bramuglia
BACKGROUND: Inhibitors of the HIV-1 Protease currently used in therapeutic protocols, have been found to inhibit, although at higher concentrations, the HIV-2 encoded enzyme homologue. Similar to observations in HIV-1 infected individuals, therapeutic failure has also been observed for some patients infected with HIV-2 as a consequence of the emergence of viral strains resistant to the anti-retroviral molecules. In order
Najoua Ben M'Barek; Gilles Audoly; Didier Raoult; Pablo Gluschankof
Current antiretroviral therapy (ART) efficiently controls HIV-1 replication but fails to eradicate the virus. Even after years of successful ART, HIV-1 can conceal itself in a latent state in long-lived CD4(+) memory T cells. From this latent reservoir, HIV-1 rebounds during treatment interruptions. Attempts to therapeutically eradicate this viral reservoir have yielded disappointing results. A major problem with previously utilized activating agents is that at the concentrations required for efficient HIV-1 reactivation, these stimuli trigger high-level cytokine gene expression (hypercytokinemia). Therapeutically relevant HIV-1-reactivating agents will have to trigger HIV-1 reactivation without the induction of cytokine expression. We present here a proof-of-principle study showing that this is a possibility. In a high-throughput screening effort, we identified an HIV-1-reactivating protein factor (HRF) secreted by the nonpathogenic bacterium Massilia timonae. In primary T cells and T-cell lines, HRF triggered a high but nonsustained peak of nuclear factor kappa B (NF-kappaB) activity. While this short NF-kappaB peak potently reactivated latent HIV-1 infection, it failed to induce gene expression of several proinflammatory NF-kappaB-dependent cellular genes, such as those for tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8), and gamma interferon (IFN-gamma). Dissociation of cellular and viral gene induction was achievable, as minimum amounts of Tat protein, synthesized following application of a short NF-kappaB pulse, triggered HIV-1 transactivation and subsequent self-perpetuated HIV-1 expression. In the absence of such a positive feedback mechanism, cellular gene expression was not sustained, suggesting that strategies modulating the NF-kappaB activity profile could be used to selectively trigger HIV-1 reactivation. PMID:20538859
Wolschendorf, Frank; Duverger, Alexandra; Jones, Jennifer; Wagner, Frederic H; Huff, Jason; Benjamin, William H; Saag, Michael S; Niederweis, Michael; Kutsch, Olaf
Despite significant improvements, antiretroviral therapies against HIV-1 are plagued by a high frequency of therapeutic failures that have been associated with acquisition of drug resistance. We recently reported that HIV-1 exploits a host glycan binding protein, galectin-1, to increase its attachment to host cells, thereby increasing its overall infectivity in susceptible cells. This finding suggests that host molecules such as galectin-1 could reduce the expected efficiency of HIV-1 drugs targeting early steps of the replicative cycle, such as attachment and entry processes. Thus, new classes of drugs that would interfere with galectin-1/HIV-1 interactions could benefit the current antiretroviral therapy. To further explore this possibility, experiments were conducted to discover leading compounds showing specific inhibition of galectin-1 activity in a cellular model of HIV-1 infection. Three lactoside compounds were found to modestly inhibit the interaction of galectin-1 with primary human CD4+ T cells. Interestingly, these same inhibitors reduced the galectin-1-mediated increase in HIV-1 attachment to target cells in a much more efficient manner. More important, the tested lactoside derivatives also significantly decreased the galectin-1-dependent enhancement of HIV-1 infection. These observations deserve further attention when considering that the development of new drugs to prevent and treat HIV-1 infection remains a priority.
St-Pierre, Christian; Ouellet, Michel; Giguere, Denis; Ohtake, Reiko; Roy, Rene
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.
Vo, Thanh-Sang; Kim, Se-Kwon
An integral approach to the etiopathogenesis of human neurodegenerative diseases (HNDDs) and cancer. Possible therapeutic consequences within the frame of the trophic factor withdrawal syndrome (TFWS)
A novel and integral approach to the understanding of human neurodegenerative diseases (HNDDs) and cancer based upon the disruption of the intracellular dynamics of the hydrogen ion (H+) and its physiopathology, is advanced. From an etiopathological perspective, the activity and/or deficiency of different growth factors (GFs) in these pathologies are studied, and their relationships to intracellular acid-base homeostasis reviewed. Growth and trophic factor withdrawal in HNDDs indicate the need to further investigate the potential utilization of certain GFs in the treatment of Alzheimer disease and other neurodegenerative diseases. Platelet abnormalities and the therapeutic potential of platelet-derived growth factors in these pathologies, either through platelet transfusions or other clinical methods, are considered. Finally, the etiopathogenic mechanisms of apoptosis and antiapoptosis in HNDDs and cancer are viewed as opposite biochemical and biological disorders of cellular acid-base balance and their secondary effects on intracellular signaling pathways and aberrant cell metabolism are considered in the light of the both the seminal and most recent data available. The “trophic factor withdrawal syndrome” is described for the first time in English-speaking medical literature, as well as a Darwinian-like interpretation of cellular behavior related to specific and nonspecific aspects of cell biology.
Harguindey, Salvador; Orive, Gorka; Cacabelos, Ramon; Hevia, Enrique Melendez; de Otazu, Ramon Diaz; Arranz, Jose Luis; Anitua, Eduardo
Stretches of guanines can associate in vitro through Hoogsteen hydrogen bonding to form four-stranded structures. In the HIV-1 central DNA flap, generated by reverse transcriptase at the end of retrotranscrip- tion, both the two 99 nt-long overlapping (+) strands contain two adjacent tracts of guanines. This study demonstrates that oligonucleotides containing these G-clusters form highly stable G-quadruplexes of various structures
Sebastien Lyonnais; Candide Hounsou; Marie-Paule Teulade-Fichou; Josette Jeusset; Eric Le Cam; Gilles Mirambeau
A respondent-driven sampling survey was conducted to investigate HIV related serological and behavioral characteristics of\\u000a men who have sex with men (MSM) in Guangzhou, China, and to identify associated factors potentially driving the epidemic.\\u000a Respondent- Driven Sampling Analysis Tool and SPSS were used to generate adjusted estimates and to explore associated factors.\\u000a Three hundred seventy-nine eligible participants were recruited. The
Fei Zhong; Peng Lin; Huifang Xu; Ye Wang; Ming Wang; Qun He; Lirui Fan; Yan Li; Fang Wen; Yingru Liang; H. Fisher Raymond; Jinkou Zhao
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
Gessi, Marco; Gielen, Gerrit H; Hammes, Jennifer; Dörner, Evelyn; Mühlen, Anja Zur; Waha, Andreas; Pietsch, Torsten
The first step of the human immunodeficiency virus (HIV) replication cycle-binding and entry into the host cell-plays a major role in determining viral tropism and the ability of HIV to degrade the human immune system. HIV uses a complex series of steps to deliver its genome into the host cell cytoplasm while simultaneously evading the host immune response. To infect cells, the HIV protein envelope (Env) binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection. Revealing the mechanism of HIV entry has profound implications for viral tropism, transmission, pathogenesis, and therapeutic intervention. Here, we provide an overview into the mechanism of HIV entry, provide historical context to key discoveries, discuss recent advances, and speculate on future directions in the field. PMID:22908191
Wilen, Craig B; Tilton, John C; Doms, Robert W
The first step of the human immunodeficiency virus (HIV) replication cycle—binding and entry into the host cell—plays a major role in determining viral tropism and the ability of HIV to degrade the human immune system. HIV uses a complex series of steps to deliver its genome into the host cell cytoplasm while simultaneously evading the host immune response. To infect cells, the HIV protein envelope (Env) binds to the primary cellular receptor CD4 and then to a cellular coreceptor. This sequential binding triggers fusion of the viral and host cell membranes, initiating infection. Revealing the mechanism of HIV entry has profound implications for viral tropism, transmission, pathogenesis, and therapeutic intervention. Here, we provide an overview into the mechanism of HIV entry, provide historical context to key discoveries, discuss recent advances, and speculate on future directions in the field.
Wilen, Craig B.; Tilton, John C.; Doms, Robert W.
The spectrum of HIV-1 cellular reservoirs is highly diversified, and their role varies according to the milieu of the anatomical sites in which the virus replicates. In this light, mechanisms underlying HIV-1 persistence in anatomical compartments may be profoundly different from what is observed in peripheral blood. This scenario is further complicated by sub-optimal drug penetration in tissues allowing persistent and cryptic HIV-1 replication in body districts despite undetectable viremia. On this basis, this review aims at providing recent insights regarding the critical role of HIV-1 cellular reservoirs in different anatomical compartments, and their relationship with the pathogenesis of HIV-1 infection. A comprehensive definition of the complex interplay between the virus and its reservoir is critical in order to set up prophylactic and therapeutic strategies aimed at achieving the maximal virological suppression and hopefully in the near future the cure of HIV-1 infection (either functional or biological). PMID:24729094
Svicher, Valentina; Ceccherini-Silberstein, Francesca; Antinori, Andrea; Aquaro, Stefano; Perno, Carlo Federico
Abstract Rare individuals report repeated unprotected HIV-1 sexual exposures, yet remain seronegative for years. We investigated the possibility that reduced in vitro CD4+ T cell susceptibility to HIV-1 infection protects such highly exposed seronegative (ES) individuals. Susceptibility to three R5-tropic HIV-1 isolates, regardless of inoculating dose, was remarkably similar between 81 ES and 33 low-risk controls. In 94% (99/105) of donors, we observed a 1.36 log-unit range in HIV-1JR-CSF production, with similar results for HIV-11192. The median frequency of intracellular Gag+ T cells after single-round infection was similar in ES (5.2%) and controls (7.2%), p?=?0.456. However, in repeated testing, CD4+ T cells from two controls (6.1%) and four ES (4.9%) exhibited a 10- to 2500-fold reduction in HIV-1 production and required 5- to 12-fold greater HIV-11192 and HIV-1JR-CSF inocula to establish infection (TCID50). Reduced viral entry cannot explain the low producer phenotype; no differences in CCR5 receptor density or ?-chemokine production were observed. In conclusion, we have identified a remarkably narrow range of HIV-1 susceptibility in seronegative donors regardless of risk activity, which can be applied as a benchmark to assess vaccine-induced antiviral effector activities. However, CD4+ T cells from a subset of individuals demonstrated reduced HIV-1 susceptibility unexplained by impaired entry, lending support to the possibility that cellular restriction of HIV-1 may account for continued seronegativity in some of those having repeated sexual exposure. Identifying the host-virus interactions responsible for diminished in vitro susceptibility may contribute to the development of novel therapeutic strategies.
Speelmon, Emily C.; Livingston-Rosanoff, Devon; Desbien, Anthony L.; Lee, Jean; Wick, W. David; Hladik, Florian
Currently, there is a growing interest in using entry inhibitors to treat HIV-2-infected patients because, among the available drugs, few are fully active against HIV-2. Recent studies indicate that maraviroc and other experimental entry inhibitors, including new CCR5 and CXCR4 antagonists, inhibit primary isolates of HIV-2 as well as HIV-1 and may, therefore, expand the existing therapeutic armamentarium against HIV-2. There are, however, significant differences between the evolution of HIV-1 and HIV-2 envelope glycoproteins during infection that can lead to differences in the response to therapy with entry inhibitors over the course of the infection. Here, we review the available data on the susceptibility of HIV-2 to entry inhibitors in the context of the evolution of the sequence, structure, and function of envelope glycoproteins during infection. PMID:23449229
Borrego, Pedro; Taveira, Nuno
In order to better understand the possible beneficial effects of intermittent IL-2 treatment as complement of antiretroviral therapy in HIV-1+ patients, we have measured the levels of RANTES in the supernatants and the CD25 expression in cultured PBMCs obtained from HIV-1+ individuals in presence of IL-2. The results showed a significant increases in RANTES production and in the expression of CD25+ in the cultures with IL-2 of PBMC obtained from HIV-1+ patients with a detectable viral load in comparison with both, HIV-1+ patients with no detectable viral loads and with healthy individuals. These results suggest that therapeutic IL-2 administered in addition to highly active anti-retroviral therapy (HAART) may contribute to increase the effect of this therapy by rising both RANTES production and CD25 expression only in HIV-1+ patients with detectable viral loads. PMID:16644491
Lozano, José Manuel; Kindelán, José María; Cabello, Almudena; Gonzalez, Rafael; Solana, Rafael; Peña, José
Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient’s quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as “a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain”. Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a “protective” function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm2 to 128.80±95.7 cm2) and a 66% reduction after 3 months (81.38±59.19 cm2). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug–drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials.
Casale, Roberto; Di Matteo, Maria; Minella, Cristina E; Fanelli, Guido; Allegri, Massimo
Post-herpetic neuralgia (PHN) is neuropathic pain persisting after an acute episode of herpes zoster, and is associated with severe pain and sensory abnormalities that adversely affect the patient's quality of life and increase health care costs. Up to 83% of patients with PHN describe localized neuropathic pain, defined as "a type of neuropathic pain characterized by consistent and circumscribed area(s) of maximum pain". Topical treatments have been suggested as a first-line treatment for localized neuropathic pain. Use of 5% lidocaine medicated plaster could reduce abnormal nervous peripheral discharge and via the plaster could have a "protective" function in the affected area. It has been suggested that use of this plaster could reduce pain as well as the size of the painful area. To evaluate this possible outcome, we retrospectively reviewed eight patients with PHN, treated using 5% lidocaine medicated plaster. During a follow-up period of 3 months, we observed good pain relief, which was associated with a 46% reduction in size of the painful area after one month (from 236.38±140.34 cm(2) to 128.80±95.7 cm(2)) and a 66% reduction after 3 months (81.38±59.19 cm(2)). Our study cohort was composed mainly of elderly patients taking multiple drugs to treat comorbidities, who have a high risk of drug-drug interactions. Such patients benefit greatly from topical treatment of PHN. Our observations confirm the effectiveness of lidocaine plasters in the treatment of PHN, indicating that 5% lidocaine medicated plaster could reduce the size of the painful area. This last observation has to be confirmed and the mechanisms clarified in appropriate larger randomized controlled trials. PMID:25018649
Casale, Roberto; Di Matteo, Maria; Minella, Cristina E; Fanelli, Guido; Allegri, Massimo
Genome-wide search for the genes accountable for the induced resistance to HIV-1 infection in activated CD4+ T cells: apparent transcriptional signatures, co-expression networks and possible cellular processes
Background Upon co-stimulation with CD3/CD28 antibodies, activated CD4?+?T cells were found to lose their susceptibility to HIV-1 infection, exhibiting an induced resistant phenotype. This rather unexpected phenomenon has been repeatedly confirmed but the underlying cell and molecular mechanisms are still unknown. Methods We first replicated the reported system using the specified Dynal beads with PHA/IL-2-stimulated and un-stimulated cells as controls. Genome-wide expression and analysis were then performed by using Agilent whole genome microarrays and established bioinformatics tools. Results We showed that following CD3/CD28 co-stimulation, a homogeneous population emerged with uniform expression of activation markers CD25 and CD69 as well as a memory marker CD45RO at high levels. These cells differentially expressed 7,824 genes when compared with the controls on microarrays. Series-Cluster analysis identified 6 distinct expression profiles containing 1,345 genes as the representative signatures in the permissive and resistant cells. Of them, 245 (101 potentially permissive and 144 potentially resistant) were significant in gene ontology categories related to immune response, cell adhesion and metabolism. Co-expression networks analysis identified 137 “key regulatory” genes (84 potentially permissive and 53 potentially resistant), holding hub positions in the gene interactions. By mapping these genes on KEGG pathways, the predominance of actin cytoskeleton functions, proteasomes, and cell cycle arrest in induced resistance emerged. We also revealed an entire set of previously unreported novel genes for further mining and functional validation. Conclusions This initial microarray study will stimulate renewed interest in exploring this system and open new avenues for research into HIV-1 susceptibility and its reversal in target cells, serving as a foundation for the development of novel therapeutic and clinical treatments.
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.
Keener, William K. (Idaho Falls, ID)
In 1997 a Finnish group speculated on the presence of nanobacteria in vaccines. In 2001, a report on the identification of nanobacteria in a number of vaccines attracted much attention. Experiments indicated that viable nanobacteria are excreted via urine. Their extreme survivability suggests that prior to discussing any possible contamination of vaccines, sources and routes of natural infection need to be examined. In view of 30,000,000 HIV infections in sub-Saharan Africa, the recently reported occurrence of nanobacteria in HIV-infected patients deserves concern. Clearly, it could indicate the origin of a giant reservoir and dissemination cycle. Here we discuss novel therapeutic strategies to prevent or reduce nanobacterial infection. In regard of the rapid progress in this field, we start with a brief introductory summary, and analyze possible implications. PMID:16582542
Sommer, Andrei P; Milankovits, Marton; Mester, Adam R
Therapeutic options aimed at tackling the HIV pandemic face many obstacles. The lack of readily accessible and affordable therapies means that most of those affected go untreated. The array of escape mechanisms used by HIV has undermined the efficiency of many antiviral products and continually represents a barrier to the development of an effective vaccine. Recent developments have seen a shift away from a cytopathic viral model of HIV pathogenesis towards the crucial role of immunopathogenic features--notably generalised immune activation--in the development of AIDS. As conventional vaccine strategies have sought to promote viral neutralisation and suppressive cellular responses, novel strategies that aim to address HIV immunopathogenesis should be sought. We review current opinion on HIV-induced pathogenic immune activation and strategies aimed at eliminating HIV, including a potential role for non-neutralising antibodies as part of a therapeutic vaccine option. PMID:18818125
Cadogan, Martin; Dalgleish, Angus G
Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment.
Zhou, Li; Saksena, Nitin K.
Neuropathic pain is associated with numerous systemic illnesses, including HIV infection. The diagnosis and management of\\u000a peripheral neuropathy presents diagnostic and therapeutic challenges. Among various forms of HIV-associated peripheral neuropathies,\\u000a distal symmetrical polyneuropathy (DSP) is the most common. DSP may be caused or exacerbated by neurotoxic antiretrovirals,\\u000a particularly the dideoxynucleoside analogues (d-drugs). Selection of appropriate pharmacologic intervention for peripheral\\u000a neuropathy
Susama Verma; Lydia Estanislao; Letty Mintz; David Simpson
The goal of this work is to develop novel, efficacious, injectable, gene-specific therapeutics for treatment of human immunodeficiency virus (HIV) infection. These products will be nuclease resistant, stereospecific antisense inhibitors of human immunodef...
In a recent study published in Nature, Warren et al. describe the generation of a novel synthetic adenosine analogue, BCX4430, a synthetic drug-like small molecule that provides protection from Ebola and Marburg virus infection in animal models. PMID:24732011
Falzarano, Darryl; Feldmann, Heinz
Characteristic features of the panic patients is the increased sensitivity to the CO2. Respiratory pattern abnormalities such as prolonged apnea, diminished ventilatory responsiveness to hypercarbia have been observed in infants at risk for SIDS. Treating the panic attack the SSRI preparations proved to be suitable. Serotonin antagonists effect preventing SIDS is suggested.
Tuberculosis (TB) and HIV co-infections place an immense burden on health care systems and pose particular diagnostic and therapeutic challenges. Infection with HIV is the most powerful known risk factor predisposing for Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent TB reactivation 20-fold. TB is also the most common cause of AIDS-related death. Thus, M. tuberculosis and HIV act in synergy, accelerating the decline of immunological functions and leading to subsequent death if untreated. The mechanisms behind the breakdown of the immune defense of the co-infected individual are not well known. The aim of this review is to highlight immunological events that may accelerate the development of one of the two diseases in the presence of the co-infecting organism. We also review possible animal models for studies of the interaction of the two pathogens, and describe gaps in knowledge and needs for future studies to develop preventive measures against the two diseases.
Background: Majority of HIV/AIDS patients who are on Highly Active Anti Retroviral Therapy (HAART), are not aware about drug adherence and its importance which is the most important factor for drug adherence. Objectives: To study the level of drug adherence in patients accessing antiretroviral therapy (ART) through the National program and factor influencing drug adherence. Materials and Methods: In present study, we enrolled 102 newly diagnosed patients, among them in 79 patients, ART was started. To study the drug adherence a pretested, semistructured questionnaire was formed and patients were followed up for 6 months of the study. Pretest and posttest counseling was done to all such patients. Results: A total of 28 patients missed the dose in 1st follow-up, nine patients missed in 2nd follow-up, eight patients missed in 3rd follow-up. Three patients lost follow-up in 2nd follow-up, three patients further lost follow-up in 3rd follow-up. Running out of pills (40.0%), side effect (15.5%), and family problem (13.3%), poor transport facility for taking drug (8.9%) and forgetfulness (11.1%) are five major causes related to miss dose. In females patients, drug adherence (69%) was initially less than male patients (76%) but latter on female patients (96.3%) had better adherence than males (95.2%). Conclusion: This study suggest that drug adherence can be increased by proper counseling and close monitoring of the patients which may have a great role in preventing the drug resistance and ART response.
Meena, Lalit Prashant; Pandey, Shant Kumar; Rai, Madhukar; Bharti, Anju; Chakravarty, Jaya; Sundar, Shyam
To identify candidate interferons (IFNs) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection and to investigate sequence-function relationships, the antiviral activities of nine species of recombinant IFN-alpha [IFN-alpha A, IFN-alpha B, IFN-alpha C, IFN-alpha D, IFN-alpha J, [Ser116]IFN-alpha J1, IFN-alpha K, IFN-alpha J/C(Fnu4HI), and IFN-alpha A/D(BglII)] were evaluated against HIV-1. MT-2 cells were exposed to various concentrations of each IFN and were then infected with HIV. Protective effect was determined by cell viability using a tetrazolium dye assay. Activity against vesicular stomatitis virus (VSV) was assessed on MDBK and WISH cells. The 50% inhibitory concentration against HIV was 37 +/- 14 pg/ml for IFN-alpha A, and ranged from 15 +/- 3 pg/ml for IFN-alpha J/C(Fnu4HI) to > 90,000 pg/ml for IFN-alpha D. In general, relative activity against HIV was similar to relative activity against VSV on WISH cells. IFN-alpha D was notable for its decreased activity on human cells. The observations suggest that it may be possible to produce IFNs-alpha with more favorable therapeutic indices than currently available IFNs. Furthermore, the anti-HIV activity of IFNs-alpha is not determined solely by their linear amino acid sequence. PMID:1331260
Sperber, S J; Gocke, D J; Haberzettl, C; Kuk, R; Schwartz, B; Pestka, S
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.
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
Concurrent infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients positive for human immunodeficiency virus (HIV) is relatively common. The treatment of co-infected individuals is rather complex because the anti-viral therapy may be associated with drug-resistance, hepatotoxicity and lack of response. Herein, we present a summary of the available compounds and the recent recommendations concerning the therapeutic management of HIV/HBV and HIV/HCV co-infections. PMID:22530578
Masgala, A; Bonovas, S; Nikolopoulos, G K
OPTIMA (OPTions In Management with Antiretrovirals) is a clinical trial with a factorial randomization to evaluate the hypotheses that mega-antiretroviral therapy (ART) consisting of five or more anti-HIV drugs compared to standard-ART consisting of four or fewer anti-HIV drugs and a 3-month antiretroviral drug-free period (ARDFP) compared to no ARDFP will delay the occurrence of new or recurrent acquired immunodeficiency
Tassos C. Kyriakides; Abdel Babiker; Joel Singer; William Cameron; Martin T. Schechter; Mark Holodniy; Sheldon T. Brown; Mike Youle; Brian Gazzard
The persistence of human immunodeficiency virus type-1 (HIV-1) has long been attributed to its high mutation rate and the capacity of its resulting heterogeneous virus populations to evade host immune responses and antiviral drugs. However, this view is incomplete because it does not explain how the virus persists in light of the adverse effects mutations in the viral genome and variations in host functions can potentially have on viral functions and growth. Here we show that the resilience of HIV-1 can be credited, at least in part, to a robust response to perturbations that emerges as an intrinsic property of its intracellular development. Specifically, robustness in HIV-1 arises through the coupling of two feedback loops: a Rev-mediated negative feedback and a Tat-mediated positive feedback. By employing a mechanistic kinetic model for its growth we found that HIV-1 buffers the effects of many potentially detrimental variations in essential viral and cellular functions, including the binding of Rev to mRNA; the level of rev mRNA in the pool of fully spliced mRNA; the splicing of mRNA; the Rev-mediated nuclear export of incompletely-spliced mRNAs; and the nuclear import of Tat and Rev. The virus did not, however, perform robustly to perturbations in all functions. Notably, HIV-1 tended to amplify rather than buffer adverse effects of variations in the interaction of Tat with viral mRNA. This result shows how targeting therapeutics against molecular components of the viral positive-feedback loop open new possibilities and potential in the effective treatment of HIV-1.
Kim, Hwijin; Yin, John
Quantification of plasma HIV-1 RNA below the limit of FDA-approved assays by a single copy quantitative PCR assays (SCA) has provided significant insights into HIV-1 persistence despite potent antiretroviral therapy as well as a means to assess the impact of therapeutic strategies, such as treatment intensification, on residual viremia. In this review, we discuss insights gained from plasma HIV-1 RNA SCA and highlight the need for additional assays to characterize better the cellular and tissue reservoirs of HIV-1. Accurate, reproducible, and sensitive assays to quantify HIV-1 reservoirs, before and after therapeutic interventions, are essential tools in the quest for a cure of HIV-1 infection.
Hilldorfer, Benedict B.; Cillo, Anthony R.; Besson, Guillaume J.; Bedison, Margaret Anne; Mellors, John W.
In the era of effective antiretroviral therapy (ART), epidemiologic studies have found that HIV-infected persons have a higher prevalence and incidence of chronic obstructive pulmonary disease than HIV-uninfected persons. Recently, pulmonary function studies in HIV-infected persons have shown a high prevalence of airway obstruction, bronchodilator reversibility, and impaired diffusing capacity. In comparison to HIV-uninfected persons and those with well-controlled HIV disease, HIV-infected persons with poor viral control or lower CD4 cell count have more airflow obstruction, a greater decline in lung function, and possibly more severe diffusing impairment. This chapter will review the evidence linking HIV infection to obstructive lung disease and discuss management issues related to the treatment of obstructive lung disease in HIV-infected patients.
Gingo, Matthew R.; Morris, Alison; Crothers, Kristina
Abstract As HIV continues to be a global public health problem with no effective vaccine available, new and innovative therapies, including HIV gene therapies, need to be developed. Due to low transduction efficiencies that lead to low in vivo gene marking, therapeutically relevant efficacy of HIV gene therapy has been difficult to achieve in a clinical setting. Methods to improve the transplantation of enriched populations of anti-HIV vector-transduced cells may greatly increase the in vivo efficacy of HIV gene therapies. Here we describe the development of preselective anti-HIV lentiviral vectors that allow for the purification of vector-transduced cells to achieve an enriched population of HIV-resistant cells. A selectable protein, human CD25, not normally found on CD34+ hematopoietic progenitor cells (HPCs), was incorporated into a triple combination anti-HIV lentiviral vector. Upon purification of cells transduced with the preselective anti-HIV vector, safety was demonstrated in CD34+ HPCs and in HPC-derived macrophages in vitro. Upon challenge with HIV-1, improved efficacy was observed in purified preselective anti-HIV vector-transduced macrophages compared to unpurified cells. These proof-of-concept results highlight the potential use of this method to improve HIV stem cell gene therapy for future clinical applications.
Kalomoiris, Stefanos; Lawson, Je'Tai; Chen, Rachel X.; Bauer, Gerhard; Nolta, Jan A.
HIV-1 integrase (IN) is indispensable for HIV-1 replication and has become a validated target for developing anti-AIDS agents. In two decades of development of IN inhibition-based anti-HIV therapeutics, a significant number of compounds were identified as IN inhibitors, but only some of them showed antiviral activity. This article reviews a number of patented HIV-1 IN inhibitors, especially those that possess high selectivity for the strand transfer reaction. These compounds generally have a polar coplanar moiety, which is assumed to chelate two magnesium ions in the binding site. Resistance to those compounds, when given to patients, can develop as a result of IN mutations. We refer to those compounds as authentic IN inhibitors. Continued drug development has so far delivered one authentic IN inhibitor to the market (raltegravir in 2007). Current and future attention will be focused on the development of novel authentic IN inhibitors with the goal of overcoming viral resistance.
Liao, Chenzhong; Marchand, Christophe; Burke, Terrence R; Pommier, Yves; Nicklaus, Marc C
HIV Medicine is an online medical textbook that provides comprehensive and timely information on HIV treatment. Chapters include background information on Acute HIV-1 Infection, and a detailed guide to HIV Therapy. There is also current information about side effects, Lipodystrophy Syndrome, and resistance testing. The online textbook includes an impressive, in-depth index of HIV drugs. Editors Christian Hoffmann and Bernd Sebastian Kamps have years of experience in the medical field and provide free and anonymous access of their text to the public. Collaborators include Nyasha Bakare, MD who has worked at the Research Institute for Genetic and Human Therapy (RIGHT) since 2001, and has been working on the clinical development of a therapeutic HIV vaccine. This Web site is easy to navigate and its layout nicely mirrors the organization of a paper textbook. It will be useful as a research tool for college and graduate students as well as for the layperson who desires more in-depth information on HIV and treatments. Join the mailing list to be notified of new chapters and updates. [TJS
Hoffmann, Christian; Kamps, Bernd S.
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.
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'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.
Lee, Stephen; Ruegsegger, Mark; Barnes, Philip; Smith, Bryan; Ferrari, Mauro
Unless proper perspective is maintained in medical therapeutics, a physician in his earnest desire to cure disease may often use measures which may ultimately cause more damage than the disease being treated. In order to avoid loss of perspective, it is necessary to balance the known consequences of the disease against the expected benefits of the treatment minus the known hazards of the treatment.
Scholtz, Jud R.; Williamson, Craig
Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return and swelling of the extremities. Lymphedema is divided into primary and secondary forms based on the underlying etiology. Despite substantial advances in both surgical and conservative techniques, therapeutic options for the management of lymphedema are limited. Although rarely lethal, lymphedema is a disfiguring and disabling condition with an associated decrease in the quality of life. The recent impressive expansion of knowledge on the molecular mechanisms governing lymphangiogenesis provides new possibilities for the treatment of lymphedema. This review highlights the lymphatic biology, the pathophysiology of lymphedema, and the therapeutic lymphangiogenesis using hepatocyte growth factor.
Nakagami, Hironori; Kaneda, Yasufumi; Morishita, Ryuichi
Purpose of review This review highlights recent studies undertaken to further advance the search for successful approaches to eradicate HIV infection. Recent findings Small pharmacological compounds such as histone deacetylase inhibitors, inhibitors of bromodomain and extraterminal proteins such as JQ1, and protein kinase C activators such as bryostatin and prostratin are proposed as putative candidates for inducing the expression of latent HIV in a so-called ‘shock and kill’ or ‘kick and kill’ strategy for HIV eradication. However, in order to achieve viral clearance, it is thought likely these compounds will have to be administered in concert with strategies that augment clearance of virus-infected cells in patients that have long been aviremic on successful antiretroviral therapy (ART). Several candidate therapies for this purpose are at hand, such as therapeutic HIV vaccines – recently shown to promote robust cytotoxic T cell responses and blunt viral rebound after ART interruption in clinical studies. HIV-infected patients treated during early infection may be ideal candidates for early studies to test these strategies, as early ART has been shown to limit the establishment of an HIV reservoir. Summary HIV latency is multifactorial and thus the eradication of HIV infection may require multiple approaches. Translational efforts employing pharmacological methods to target HIV latency should evaluate in parallel the additional potential benefits of invigorating the immune response of HIV-infected individuals, and limiting the size of the reservoir via early ART.
Archin, Nancie M.; Margolis, David M.
Therapeutic mammaplasty is a term for the oncoplastic application of breast reduction and mastopexy techniques to treat selected breast tumours by breast conserving surgery (BCS). It has the potential to increase the indications for BCS as well as achieve more acceptable aesthetic results from it in suitable women. Now an established technique in the range of oncoplastic options for women with breast cancer, it finds common application and is associated with good oncological and quality of life outcomes. PMID:24889526
Macmillan, R D; James, R; Gale, K L; McCulley, S J
The association of immune dysfunction in patients with human immunodeficiency virus (HIV) infection and AIDS and the development of autoimmune diseases is intriguing. Yet, the spectrum of reported autoimmune phenomena in these patients is increasing. An infectious trigger for immune activation is one of the postulated mechanisms and derives from molecular mimicry. During frank loss of immunocompetence, autoimmune diseases that are predominantly T cell subtype CD8 driven predominate. There is evidence for B cell stimulation and many autoantibodies are reported in HIV patients. We propose a staging of autoimmune manifestations related to HIV/AIDS manifestations and the total CD4 count and viral load that may be beneficial in identifying the type of autoimmune disease and establishing the proper therapy. In stage I there is the acute HIV infection, and the immune system is intact. In this stage, autoimmune diseases may develop. Stage II describes the quiescent period without overt manifestations of AIDS. However, there is a declining CD4 count indicative of some immunosuppression. Autoimmune diseases are not found. During stage III there is immunosuppression with a low CD4 count and the development of AIDS. CD8 T cells predominant and diseases such as psoriasis and diffuse immune lymphocytic syndrome (similar to Sjogren's syndrome) may present or even be the initial manifestation of AIDS. Also during this stage no autoimmune diseases are found. In stage IV there is restoration of immune competence following highly active anti-retroviral therapy (HAART). In this setting, there is a resurgence of autoimmune diseases. The frequency of reported rheumatological syndromes in HIV-infected patients ranges from 1 to 60%. The list of reported autoimmune diseases in HIV/AIDS include systemic lupus erythematosus, anti-phospholipid syndrome, vasculitis, primary biliary cirrhosis, polymyosits, Graves' disease, and idiopathic thrombocytopenic purpura. Also, there is an array of autoantibodies reported in HIV/AIDS patients which include anti-cardiolipin, anti-beta2 GPI, anti-DNA, anti-small nuclear ribonucleoproteins (snRNP), anti-thyroglobulin, anti-thyroid peroxidase, anti-myosin, and anti-erythropoietin antibodies. The association of autoantibodies in HIV-infected patients to clinical autoimmune disease is yet to be established. With the upsurge of HAART, the incidence of autoimmune diseases in HIV-infected patients is increasing. In this review, we describe the various autoimmune diseases that develop in HIV/AIDS patients through possible mechanisms related to immune activation. PMID:12848988
Zandman-Goddard, Gisele; Shoenfeld, Yehuda
HIV-1-associated ocular complications, such as microvasculopathies, can lead to the loss of vision in HIV-1-infected patients. Even in patients under highly active antiretroviral therapy, ocular lesions are unavoidable. Ocular complications have been demonstrated to be closely related to the breakdown of the blood-retinal-barrier (BRB); however, the underlying mechanism is not clear. The data from this study indicated that the HIV-1 Tat protein induced the apoptosis of human retinal microvascular endothelial cells (HRMECs) and retinal pigmen epithelium (RPE) cells, which compose the inner BRB and the outer BRB, respectively. In addition, this study found that the activation of N-methyl-D-aspartate receptors (NMDARs) was involved in the apoptosis of RPE cells, but it caused no changes in HRMECs. Furthermore, both cell types exhibited enhanced expression of Bak, Bax and Cytochrome c. The inhibition of Tat activity protected against the apoptosis induced by NMDAR activation and prevented the dysregulation of Bak, Bax and Cytochrome c, revealing an important role for the mitochondrial pathway in HIV-1 Tat-induced apoptosis. Together, these findings suggest a possible mechanism and may identify a potential therapeutic strategy for HIV-1-associated ocular complications. PMID:24739951
Che, Xin; He, Fanglin; Deng, Yuan; Xu, Shiqiong; Fan, Xianqun; Gu, Ping; Wang, Zhiliang
HIV-1-associated ocular complications, such as microvasculopathies, can lead to the loss of vision in HIV-1-infected patients. Even in patients under highly active antiretroviral therapy, ocular lesions are unavoidable. Ocular complications have been demonstrated to be closely related to the breakdown of the blood-retinal-barrier (BRB); however, the underlying mechanism is not clear. The data from this study indicated that the HIV-1 Tat protein induced the apoptosis of human retinal microvascular endothelial cells (HRMECs) and retinal pigmen epithelium (RPE) cells, which compose the inner BRB and the outer BRB, respectively. In addition, this study found that the activation of N-methyl-D-aspartate receptors (NMDARs) was involved in the apoptosis of RPE cells, but it caused no changes in HRMECs. Furthermore, both cell types exhibited enhanced expression of Bak, Bax and Cytochrome c. The inhibition of Tat activity protected against the apoptosis induced by NMDAR activation and prevented the dysregulation of Bak, Bax and Cytochrome c, revealing an important role for the mitochondrial pathway in HIV-1 Tat-induced apoptosis. Together, these findings suggest a possible mechanism and may identify a potential therapeutic strategy for HIV-1-associated ocular complications.
Che, Xin; He, Fanglin; Deng, Yuan; Xu, Shiqiong; Fan, Xianqun; Gu, Ping; Wang, Zhiliang
Antiretroviral therapy has transformed the management of HIV-infected individuals over the past quarter century. However, important challenges remain. These include attempts to eradicate HIV from reservoirs within the body, thereby eliminating the need for lifetime therapy. In addition, improvements in drug development, clinical trial, and regulatory pathways are necessary to expeditiously evaluate novel therapeutic regimens and strategies. Antiretroviral drug scarcity remains a major problem in underserved populations worldwide, and partnerships among pharmaceutical companies, academic investigators, and both governmental and nongovernmental agencies are necessary to improve access to these life-saving regimens. PMID:22772389
Hirsch, Martin S; Kuritzkes, Daniel R
Background Ultrasound can rapidly identify abnormal signs, which in high prevalence settings, are highly suggestive of extra-pulmonary tuberculosis (EPTB). Unfortunately experienced sonographers are often scarce in these settings. Methods A protocol for focused assessment with sonography for HIV-associated tuberculosis (FASH) which can be used by physicians who are relatively inexperienced in ultrasound was developed. Results The technique as well as normal and pathological findings are described and the diagnostic and possible therapeutic reasoning explained. The protocol is intended for settings where the prevalence of HIV/TB co-infected patients is high. Conclusion FASH is suitable for more rapid identification of EPTB even at the peripheral hospital level where other imaging modalities are scarce and most of the HIV and TB care will be delivered in the future.
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.
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
The goal of antiretroviral therapy for the prevention of mother-to-child transmission (PMTCT) of HIV is to achieve maximal suppression of maternal viral load with minimal maternal, fetal and infant toxicity during pregnancy, delivery and postpartum. In addition to the efficacy and toxicity of antiretroviral therapy, the consideration of HIV resistance in mothers and infected newborns further complicates therapeutic choices for PMTCT. This manuscript summarizes current approaches to PMTC in diverse international settings. PMID:24709447
Rakhmanina, Natella Y; van den Anker, Johannes N
Human immunodeficiency virus type 1 (HIV-1) primarily infects CD4+ T cells and cells of the monocyte-macrophage lineage, resulting in immunodeficiency in an infected patient. Along with this immune deficiency, HIV-1 has been linked to a number of neurological symptoms in the absence of opportunistic infections or other co-morbidities, suggesting that HIV-1 is able to cross the blood-brain barrier (BBB), enter the central nervous system (CNS), and cause neurocognitive impairment. HIV-1-infected monocyte-macrophages traverse the BBB and enter the CNS throughout the course of HIV-1 disease. Once in the brain, both free virus and virus-infected cells are able to infect neighboring resident microglia and astrocytes and possibly other cell types. HIV-1-infected cells in both the periphery and the CNS give rise to elevated levels of viral proteins, including gp120, Tat, and Nef, and of host inflammatory mediators such as cytokines and chemokines. It has been shown that the viral proteins may act alone or in concert with host cytokines and chemokines, affecting the integrity of the BBB. The pathological end point of these interactions may facilitate a positive feedback loop resulting in increased penetration of HIV into the CNS. It is proposed in this review that the dysregulation of the BBB during and after neuroinvasion is a critical component of the neuropathogenic process and that dysregulation of this protective barrier is caused by a combination of viral and host factors including secreted viral proteins, components of the inflammatory process, the aging process, therapeutics, and drug or alcohol abuse.
Strazza, Marianne; Pirrone, Vanessa; Wigdahl, Brian; Nonnemacher, Michael R.
Antiretroviral therapy 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 has 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 have recently been shown to have persistence that outperforms chimeric antigen receptors 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 are available highlight the potential for T-cell therapy to decrease or eliminate HIV patients' dependency on antiretroviral therapy. PMID:23557423
Lam, Sharon; Bollard, Catherine
Describes a continuous differential equation model of the interaction dynamics of HIV-1 and CD4 and CD8 lymphocytes in the human body. The authors demonstrate several methods of stable control of the HIV-1 population using an external feedback control term that is analogous to the introduction of a therapeutic drug regimen. They also show how the immune system components can be
Michael E. Brandt; Guanrong Chen
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
Silvia Peretti; Ilaria Schiavoni; Katherina Pugliese; Maurizio Federico
In the ideal situation, use of WHO therapeutic guidelines for management of severe mal- nutrition 5 and a continuum of care for malnourished chil- dren 6 through community therapeutic care programmes would successfully improve survival in children without HIV infection. An alarming consequence of the HIV epidemic is an increase in the need by severely malnourished, seriously ill children for
Geert Tom Heikens; James Bunn FRCPCH; Beatrice Amadi MMedPaeds; Meera Chhagan FCPaed; James A Berkley MRCP; Nigel Rollins FRCPCH; Paul Kelly FRCP; Kathryn Maitland MRCP; Andrew Tomkins FMedSci
Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS.
McCance-Katz, Elinore F.
Pregnancy in substance-abusing women with HIV/AIDS presents a complex clinical challenge. Opioid-dependent women need treatment with opioid therapy during pregnancy to protect the health of mother and developing fetus. However, opioid therapies, methadone and buprenorphine, may have drug interactions with some HIV medications that can have adverse effects leading to suboptimal clinical outcomes. Further, many opioid-dependent individuals have problems with other forms of substance abuse, for example, cocaine abuse, that could also contribute to poor clinical outcomes in a pregnant woman. Physiological changes, including increased plasma volume and increased hepatic and renal blood flow, occur in the pregnant woman as the pregnancy progresses and may alter medication needs with the potential to exacerbate drug interactions, although there is sparse literature on this issue. Knowledge of possible drug interactions between opioids, other abused substances such as cocaine, HIV therapeutics, and other frequently required medications such as antibiotics and anticonvulsants is important to assuring the best possible outcomes in the pregnant woman with opioid dependence and HIV/AIDS. PMID:20965297
McCance-Katz, Elinore F
Due to considerable technical progress during the last few years the diagnosis of HIV-infection has been substantially improved. Third generation antibody screening assays, which also detect antibodies of the IgM and IgA type, have considerably narrowed the immunological window. The determination of the viral load in peripheral blood employing nucleic acid amplification techniques is now generally available and used for diagnostic and prognostic purposes as well as for the monitoring of antiviral therapy. To detect a HIV-infection the antibody screening assay is primarily used and complemented by the HIV-1 p24 antigen assay provided an early primary infection is suspected. In the latter case the antibody screening assay is often negative or indeterminate, while the p24 antigen assay is positive. According to the 1998 guidelines of the Federal Office for Public Health, the physician will be informed of the screening assay result without the need to await a confirmatory test in case of a reactive screening assay in the first sample. Confirmation, e.g. by immunoblot, will be done in a second blood sample which should be sent to the laboratory as soon as possible. EDTA-blood is recommended for this purpose, because it is best suited for quantification of plasma viremia, which has become a prerequisite for the institution and follow-up of antiretroviral treatment. The second sample will also serve to exclude false positive results due to clerical errors, and to determine the type of HIV, i.e. HIV-1 or HIV-2. The concept outlined should accelerate the availability of reactive test results to the physician and should reduce the cost of the diagnostic procedure. PMID:9643124
Erb, P; Matter, L
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.
Manjunath, N.; Yi, Guohua; Dang, Ying; Shankar, Premlata
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.
Spreen, William R.; Margolis, David A.; Pottage, John C.
Background The Cuban HIV/AIDS epidemic has the lowest prevalence rate of the Caribbean region. The objective of this paper is to give an overview of the HIV/AIDS epidemic in Cuba and to explore the reasons for this low prevalence. Methods Data were obtained from the Cuban HIV/AIDS programme established in 1983. This programme has an extensive adult HIV testing policy, including testing of all pregnant women. HIV and AIDS cases have been recorded since 1986. Persons found to be HIV-positive are interviewed on their sexual behaviour and partners. Tracing and voluntary testing of these partners are organised. Epidemiological description of this epidemic was obtained from analysis of this data set. Using elementary mathematical analyses, we estimated the coverage of the detection system (percentage of HIV-positive adults detected) and the average period between HIV infection and detection. Estimated HIV prevalence rates were corrected to account for the coverage. Results HIV prevalence has increased since 1996. In 2005, the prevalence among pregnant women was 1.2 per 10,000 (16/137000). Estimated HIV prevalence among 15- to 49-year-olds was 8.1 per 10,000 (4913/6065000; 95%CI: 7.9 per 10,000 – 8.3 per 10,000). Most (77%) of the HIV-positive adults were men, most (85.1%) of the detected HIV-positive men were reported as having sex with men (MSM), and most of the HIV-positive women reported having had sex with MSM. The average period between HIV infection and detection was estimated to be 2.1 years (IQR = 1.7 – 2.2 years). We estimated that, for the year 2005, 79.6% (IQR: 77.3 – 81.4%) of the HIV-positive persons were detected. Conclusion MSM drive the HIV epidemic in Cuba. The extensive HIV testing policy may be an important factor in explaining the low HIV prevalence. To reduce the HIV epidemic in Cuba, the epidemic among MSM should be addressed. To understand this epidemic further, data on sexual behaviour should be collected. Now that antiretroviral therapy is more widely available, the Cuban policy, based on intensive HIV testing and tracing of partners, may be considered as a possible policy to control HIV/AIDS epidemics in other countries.
de Arazoza, Hector; Joanes, Jose; Lounes, Rachid; Legeai, Camille; Clemencon, Stephan; Perez, Jorge; Auvert, Bertran
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.
Duverger, Alexandra; Wolschendorf, Frank; Anderson, Joshua C.; Wagner, Frederic; Bosque, Alberto; Shishido, Takao; Jones, Jennifer; Planelles, Vicente; Willey, Christopher; Cron, Randall Q.
Introduction: the importance of neuropsycological manifestations as was to identify the presence of HIV-1 in Central Nervous System. Objectives: to evaluate possible correlation among HIV-1 in central nervous system (CNS), pathological mechanism, protection of CNS and cognitive neurops- ychological disorders. To identify the existence or lack of cognitive neuropsychological symptoms and their importance as HIV-1 enters CNS. Method: systematic review
Rosangela S Kalil; Pierre G Bauer; Ivete A Espíndola-Pereira; Fernando RA Ferry; Rogério N Motta; José Ramon
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 ?-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca2+ mobilization, ?-arrestin-1 and ?-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.
Hudson, Brian D.; Shimpukade, Bharat; Mackenzie, Amanda E.; Butcher, Adrian J.; Pediani, John D.; Christiansen, Elisabeth; Heathcote, Helen; Tobin, Andrew B.; Ulven, Trond
The Science Inside: HIV and AIDSThis booklet helps to explain what doctors and scientists know about the HIV and AIDS epidemic. It summarizes what HIV and AIDS are and what happens when HIV becomes AIDS, including the health problems that can result. The e-book explains how the diseases are spread, what groups suffer most from them, how they may be prevented, how they are treated, and what the latest research reveals.The Science Inside e-book series is intended to be a bridge between the consumer health brochure and the scientific paper, the booklets in this series focus on the science that is inside of, or behind, the disease its cause, its possible cure, its treatment, promising research, and so on. These booklets are designed to appeal to people who have not had the opportunity to study the science and to understand why they may have been given some of the advice that they have been given through some of the more consumer-oriented materials.
American Association for the Advancement of Science (;)
HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV-1/host cell and opens new possibilities for antiviral strategies.
Rato, Sylvie; Maia, Sara; Brito, Paula M.; Resende, Leonor; Pereira, Carina F.; Moita, Catarina; Freitas, Rui P.; Moniz-Pereira, Jose; Hacohen, Nir; Moita, Luis Ferreira; Goncalves, Joao
The present paper describes the possible connection between alcohol consumption and adherence to medicine used to treat human deficiency viral (HIV) infection. Highly active antiretroviral therapy (HAART) has a positive influence on longevity in patients with HIV, substantially reducing morbidity and mortality, including resource-poor settings such as South Africa. However, in a systematic comparison of HAART outcomes between low-income and high-income countries in the treatment of HIV-patients, mortality was higher in resource-poor settings. Specifically, in South Africa, patients often suffer from concomitant tuberculosis and other infections that may contribute to these results. Alcohol influences the use of medicine for opportunistic infections (e.g., pneumonia, tuberculosis), or coinfections HIV-hepatitis viruses-B (HBV) and C (HCV), cytomegalovirus, or herpes simplex virus. Furthermore, alcohol use may negatively impact on medication adherence contributing to HIV progression. The materials used provide a data-supported approach. They are based on analysis of published (2006–2011) world literature and the experience of the authors in the specified topic. Intended for use by health care professionals, these recommendations suggest approaches to the therapeutic and preventive aspects of care. Our intention was to fully characterize the quality of evidence supporting recommendations, which are reflecting benefit versus risk, and assessing strength or certainty.
Neuman, Manuela G.; Schneider, Michelle; Nanau, Radu M.; Parry, Charles
Background Inhibitors of the HIV-1 Protease currently used in therapeutic protocols, have been found to inhibit, although at higher concentrations, the HIV-2 encoded enzyme homologue. Similar to observations in HIV-1 infected individuals, therapeutic failure has also been observed for some patients infected with HIV-2 as a consequence of the emergence of viral strains resistant to the anti-retroviral molecules. In order to be able to define the specific mutations in the Protease that confer loss of susceptibility to Protease Inhibitors, we set up an experimental model system based in the expression of the viral protein in yeast. Results Our results show that the HIV-2 Protease activity kills the yeast cell, and this process can be abolished by inhibiting the viral enzyme activity. Since this inhibition is dose dependent, IC50 values can be assessed for each anti-retroviral molecule tested. We then defined the susceptibility of HIV-2 Proteases to Protease Inhibitors by comparing the IC50 values of Proteases from 7 infected individuals to those of a sensitive wild type laboratory adapted strain. Conclusion This functional assay allowed us to show for the first time that the L90M substitution, present in a primary HIV-2 isolate, modifies the HIV-2 Protease susceptibility to Saquinavir but not Lopinavir. Developing a strategy based on the proposed yeast expressing system will contribute to define amino acid substitutions conferring HIV-2 Protease resistance.
M'Barek, Najoua Ben; Audoly, Gilles; Raoult, Didier; Gluschankof, Pablo
HIV-1 protease is one of the main therapeutic targets in HIV. However, a major problem in treatment of HIV is the rapid emergence of drug-resistant strains. It should be particularly helpful to clinical therapy of AIDS if one method can be used to predict antivirus capability of compounds for different variants. In our study, proteochemometric (PCM) models were created to
Qi Huang; Haixiao Jin; Qi Liu; Qiong Wu; Hong Kang; Zhiwei Cao; Ruixin Zhu
In this study we sought to characterize the relationship between several pharmacokinetic (PK) and pharmacodynamic (PD) parameters and virologic responses among HIV/HCV genotype-1 co-infected patients receiving pegylated interferon-alpha-2b (peg-IFN2b) and ribavirin. We also tried to establish the underlying mechanisms that lead to poor SVR rates observed with African Americans (AA) against Caucasians and compared their results with those observed in a cohort of HCV mono-infected patients. Among our studied population, a viral decline of more than 1.0 log at day 3 combined with viral load of less than 5.0 log IU/ml at day 28 predicted SVR with NPV=100% and PPV=100%. AA had significantly (P<0.01) slower HCV VK as compared to Caucasians. However, peg-IFN2b concentrations and PK parameters, peg-IFN2b max and peg-IFN2b half-life, were similar in both groups and did not predict SVR. Nevertheless, the PD parameter Ec50, estimated from non-linear fitting of the viral kinetics together with peg-IFN2b concentration data, showed that HIV/HCV co-infected AA have lower sensitivity to interferon-alpha thus giving rise to slower viral decline. The combined PK/PD parameter IFNmax/Ec90 was excellent predictor of SVR, thus showing the importance to maintain peg-IFN2b levels above Ec90 to achieve successful treatment. Further studies are needed to evaluate whether these pharmacodynamical predictions are a result of differential host response to peg-IFN2b or other viral factors conferring relative resistance to peg-IFN2b.
Rozenberg, L; Haagmans, BL; Neumann, AU; Chen, G.; McLaughlin, M; Levy-Drummer, RS; Masur, H; Dewar, RL; Ferenci, P; Silva, M.; Viola, MS; Polis, MA; Kottilil, S.
Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host. PMID:24759213
Kumar, Amit; Abbas, Wasim; Herbein, Georges
Sexual health is defined in terms of well-being, but is challenged by the social, cultural and economic realities faced by women and men with HIV. A sexual rights approach puts women and men with HIV in charge of their sexual health. Accurate, accessible information to make informed choices and safe, pleasurable sexual relationships possible is best delivered through peer education and health professionals trained in empathetic approaches to sensitive issues. Young people with HIV especially need appropriate sex education and support for dealing with sexuality and self-identity with HIV. Women and men with HIV need condoms, appropriate services for sexually transmitted infections, sexual dysfunction and management of cervical and anogenital cancers. Interventions based on positive prevention, that combine protection of personal health with avoiding HIV/STI transmission to partners, are recommended. HIV counselling following a positive test has increased condom use and decreased coercive sex and outside sexual contacts among discordant couples. HIV treatment and care have reduced stigma and increased uptake of HIV testing and disclosure of positive status to partners. High adherence to antiretroviral therapy and safer sexual behaviour must go hand-in-hand. Sexual health services have worked with peer educators and volunteer groups to reach those at higher risk, such as sex workers. Technological advances in diagnosis of STIs, microbicide development and screening and vaccination for human papillomavirus must be available in developing countries and for those with the highest need globally. PMID:17531749
Shapiro, Kathy; Ray, Sunanda
Human immunodeficiency virus type 1 (HIV-1) targets CD4+ T cells and cells of the monocyte/macrophage lineage. HIV pathogenesis is characterized by the depletion of T lymphocytes and by the presence of a population of cells in which latency has been established called the HIV-1 reservoir. Highly active antiretroviral therapy (HAART) has significantly improved the life of HIV-1 infected patients. However, complete eradication of HIV-1 from infected individuals is not possible without targeting latent sources of infection. HIV-1 establishes latent infection in resting CD4+ T cells and findings indicate that latency can also be established in the cells of monocyte/macrophage lineage. Monocyte/macrophage lineage includes among others, monocytes, macrophages and brain resident macrophages. These cells are relatively more resistant to apoptosis induced by HIV-1, thus are important stable hideouts of the virus. Much effort has been made in the direction of eliminating HIV-1 resting CD4+ T-cell reservoirs. However, it is impossible to achieve a cure for HIV-1 without considering these neglected latent reservoirs, the cells of monocyte/macrophage lineage. In this review we will describe our current understanding of the mechanism of latency in monocyte/macrophage lineage and how such cells can be specifically eliminated from the infected host.
Kumar, Amit; Abbas, Wasim; Herbein, Georges
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.
Schutz, Sonja G; Robinson-Papp, Jessica
The success of antiretroviral therapies in improving the survival of patients infected with HIV and reducing HIV-associated opportunistic infections is undisputed. Nevertheless, long-term outcomes such as noninfectious cardiovascular complications, including cardiomegaly, pericarditis, myocarditis, and pulmonary arterial hypertension, are now serious concerns. The lung is a frequent target organ for disorders associated with HIV infection. HIV-related pulmonary arterial hypertension (HRPAH) affects more individuals who are infected with HIV than individuals who are uninfected. Moreover, the long-standing estimated prevalence of HRPAH in developed countries (calculated at 0.5%) is increasing as more clinician-scientists unify their efforts to screen patients who are pulmonary asymptomatic for pulmonary arterial hypertension. In order to decrease mortality, efforts are directed at early detection, diagnosis, and therapeutic interventions before the disease compromises patients’ quality of life. This article reviews the logistics of screening approaches for HRPAH and discusses the substantial disease burden currently faced by developing countries, where the prevalence of HIV infection is higher and complicated by hyperendemic risk factors, limited access to antiretrovirals, and lack of screening tools. We also present mechanistic insights into HRPAH, including the role of HIV proteins and their potential use as screening tools, and, finally, areas that still need intense research.
Cicalini, Stefania; Petrosillo, Nicola; Flores, Sonia C.
Human immunodeficiency virus type 1(HIV-1) infection is the leading cause of death worldwide in adults attributable to infectious diseases. Although the majority of infections are in sub-Saharan Africa and Southeast Asia, HIV-1 is also a major health concern in most countries throughout the globe. While current antiretroviral treatments are generally effective, particularly in combination therapy, limitations exist due to drug resistance occurring among the drug classes. Traditionally, HIV-1 drugs have targeted viral proteins, which are mutable targets. As cellular genes mutate relatively infrequently, host proteins may prove to be more durable targets than viral proteins. HIV-1 replication is dependent upon cellular proteins that perform essential roles during the viral life cycle. Maraviroc is the first FDA-approved antiretroviral drug to target a cellular factor, HIV-1 coreceptor CCR5, and serves to intercept viral-host protein-protein interactions mediating entry. Recent large-scale siRNA and shRNA screens have revealed over 1000 candidate host factors that potentially support HIV-1 replication, and have implicated new pathways in the viral life cycle. These host proteins and cellular pathways may represent important targets for future therapeutic discoveries. This review discusses critical cellular factors that facilitate the successive steps in HIV-1 replication. PMID:21871504
Friedrich, Brian M; Dziuba, Natallia; Li, Guangyu; Endsley, Mark A; Murray, James L; Ferguson, Monique R
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
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
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.
Tyagi, Mudit; Bukrinsky, Michael
BACKGROUND: This study aimed to determine the therapeutic effects of highly active anti-retroviral therapy (HAART) on the clinical presentations of HIV related oral lesions (HIV-ROLs) in an adult Nigerian population. METHODS: A 5 month prospective study on HAART naïve HIV positive adults recruited into the HAART program of an AIDS referral centre. HIV-ROLs were diagnosed clinically by the EEC Clearinghouse
Olaniyi O Taiwo; Zuwaira Hassan
The National Cancer Institute, Laboratory of Cellular Oncology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize therapeutics for diseases or conditions associated with target receptors, such as cancer, angiogenesis, or HIV infections.
Demandas reprodutivas e a assistência às pessoas vivendo com HIV\\/AIDS: limites e possibilidades no contexto dos serviços de saúde especializado s Reproductive demands and health care for people living with HIV\\/AIDS: limits and possibilities within the context of specialized health service s
This qualitative study discusses how professionals in specialized health care service s in the city of São Paulo have responded to the reproductive demands of people living wit h HIV\\/AIDS. Participant observation was the main methodological strategy; the concept of healt h demands was an important theoretical reference in the analysis. According to the health profe s - sionals, reproductive
Luzia Aparecida Oliveira; Ivan França Junior
Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells.
Burke, Bryan P.; Boyd, Maureen P.; Impey, Helen; Breton, Louis R.; Bartlett, Jeffrey S.; Symonds, Geoff P.; Hutter, Gero
Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection-this without detrimental effects to the host-and transplantation of CCR5-delta32 stem cells in a patient with HIV ("Berlin patient") achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase I/II trials by engineering HIV-resistant hematopoietic cells. PMID:24381033
Burke, Bryan P; Boyd, Maureen P; Impey, Helen; Breton, Louis R; Bartlett, Jeffrey S; Symonds, Geoff P; Hütter, Gero
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
Husstedt, I W; Böckenholt, S; Kammer-Suhr, B; Evers, S
A 45-year-old male active homosexual was given a diagnosis of HIV-1 and acute hepatitis B in August 2007. Since his liver function became rapidly impaired, anti-HBV therapy with oral administration of entecavir (ETV) was started, and resulted in a favorable outcome. However, serum concentration of HIV-RNA decreased by log 1.26 within 60 days, which strongly suggested the inhibition of HIV proliferation by ETV. To prevent the appearance of mutated HIV, novel therapeutic strategies should be established in HIV/HBV-coinfected patients. PMID:19966518
Yamada, Akihiro; Sako, Akahito; Nishimura, So; Nakashima, Ryo; Ogami, Toshiko; Fujiya, Keiichi; Tsuda, Naonori; Asayama, Naoki; Yada, Tomoyuki; Shirai, Kiyokazu; Akazawa, Naoki; Sakurai, Toshiyuki; Yago, Yuzo; Nagata, Naoyoshi; Oshima, Takao; Yokoi, Chizu; Sasajima, Keita; Kobayakawa, Masao; Akiyama, Junichi; Imamura, Masatoshi; Yanase, Mikio; Uemura, Naomi; Masaki, Naohiko
A human immunodeficiency virus (HIV) vaccine remains a central component in the quest to control the worldwide epidemic. To examine the status of the development of HIV vaccines, we review the results of the efficacy trials carried out to date and the immunologic principles that guided them. Four vaccine concepts have been evaluated in HIV-1 vaccine efficacy trials, and the results of these trials have provided significant information for future vaccine development. While one of these trials demonstrated that a safe and effective HIV vaccine is possible, many questions remain regarding the basis for the observed protection and the most efficient way to stimulate it. Novel HIV vaccine strategies including induction of highly potent broadly neutralizing antibodies, use of novel homologous and heterologous vector systems, and vectored immunoprophylaxis seek to expand and build upon the knowledge gained from these trials.
Over the past 15 years, antiretroviral treatment guidelines for HIV infection have evolved significantly, reflecting the major advances in this therapeutic area. Evidenced-based recommendations have largely replaced expert opinion, while diagnostic monitoring and therapeutic interventions have become more sophisticated and effective. Just 10 years ago, there was a marked difference in access to antiretroviral therapy for patients in wealthy and impoverished countries. The increasing availability of therapy across the globe, however, has made it possible for international guidelines to resemble more closely those in high-income countries. This article compares the evolution of antiretroviral therapy treatment guidelines from the United States Department of Health and Human Services and the World Health Organization, focusing on when to initiate ART in asymptomatic patients and in those with an opportunistic infection; initial regimens in the general population and in special populations; when to change and what to change; and laboratory monitoring. PMID:24374148
Richardson, Eugene T; Grant, Philip M; Zolopa, Andrew R
Treatment of cancer is a double-edged sword: it should be as aggressive as possible to completely destroy the tumour, but it is precisely this aggressiveness which often causes severe side effects — a reason why some promising therapeutics can not be applied systemically. In addition, therapeutics such as cytokines that physiologically function in a para- or autocrine fashion require a
David Schrama; Ralph A. Reisfeld; Jürgen C. Becker
While there has been remarkable progress in understanding the biology of HIV-1 and its recognition by the human immune system, we have not yet developed an efficacious HIV-1 vaccine. Vaccine challenges include the genetic diversity and mutability of HIV-1 which create a plethora of constantly changing antigens, the structural features of the viral envelope glycoprotein that disguise conserved receptor-binding sites from the immune system, and the presence of carbohydrate moieties that shield potential epitopes from antibodies. Despite these challenges, there has been significant scientific progress in recent years. In 2009, a large-scale clinical trial known as RV144 demonstrated that a HIV-1 vaccine could modestly reduce the incidence of HIV-1 infection. Further, the identification of broadly neutralizing monoclonal antibodies (such as VRC01, a human monoclonal antibody capable of neutralizing over 90% of natural HIV-1 isolates, as well as PG and PGT antibodies that recognize conserved glycopeptide epitopes) has revealed new opportunities for vaccine design. Our ability to understand HIV-1 structure and antibody epitopes at the atomic level, the rapid advance of computational and bioinformatics approaches to immunogen design, and our newly acquired knowledge that it is possible for a vaccine to reduce the risk of HIV-1 infection, have all opened up new and promising pathways towards the development of an urgently needed effective HIV-1 vaccine. This article summarizes challenges to the development of an HIV-1 vaccine, lessons learned from scientific investigation and completed vaccine trials, and promising developments in HIV-1 vaccine design.
Kwong, Peter D; Mascola, John R; Nabel, Gary J
Until now, decisions about how to allocate ART have largely been based on maximising the therapeutic benefit of ART for patients. Since the results of the HPTN 052 study showed efficacy of antiretroviral therapy (ART) in preventing HIV transmission, there has been increased interest in the benefits of ART not only as treatment, but also in prevention. Resources for expanding
Wim Delva; Jeffrey W. Eaton; Fei Meng; Christophe Fraser; Richard G. White; Peter Vickerman; Marie-Claude Boily; Timothy B. Hallett
According to CD28 molecule expression, CD8+ T cells can be classed as CD28bright, CD28dim, and CD28-. The CD28dim T cells were found to derive from mitogenic stimulated CD28-T cells but also from CD28bright T cells through a mechanism of CD28 down-modulation. Moreover, after prolonged in vitro interleukin-2 stimulation, clonal CD28bright, cells showed a CD28dim expression before further evolution to a stable CD28-phenotype. This loss was concomitant with the disappearance of CD28 mRNA. A study of the cytokine production pattern revealed that CD28dim and CD28- T cell clones produced similar levels of type 1 and type 2 cytokines, which differed from those produced by the CD28bright T cell clones. A high percentage of CD28dim and CD28- cells, with similarities in their cytokine production pattern, were found in the blood samples of HIV-infected patients, as compared to healthy donors. The CD28 down-modulation may account for the increased number of CD8+CD28- T cells in HIV-infected patients. PMID:10331493
Fiorentini, S; Malacarne, F; Ricotta, D; Licenziati, S; Solis, A A; Ausenda, S; De Francesco, M; Garrafa, E; Simonini, A; Imberti, L; Balsari, A; Turano, A; Caruso, A
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
Miró, José M; Blanes, Marino; Norman, Francesca; Martín-Dávila, Pilar
OBJECTIVES: This study identified age-related differences in diagnosis and progression of HIV by analyzing a nationally representative sample of HIV-infected adults under care in the United States. METHODS: We compared older (> or = 50 years) and younger participants stratified by race/ethnicity. Regression models controlled for demographic, therapeutic, and clinical factors. RESULTS: Older non-Whites more often had HIV diagnosed when they were ill. Older and younger patients were clinically similar. At baseline, however, older non-Whites had fewer symptoms and were less likely to have AIDS, whereas at follow-up they had a trend toward lower survival. CONCLUSIONS: Later HIV diagnosis in non-Whites merits public health attention; clinical progression in this group requires further study.
Zingmond, D S; Wenger, N S; Crystal, S; Joyce, G F; Liu, H; Sambamoorthi, U; Lillard, L A; Leibowitz, A A; Shapiro, M F; Bozzette, S A
Soluble forms (sCD4) of human CD4, the HIV-1 primary receptor, are potent HIV-1 entry inhibitors. Both four-domain (D1-4) and two-domain (D1D2) sCD4 and their fusion proteins have been tested as candidate therapeutics in animal models and in human clinical trials and were well tolerated by patients with no significant clinical or immunologic toxicities and exhibited significant inhibitory activities. However, their activities were transient and the virus rapidly rebound.
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.
HIV-1-associated dementia (HAD)-relevant proinflammatory cytokines robustly induce astrocyte tissue inhibitor of metalloproteinases-1 (TIMP-1). As TIMP-1 displays pleotropic functions, we hypothesized that TIMP-1 expression may serve as a neuroprotective response of astrocytes. Previously, we reported that chronically activated astrocytes fail to maintain elevated TIMP-1 expression, and TIMP-1 levels are lower in the brain of HAD patients; a phenomenon that may contribute to central nervous system pathogenesis. Further, the role of TIMP-1 as a neurotrophic factor is incompletely understood. In this study, we report that staurosporine (STS) and HIV-1ADA virus, both led to induction of apoptosis in cultured primary human neurons. Interestingly, cotreatment with TIMP-1 protects neurons from apoptosis and reverses neuronal morphological changes induced by these toxins. Further, the anti-apoptotic effect was not observed with TIMP-2 or -3, but was retained in a mutant of the N-terminal TIMP-1 protein with threonine-2 mutated to glycine (T2G) that is deficient in matrix metalloproteinase (MMP)-1, -2 and -3 inhibitory activity. Therefore, the mechanism is specific to TIMP-1 and partially independent of MMP-inhibition. Additionally, TIMP-1 modulates the Bcl-2 family of proteins and inhibits opening of mitochondrial permeability transition pores induced by HIV-1 or STS. Together, these findings describe a novel function, mechanism and direct role of TIMP-1 in neuroprotection, suggesting its therapeutic potential in HAD and possibly in other neurodegenerative diseases.
Ashutosh; Chao, C; Borgmann, K; Brew, K; Ghorpade, A
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-/-?c-/- 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.
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
Since its discovery in 1983, a lot of knowledge about the human immunodeficiency virus (HIV) has been accumulated. Our paper gives a brief survey on what is known at present about the structure, molecular biology, and the cell tropism of this virus. We discuss its relationship to other lentiviruses as well as its possible origin; in addition, we refer to the immune response to HIV and its interactions with the infected host. We also briefly summarize the difficulties encountered in the attempts to produce a vaccine against HIV and highlight some promising approaches in the development of such a vaccine. PMID:2205059
Schulz, T F; Larcher, C; Dierich, M P
Abstract—We describe a continuous differential equation model of the interaction dynamics of HIV-1 and CD4 and CD8 lympho- cytes in the human body. We demonstrate several methods of stable control of the HIV-1 population using an external feedback control term that is analogous to the introduction of a therapeutic drug regimen. We also show how the immune,system components can be
Michael E. Brandt; Guanrong Chen
HIV type-1 (HIV-1) accounts for more than 25 million deaths and nearly 40 million people are infected worldwide. A significant obstacle in clearing virus from infected individuals is latently infected viral reservoirs. Latent HIV-1 can emerge with recrudescence as a productive infection later in disease progression and could provide a source for the emergence of resistant HIV-1. It is widely recognized that macrophages represent a latently infected viral reservoir and are a significant and critical HIV-1 target cell in vivo. Macrophages can be divided into multiple subsets of macrophage-like cells, all of which are susceptible to HIV-1 infection, including dendritic cells, Langerhans cells, alveolar macrophages, mucosal macrophages and microglial cells. Current antiretroviral therapy (ART) often displays differential antiviral activity in macrophages relative to CD4+ T-lymphocytes. Significant work has been performed to establish antiviral activity of many clinically approved ART in macrophages; however, a direct link between antiviral activity and specific mechanisms responsible for these antiviral effects are incompletely understood. This review identifies many understudied areas of research, along with topics for further research in the field of HIV therapy and eradication. Discussion focuses upon the known cellular pharmacology and antiviral activity of antiretroviral agents in macrophages and its relationship to latency, chronic HIV-1 infection and therapeutic strategies to eradicate systemic HIV-1 infection.
Gavegnano, Christina; Schinazi, Raymond F
Older individuals (? 50 years of age) are increasingly becoming a new at-risk group for HIV-1 infection and, together with those surviving longer due to the introduction of anti-retroviral therapy (ART), it is predicted that more than half of all HIV-1-infected individuals in the U.S. will be greater than 50 years of age in the year 2015. Older individuals diagnosed with HIV-1 are prone to faster disease progression and reduced T-cell reconstitution despite successful virologic control with anti-retroviral therapy (ART). There is also growing evidence that the T-cell compartment in HIV-1+ adults displays an aged phenotype and HIV-1-infected individuals are increasingly diagnosed with clinical conditions more commonly seen in older uninfected persons. As aging in the absence of HIV infection is associated with alterations in T-cell function and immunosenescence, the combined impact of both HIV-1 infection and aging may provide an explanation for poorer clinical outcomes observed in older HIV-1-infected individuals. Thus, the development of novel therapeutics to stimulate immune function and delay immunosenescence is critical and would be beneficial to both the elderly and HIV-1 infected individuals.
Rickabaugh, Tammy M.; Jamieson, Beth D.
The TREAT Asia (Therapeutics, Research, Education, and AIDS Training in Asia) Network is building capacity for Human Immunodeficiency Virus Type-1 (HIV-1) drug resistance testing in the region. The objective of the TREAT Asia Quality Assessment Scheme – designated TAQAS – is to standardize HIV-1 genotypic resistance testing (HIV genotyping) among laboratories to permit rigorous comparison of results from different clinics
Sally Land; Philip Cunningham; Jialun Zhou; Kevin Frost; David Katzenstein; Rami Kantor; Yi-Ming Arthur Chen; Shinichi Oka; Allison DeLong; David Sayer; Jeffery Smith; Elizabeth M. Dax; Matthew Law
The aim of this paper was to develop a consensus on clinical recommendations for health care assistance for women with HIV infection. To this end, a panel of experts, appointed by the Secretariat of the National AIDS Plan and GeSIDA was assembled, that included internal medicine physicians with expertise in the field of HIV infection, gynecologists, pediatricians and psychologists, with two members of the panel acting as coordinators. Scientific information was reviewed in publications and conference reports up to October 2012. In keeping with the criteria of the Infectious Disease Society of America, two levels of evidence were applied to support the proposed recommendations: the strength of the recommendation according to expert opinion (A, B, C) and the level of empirical evidence (I, II, III), already used in previous documents from SPNS/GESIDA. Multiple recommendations are provided for the clinical management of women with HIV infection, considering both the diagnostic and possible therapeutic strategies. This document presents recommendations for the treatment of women with HIV infection. This must be multidisciplinary, taking into account the differences that can be found in the diagnosis, development of disease and treatment between men and women. PMID:23931832
Antiretroviral drug susceptibility tests facilitate therapeutic management of HIV-1-infected patients. Although genotyping systems are affordable, inaccuracy in the interpretation of complex mutational patterns may limit their usefulness. Currently available HIV-1 phenotypic assays are based on the generation of recombinant viruses in which the specific viral gene of interest, derived from a patient plasma sample, is cloned into a susceptible genetic viral backbone prior to in vitro drug susceptibility evaluation. Nevertheless, in the case of protease inhibitors, not only are mutations in the HIV-1 protease-coding region involved in resistance, but the role of Gag in drug susceptibility has also recently been reported. In order to avoid the inherent limitations resulting from partial cloning of the viral genome, we designed and evaluated a new experimental strategy to test the in vitro susceptibility of primary viral isolates to protease inhibitors. Our protocol, which is based on a two-round infection protocol using the reporter TZM-bl cell line, showed a good correlation with genotypic resistance prediction and with the Antivirogram phenotypic assay, in both protease-recombinant viruses and primary viral isolates. The protocol is suitable for any HIV-1 subtype and enables rapid in-house measurement of protease inhibitor susceptibility, thus making it possible to evaluate the concomitant effects of both patient-derived gag and protease-coding regions. PMID:23015664
Puertas, Maria C; Buzón, Maria J; Ballestero, Mònica; Van Den Eede, Peter; Clotet, Bonaventura; Prado, Julia G; Martinez-Picado, Javier
Antiretroviral drug susceptibility tests facilitate therapeutic management of HIV-1-infected patients. Although genotyping systems are affordable, inaccuracy in the interpretation of complex mutational patterns may limit their usefulness. Currently available HIV-1 phenotypic assays are based on the generation of recombinant viruses in which the specific viral gene of interest, derived from a patient plasma sample, is cloned into a susceptible genetic viral backbone prior to in vitro drug susceptibility evaluation. Nevertheless, in the case of protease inhibitors, not only are mutations in the HIV-1 protease-coding region involved in resistance, but the role of Gag in drug susceptibility has also recently been reported. In order to avoid the inherent limitations resulting from partial cloning of the viral genome, we designed and evaluated a new experimental strategy to test the in vitro susceptibility of primary viral isolates to protease inhibitors. Our protocol, which is based on a two-round infection protocol using the reporter TZM-bl cell line, showed a good correlation with genotypic resistance prediction and with the Antivirogram phenotypic assay, in both protease-recombinant viruses and primary viral isolates. The protocol is suitable for any HIV-1 subtype and enables rapid in-house measurement of protease inhibitor susceptibility, thus making it possible to evaluate the concomitant effects of both patient-derived gag and protease-coding regions.
Puertas, Maria C.; Buzon, Maria J.; Ballestero, Monica; Van Den Eede, Peter; Clotet, Bonaventura; Prado, Julia G.
INHIBITORS of the human immunodeficiency virus type 1 (HIV-1) protease have entered clinical study as potential therapeutic agents for HIV-1 infection. The clinical efficacy of HIV-1 reverse transcriptase inhibitors has been limited by the emergence of resistant viral variants. Similarly, variants expressing resistance to protease inhibitors have been derived in cell culture1-10. We now report the characterization of resistant variants
Jon H. Condra; William A. Schleif; Olga M. Blahy; Lori J. Gabryelski; Donald J. Graham; Julio Quintero; Audrey Rhodes; Helen L. Robbins; Elizabeth Roth; Malathi Shivaprakash; Donna Titus; Tao Yang; Hedy Tepplert; Kathleen E. Squires; Paul J. Deutsch; Emilio A. Emini
In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead. PMID:22592973
Tang, Chunlei; Liu, Yajuan; Wang, Bin; Gu, Guolong; Yang, Liumeng; Zheng, Yongtang; Qian, Hai; Huang, Wenlong
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.
Dhurve, Sharad A.; Dhurve, Alka S.
HIV-1 replication can be efficiently inhibited by intracellular expression of an siRNA targeting the viral RNA. We used a well-validated siRNA (si510) which targets the poly A/TAR (transactivator of the HIV-1 LTR) site and suppresses viral replication. Nanotechnology holds much potential for impact in the field of HIV-1 therapeutics, and nanoparticles such as quantum rods (QRs) can be easily functionalized to incorporate siRNA forming stable nanoplexes that can be used for gene silencing. We evaluated the efficacy of the QR-si510 HIV-1 siRNA nanoplex in suppressing viral replication in the HIV-1-infected monocytic cell line THP-1 by measuring p24 antigen levels and gene expression levels of HIV-1 LTR. Our results suggest that the QR-si510 HIV-1 siRNA nanoplex is not only effective in delivering siRNA, but also in suppressing HIV-1 viral replication for a longer time period. HIV-1 nanotherapeutics can thus enhance systemic bioavailability and offer multifunctionality.
Mahajan, Supriya D.; Aalinkeel, Ravikumar; Reynolds, Jessica L.; Nair, Bindukumar; Sykes, Donald E.; Law, Wing-Cheung; Ding, Hong; Bergey, Earl J.; Prasad, Paras N.; Schwartz, Stanley A.
The human immunodeficiency virus type 1 (HIV-1) promoter or long-terminal repeat (LTR) regulates viral gene expression by interacting with multiple viral and host factors. The viral transactivator protein Tat plays an important role in transcriptional activation of HIV-1 gene expression. Functional domains of Tat and its interaction with transactivation response element RNA and cellular transcription factors have been examined. Genetic variation within tat of different HIV-1 subtypes has been shown to affect the interaction of the viral transactivator with cellular and/or viral proteins, influencing the overall level of transcriptional activation as well as its action as a neurotoxic protein. Consequently, the genetic variability within tat may impact the molecular architecture of functional domains of the Tat protein that may impact HIV pathogenesis and disease. Tat as a therapeutic target for anti-HIV drugs has also been discussed.
Li, Luna; Dahiya, Satinder; Kortagere, Sandhya; Aiamkitsumrit, Benjamas; Cunningham, David; Pirrone, Vanessa; Nonnemacher, Michael R.; Wigdahl, Brian
HIV-1 infection of the brain results in a large number of behavioural defecits accompanied by diverse neuropathological signs. However,it is not clear how the virus produces these effects or exactly how the neuropathology and behavioural defecits are related. In this article we discuss the possibility that HIV-1 infection may negatively impact the process of neurogenesis in the adult brain and that this may contribute to HIV-1 related effects on the nervous system. We have previously demonstrated that the development of the dentate gyrus during embryogenesis requires signaling by the chemokine SDF-1 via its receptor CXCR4. We demonstrated that neural progenitor cells that give rise to dentate granule neurons express CXCR4 and other chemokine receptors and migrate into the nascent dentate gyrus along SDF-1 gradients. Animals deficient in CXCR4 receptors exhibit a malformed dentate gyrus in which the migration of neural progenitors is stalled. In the adult, neurogenesis continues in the dentate gyrus. Adult neural progenitor cells existing in the subgranlar zone, that produce granule neurons, express CXCR4 and other chemokine receptors, and granule neurons express SDF-1 suggesting that SDF-1/CXCR4 signaling is also important in adult neurogenesis. Because the cellular receptors for HIV-1 include chemokine receptors such as CXCR4 and CCR5 it is possible that the virus may interfere with SDF-1/CXCR4 signaling in the brain including disruption of the formation of new granule neurons in the adult brain.
Tran, Phuong B.; Miller, Richard J.
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.
Burnett, John C.; Rossi, John J.
Our survey of kidney and liver transplant centers in New York State found a wide variation among transplant centers in evaluation and screening for HIV risk and infection among prospective living donors. Survey results underscore the need to standardize practices. A recent transmission of human immunodeficiency virus (HIV) from a living donor to a kidney recipient revealed a possible limitation in existing screening protocols for HIV infection in living donors. We surveyed kidney and liver transplant centers (N = 18) in New York State to assess HIV screening protocols for living donors. Although most transplant centers evaluated HIV risk behaviors in living donors, evaluation practices varied widely, as did the extent of HIV testing and prevention counseling. All centers screened living donors for serologic evidence of HIV infection, either during initial evaluation or ?1 month before surgery; however, only 50% of transplant centers repeated HIV testing within 14 days before surgery for all donors or donors with specific risk behaviors. Forty-four percent of transplant centers used HIV nucleic acid testing (NAT) to screen either all donors or donors with recognized risk behaviors, and 55% never performed HIV NAT. Results suggest the need to standardize evaluation of HIV risk behaviors and prevention counseling in New York State to prevent acquisition of HIV by prospective living organ donors, and to conduct HIV antibody testing and NAT as close to the time of donation as possible to prevent HIV transmission to recipients. PMID:22752517
Kwan, Candice K; Al-Samarrai, Teeb; Smith, Lou C; Sabharwal, Charulata J; Valente, Kim A; Torian, Lucia V; McMurdo, Lisa M; Shepard, Colin W; Brooks, John T; Kuehnert, Matthew J
The success of new therapeutic procedures based on combination of antiretroviral components is driving the need of new care models for HIV/AIDS patients. This paper addresses the definition and implementation of an HIV/AIDS integral care model grounded on...
C. Caceres E. J. Gomez F. D. Pozo
BACKGROUND: In Tanzania, the International Working Formulation [WF] rather than the WHO Classification is still being used in diagnosing malignant lymphomas (ML) and the biological characterization including the HIV\\/EBV association is sketchy, thus restraining comparison, prognostication and application of established therapeutic protocols. METHODS: Archival, diagnostic ML biopsies (N = 336), available sera (N = 35) screened by ELISA for HIV
Amos R Mwakigonja; Ephata E Kaaya; Thomas Heiden; German Wannhoff; Juan Castro; Fatemeh Pak; Anna Porwit; Peter Biberfeld
HIV-1 integrase, the retroviral-encoded enzyme involved in the integration of the retrotranscribed viral genome into the host nuclear DNA, is an attractive and still unexploited target. To date, very few inhibitors of this enzyme with a potential therapeutic value have been described. During the search for new HIV-1 targets, we recently described DNA oligodeoxynucleotide aptamers (ODN 93 and ODN 112)
V. R de Soultrait; Pierre-Yves Lozach; Ralf Altmeyer; L Tarrago-Litvak; S Litvak; M. L Andréola
During the mid-1980s Australia experienced a remarkable decline in HIV incidence that can rightly be considered a public health milestone of global importance. The effects of this decline lasted for about 20 years and greatly benefited all Australians. In contrast, as we enter the mid-2000s, we see the global epidemic continues to intensify, HIV vaccines remain a distant possibility, and Australia is experiencing rising HIV incidence again. Clearly, better understanding of HIV prevention has important implications both for Australia and the world. Therefore, we believe, it is timely to revisit Australian experiences of the mid-1980s in order to understand those early events better. To gauge the influence (if any) of government strategies, funding levels and other events during a period of dramatic decline in HIV transmission, incidence figures are mapped against Federal HIV/AIDS funding patterns and the occurrence of key national interventions and events. The analysis reveals that the greatest decline in HIV preceded almost all substantive initiatives undertaken at the national level, which are often held responsible for Australia's successful early containment of HIV. In particular, dramatic declines were already well advanced and/or preceded (i) substantive growth in national HIV/AIDS prevention education funding, (ii) publication of the first National AIDS Strategy, (iii) establishment of key national HIV/AIDS bodies and (iv) promulgation of the 'Ottawa Charter'. Explanations for, and lessons learned from Australia's dramatic early declines in HIV incidence are discussed. PMID:17212850
Plummer, D; Irwin, L
Background HIV-infected women, particularly those with advanced disease, may have higher rates of pregnancy loss (miscarriage and stillbirth) and neonatal mortality than uninfected women. Here we examine risk factors for these adverse pregnancy outcomes in a cohort of HIV-infected women in Zambia considering the impact of infant HIV status. Methods A total of 1229 HIV-infected pregnant women were enrolled (2001–2004) in Lusaka, Zambia and followed to pregnancy outcome. Live-born infants were tested for HIV by PCR at birth, 1 week and 5 weeks. Obstetric and neonatal data were collected after delivery and the rates of neonatal (<28 days) and early mortality (<70 days) were described using Kaplan-Meier methods. Results The ratio of miscarriage and stillbirth per 100 live-births were 3.1 and 2.6, respectively. Higher maternal plasma viral load (adjusted odds ratio [AOR] for each log10 increase in HIV RNA copies/ml?=?1.90; 95% confidence interval [CI] 1.10–3.27) and being symptomatic were associated with an increased risk of stillbirth (AOR?=?3.19; 95% CI 1.46–6.97), and decreasing maternal CD4 count by 100 cells/mm3 with an increased risk of miscarriage (OR?=?1.25; 95% CI 1.02–1.54). The neonatal mortality rate was 4.3 per 100 increasing to 6.3 by 70 days. Intrauterine HIV infection was not associated with neonatal morality but became associated with mortality through 70 days (adjusted hazard ratio?=?2.76; 95% CI 1.25–6.08). Low birth weight and cessation of breastfeeding were significant risk factors for both neonatal and early mortality independent of infant HIV infection. Conclusions More advanced maternal HIV disease was associated with adverse pregnancy outcomes. Excess neonatal mortality in HIV-infected women was not primarily explained by infant HIV infection but was strongly associated with low birth weight and prematurity. Intrauterine HIV infection contributed to mortality as early as 70 days of infant age. Interventions to improve pregnancy outcomes for HIV-infected women are needed to complement necessary therapeutic and prophylactic antiretroviral interventions.
The work presented here was initiated to determine the possibilities of\\u000amolecular methods for the detection and epidemiological investigation of\\u000aHIV and HTLV infections. We present the results of a literature research\\u000aand describe the development and partial evaluation of a new PCR method\\u000afor the amplification of RNA and DNA sequences of the HIV-1 pol, env and\\u000agag, HIV-2
Meijer A; Borleffs JCC; Roosendaal G; Loon AM van
Background Anti-HIV-1 therapy depends upon multiple agents that target different phases of the viral replication cycle. Recent reports indicate that plant and human DING proteins are unique in targeting viral gene transcription as the basis of their anti-HIV-1 therapy. Methods Two cloned DING genes from Pseudomonas were transiently expressed in human cells, and effects on NF?B-mediated transcription, HIV-1 transcription, and HIV-1 production were measured. Results Both DING proteins elevated NF?B-mediated transcription. In microglial cells, one protein, from P. aeruginosa PA14, suppressed HIV-1 transcription; the other protein, from P. fluorescens SBW25, was inactive. The PA14DING protein also reduces HIV-1 production in microglial cells. Conclusions Structural differences between the two DING proteins highlight regions of the PA14DING protein essential to the anti-HIV-1 activity, and may guide the design of therapeutic agents.
The effectiveness of antiretroviral therapy to control HIV infection has led to the emergence of an older HIV population who are at risk of chronic diseases. Through a comprehensive search of major databases, this Review summarises information about the associations between chronic obstructive pulmonary disease (COPD), asthma, and HIV infection. Asthma and COPD are more prevalent in HIV-infected populations; 16–20% of individuals with HIV infection have asthma or COPD, and poorly controlled HIV infection worsens spirometric and diffusing capacity measurements, and accelerates lung function decline by about 55–75 mL/year. Up to 21% of HIV-infected individuals have obstructive ventilatory defects and reduced diffusing capacity is seen in more than 50% of HIV-infected populations. Specific pharmacotherapy considerations are needed to care for HIV-infected populations with asthma or COPD–protease inhibitor regimens to treat HIV (such as ritonavir) can result in systemic accumulation of inhaled corticosteroids and might increase pneumonia risk, exacerbating the toxicity of this therapy. Therefore, it is essential for clinicians to have a heightened awareness of the increased risk and manifestations of obstructive lung diseases in HIV-infected patients and specific therapeutic considerations to care for this population. Screening spirometry and tests of diffusing capacity might be beneficial in HIV-infected people with a history of smoking or respiratory symptoms.
Drummond, M Bradley; Kirk, Gregory D
Background: Hair loss is common in patients with HIV-1 infection, and in black patients this loss may be associated with straightening. Possible causes are frequently present in patients with HIV-1. These causes include chronic HIV-1 infection itself and recurrent secondary infections, nutritional deficiencies, immunologic and endocrine dysregulation, and exposure to multiple drugs. However, histopathologic features have rarely been reported in
Kathleen J Smith; Henry G Skelton; Deanna DeRusso; Leonard Sperling; Josef Yeager; Kenneth F Wagner; Peter Angritt
Anti-retroviral therapy (ART) has had a tremendous impact on the clinical outcomes of HIV-1 infected individuals. While ART has produced many tangible benefits, chronic, long-term consequences of HIV infection have grown in importance. HIV-1-associated neurocognitive disorder (HAND) represents a collection of neurological syndromes that have a wide range of functional cognitive impairments. HAND remains a serious threat to AIDS patients, and there currently remains no specific therapy for the neurological manifestations of HIV-1. Based upon work in other models of neuroinflammation, kappa opioid receptors (KOR) and synthetic cannabinoids have emerged as having neuroprotective properties and the ability to dampen pro-inflammatory responses of glial cells; properties that may have a positive influence in HIV-1 neuropathogenesis. The ability of KOR ligands to inhibit HIV-1 production in human microglial cells and CD4 T lymphocytes, demonstrate neuroprotection, and dampen chemokine production in astrocytes provides encouraging data to suggest that KOR ligands may emerge as potential therapeutic agents in HIV neuropathogenesis. Based upon findings that synthetic cannabinoids inhibit HIV-1 expression in human microglia and suppress production of inflammatory mediators such as nitric oxide (NO) in human astrocytes, as well as a substantial literature demonstrating neuroprotective properties of cannabinoids in other systems, synthetic cannabinoids have also emerged as potential therapeutic agents in HIV neuropathogenesis. This review focuses on these two classes of compounds and describes the immunomodulatory and neuroprotective properties attributed to each in the context of HIV neuropathogenesis. PMID:21850403
Hu, Shuxian; Sheng, Wen S; Rock, Robert Bryan
Human and simian immunodeficiency viruses (HIV and SIV) require a seven transmembrane chemokine (7TM) receptor in addition to CD4 for efficient entry into cells. CCR5 and CXCR4 act as major co-receptors for non-syncytium-inducing and syncytium-inducing strains respectively. We have examined the co-receptor requirement for HIV-1 infection of cells of macrophage lineage. Both CCR5 and CXCR4 can operate as functional co-receptors for infection in these cell types. Other co-receptors utilised by multi-co-receptor-using strains of HIV-1, including CCR3 and STRL33, were not used for macrophage infection. HIV-2 and SIV strains, however, can replicate in both peripheral blood mononuclear cells (PBMCs) and other primary cell types such as fibroblasts independently of CCR5 or CXCR4. HIV co-receptors, particularly CCR5, will be major targets for new therapeutics in this decade. We have therefore investigated different chemokines and derivatives that bind co-receptors for their capacity to inhibit HIV infection. These included derivatives of a CCR5 ligand, RANTES, with modified N-termini as well as Kaposi's sarcoma-associated herpesvirus-encoded chemokines that bind a wide range of co-receptors, including CCR5, CXCR4, CCR3 and CCR8, as well as the orphan 7TM receptors GPR1 and STRL33. One compound, aminooxypentane or AOP-RANTES, was a particularly potent inhibitor of HIV infection on PBMCs, macrophages and CCR5+ cell lines and demonstrated the great promise of therapeutic strategies aimed at CCR5. PMID:11138769
Simmons, G; Reeves, J D; Hibbitts, S; Stine, J T; Gray, P W; Proudfoot, A E; Clapham, P R
Eradication of HIV-1 from an infected individual cannot be achieved by current regimens. Viral reservoirs established early during the infection remain unaffected by anti-retroviral therapy for a long time and are able to replenish systemic infection upon interruption of the treatment. Therapeutic targeting of viral latency will require a better understanding of the basic mechanisms underlying the establishment and long-term
HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared
Steven P. Tanis; Michael B. Plewe; Ted W. Johnson; Scott L. Butler; Deepak Dalvie; Dorothy DeLisle; Klaus R. Dress; Qiyue Hu; Buwen Huang; Jon E. Kuehler; Atsuo Kuki; Wen Liu; Qinghai Peng; Graham L. Smith; Jim Solowiej; Khanh T. Tran; Hai Wang; Anle Yang; Chunfeng Yin; Xiaoming Yu; Junhu Zhang; Huichun Zhu
Persistent viral infections are associated with host and viral factors that impair effective antiviral immunity. Natural killer (NK) cells contribute to establishment of persistent lymphocytic choriomeningitis virus (LCMV) infection in mice through suppression of virus-specific T cell responses during the first few days of infection, but NK cell depletion during those early time points can enable severe T cell-mediated immune pathology and death of the host. Here we show that long after their peak in cytolytic activation, NK cells continue to support viral persistence at later times of infection. Delayed depletion of NK cells, 2 to 3 weeks after infection, enhanced virus-specific T cell responses and viral control. This enhancing effect of delayed NK cell depletion on antiviral immunity, in contrast to early NK cell depletion, was not associated with increased morbidity and mortality, and mice quickly regained weight after treatment. The efficacy of the depletion depended in part upon the size of the original virus inoculum, the viral load at the time of depletion, and the presence of CD4 T cells. Each of these factors is an important contributor to the degree of CD8 T cell dysfunction during viral persistence. Thus, NK cells may continuously contribute to exhaustion of virus-specific T cells during chronic infection, possibly by depleting CD4 T cells. Targeting of NK cells could thus be considered in combination with blockade of other immunosuppressive pathways, such as the interleukin-10 (IL-10) and programmed death 1 (PD-1) pathways, as a therapy to cure chronic human infections, including those with HIV or hepatitis C virus. IMPORTANCE Persistent virus infections are a major threat to global human health. The capacity of viruses, including HIV and hepatitis C virus, to overwhelm or subvert host immune responses contributes to a prolonged state of dampened antiviral immune functionality, which in turn facilitates viral persistence. Recent efforts have focused on therapeutics that can restore the effector functions of these functionally exhausted virus-specific T cells in order to expedite viral clearance. Here we establish that natural killer (NK) cells actively contribute to immune dysfunction and viral persistence at later stages of infection. This previously undescribed mechanism of immune suppression during chronic infection provides a vital clue for the design of novel therapeutic strategies targeting NK cell immunosuppressive activity in order to restore immune function and enhance viral control in chronically infected individuals. PMID:24284324
Waggoner, Stephen N; Daniels, Keith A; Welsh, Raymond M
OBJECTIVES There is a growing public health interest in the aging HIV-infected (HIV+) population, although there is a dearth of research on successful aging with HIV. This study aimed to understand the risk and protective factors associated with self-rated successful aging (SRSA) with HIV. DESIGN Cross-sectional, case-controlled. SETTING HIV Neurobehavioral Research Program and the Stein Institute for Research on Aging at University of California, San Diego. PARTICIPANTS Eighty-three community-dwelling HIV+ and 83 demographically matched HIV-uninfected (HIV?) individuals, enrolled between 12/1/11 and 5/10/12, mean age of 59 years, primarily Caucasian males, 69% with AIDS, who had been living with an HIV diagnosis for 16 years. Diagnostic criteria for HIV/AIDS was obtained through a blood draw. MEASUREMENTS Participants provided ratings of SRSA as part of a comprehensive survey which included measures of physical and emotional functioning and positive psychological traits. Relationships between how the different variables related to SRSA were explored. RESULTS While SRSA was lower in the HIV+ individuals than their HIV? counterparts, 66% of adults with HIV reported scores of 5 or higher on a 10-point scale of SRSA. Despite worse physical and mental functioning and greater psychosocial stress among the HIV+ participants, the two groups had comparable levels of optimism, personal mastery, and social support. SRSA in HIV+ individuals was associated with better physical and emotional functioning and positive psychological factors, but not HIV disease status or negative life events. CONCLUSION Successful psychosocial aging is possible in older HIV+ individuals. Positive psychological traits such as resilience, optimism, and sense of personal mastery have stronger relationship with SRSA than duration or severity of HIV disease. Research on interventions to enhance these positive traits in HIV+ adults is warranted.
Moore, Raeanne C.; Moore, David J.; Thompson, Wesley; Vahia, Ipsit V.; Grant, Igor; Jeste, Dilip V.
Around 33 million people worldwide are living with Human Immunodeficiency Virus (HIV) infection, and approximately 20-30% of HIV-infected individuals are also infected with Hepatitis C virus (HCV). The main form of HCV transmission is via the blood borne route; high rates of co-infection are found in intravenous drug users with HCV prevalence rates as high as 90%. Introduction of effective antiretroviral therapy (ART) has led to a significant decline in HIV-related morbidity, but at the same time the incidence of HCV related liver disease is increasing in the co-infected population. Meta analysis has revealed that individuals who are co-infected with HIV/HCV harbor three times greater risk of progression to liver disease than those infected with HCV alone. Increased risk of progression to Acquired Immunodeficiency Syndrome (AIDS) and AIDS-related deaths is shown among the co-infected patients by some studies, suggesting that HCV infection may accelerate the clinical course of HIV infection. HCV may also affect the incidence of liver toxicity associated with ART, affecting the management of HIV infection. There is a lack of optimal therapeutic approaches to treat HCV infection in HIV co-infected patients. This review discusses recent literature pertaining HIV/HCV co-infection, in addition to providing a snapshot of impact of co-infection on human genome at the level of gene expression and its regulation by microRNAs (miRNAs). PMID:24470971
. Mathematical models have proven valuable in understanding the dynamics of HIV-1infection in vivo. By comparing these models to data obtained from patients undergoing antiretroviraldrug therapy, it has been possible to determine many quantitative features of the interaction betweenHIV-1, the virus that causes AIDS, and the cells that are infected by the virus. The most dramaticfinding has been that even
Alan S. Perelson; Patrick W. Nelson
Antiretroviral therapy, where available, has transformed HIV-1 disease into a treatable and somewhat chronic infection. This article summarizes the accomplishments thus far and what lies ahead in our struggle to improve the treatment of, and possibly eliminate, HIV-1 infection.
Roger J Pomerantz; David L Horn
Virus-like particles (VLPs) of numerous viruses have been considered as possible candidates for vaccine development. We have\\u000a constructed HIV chimeric genes by coupling the gag gene of HIV-2 with the V3 domain of the gp120 gene of either HIV-1 or HIV-2 and expressed the chimeric genes in SF21 cells using the recombinant baculovirus expression\\u000a system. Although the level of expression
Lizhong Luo; Yan Li; Soon Duck Ha; C. Yong Kang
The introduction of highly active antiretroviral therapy (HAART) has been an important breakthrough in the treatment of HIV-1 infection and has also a powerful tool to upset the equilibrium of viral production and HIV-1 pathogenesis. Despite the advent of potent combinations of this therapy, the long-lived HIV-1 reservoirs like cells from monocyte-macrophage lineage and resting memory CD4+ T cells which are established early during primary infection constitute a major obstacle to virus eradication. Further HAART interruption leads to immediate rebound viremia from latent reservoirs. This paper focuses on the essentials of the molecular mechanisms for the establishment of HIV-1 latency with special concern to present and future possible treatment strategies to completely purge and target viral persistence in the reservoirs.
Abbas, W.; Herbein, G.
Purpose of the review Changing antiretroviral regimens and the introduction of new antiretroviral drugs have altered drug resistance patterns in resistance human immunodeficiency virus type 1 (HIV-1). This review summarizes recent information on antiretroviral drug resistance. Recent findings As tenofovir and abacavir have replaced zidovudine and stavudine in antiretroviral regimens, thymidine analog resistance mutations have become less common in patients failing antiretroviral therapy in developed countries. Similarly, the near universal use of ritonavir-boosted protease inhibitors (PI) in place of unboosted PIs has made the selection of PI resistance mutations uncommon in patients failing a first- or second-line PI regimen. The challenge of treating patients with multidrug-resistant HIV-1 has largely been addressed by the advent of newer PIs, second-generation non-nucleoside reverse transcriptase inhibitors and drugs in novel classes, including integrase inhibitors and CCR5 antagonists. Resistance to these newer agents can emerge, however, resulting in the appearance of novel drug resistance mutations in the HIV-1 polymerase, integrase and envelope genes. Summary New drugs make possible the effective treatment of multidrug-resistant HIV-1, but the activity of these drugs may be limited by the appearance of novel drug resistance mutations.
Kuritzkes, Daniel R.
Objectives: As HIV is currently a chronic and manageable disease, an increasing amount of people living with HIV (PLHIV) are (again) active on the labour market. Since research on this topic is scarce, this study aimed to explore experiences of PLHIV in the workplace, especially concerning disclosure and adherence to antiretroviral therapy. Methods: A questionnaire was developed and validated in collaboration with Sensoa (Flemish expertise centre for sexual health) and participants were recruited using flyers and announcements on websites. Results: A total of 54 PLHIV completed the questionnaire, among whom 50 (92·6%) males. Half of the participants did not disclose their HIV status in the workplace, mostly due to being afraid of social or professional consequences. Those who disclosed, reported no changes in the workplace or even reported receiving more empathy. A minority of participants have to take antiretroviral medication at work and they reported no particular problems related to medication intake. Conclusion: Despite improved solidarity and information campaigns, many PLHIV still do not disclose their HIV status in the workplace, most frequently due to fear for discrimination. More actions are warranted, as well as addressing possible self-stigma. Adherence to antiretroviral therapy in the workplace posed little or no problems. PMID:24820918
Degroote, S; Vogelaers, D; Koeck, R; Borms, R; De Meulemeester, L; Vandijck, D
Narrative therapy attempts to help families “reauthor” their lives through a process of externalization, unique outcomes, and performance before an audience. The interventions in this model are accomplished mostly through language. This may make narrative therapy a complicated process for many therapists and clients. The purpose of this article is to show how applying art therapy techniques to the basic
Thomas D. Carlson
Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future. PMID:23627981
Cetinkalp, Sevki; Simsir, Ilgin Y; Ertek, Sibel
Examples of patients are used as a basis for discussing the treatment of severe aplastic anaemia with clonal chromosomal aberrations in haematopoietic cells, the aplastic form of paroxysmal nocturnal haemoglobinuria and myelodysplasia, with allogeneic bone marrow transplantation. Transplantation with marrow from an HLA-identical sibling donor has curative potential in selected patients with these disorders. The procedure should preferably be carried out before the patients have received massive treatment for the complications of marrow failure. The use of matched unrelated bone marrow donors is still at the investigation stage. PMID:1412233
Brinch, L; Evensen, S A; Hammerstrøm, J; Blichfeldt, P
Research conducted by Wei Zhang, Ph.D. and his colleagues describing a method to prevent the spread of ovarian cancer in both in-vitro and in-vivo models was published in the Feb. 11, 2013 issue of Cancer Cell. Ovarian cancer develops in the tissues of one or both ovaries, which are situated in the abdominal cavity and buffered by peritoneal fluid.
Therapeutic Hypothermia has proven neuroprotective effects in global cerebral ischemia. Indications for hypothermia induction include cardiac arrest and neonatal asphyxia. The two general methods of induced hypothermia are either surface cooling or endovascular cooling. Hypothermia should be induced as early as possible to achieve maximum neuroprotection and edema blocking effect. Endovascular cooling has the benefit of shorter time to reach target temperature but catheter insertion requires expertise and training, which may be a barrier to widespread availability. The optimum method of cooling is yet to be determined but a multimodal approach is necessary to address three phases of cooling: induction, maintentance, and re-warm. Specifying core practitioners who are well-versed in established guidelines can help integrate the multidisciplinary team that is needed to successfully implement cooling protocols. Reducing shivering to make heat exchange more efficient with tighter temperature control enables quicker time to target temperature and avoids re-warming which can lead to inadvertent increase in intracranial pressure and cerebral edema. Promising applications but yet to be determined is whether hypothermia treatment can improve outcomes in acute ischemic stroke or traumatic brain injury.
Song, Shlee S.; Lyden, Patrick D.
Dystonia is a neurological syndrome characterized by excessive involuntary muscle contractions leading to twisting movements and unnatural postures. It has many different clinical manifestations, and many different causes. More than 3 million people worldwide suffer from dystonia, yet there are few broadly effective treatments. In the past decade, progress in research has advanced our understanding of the pathogenesis of dystonia to a point where drug discovery efforts are now feasible. There are several strategies that can be used to develop novel therapeutics for dystonia. Existing therapies have only modest efficacy, but may be refined and improved to increase benefits while reducing side effects. Identifying rational targets for drug intervention based on the pathogenesis of dystonia is another strategy. The surge in both basic and clinical research discoveries has provided insights at all levels including etiological, physiological and nosological, to enable such a targeted approach. The empirical approach to drug discovery is complementary to the rational approach whereby compounds are identified using a non-mechanistic strategy. [MD1] With the recent development of multiple animal models of dystonia, it is now possible to develop assays and perform drug screens on vast number of compounds. This multifaceted approach to drug discovery in dystonia will likely provide lead compounds that can then be translated for clinical use.
Jinnah, H. A.; Hess, Ellen J.
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.
Fisher, Robert S.
Drugs based on amino acid sequence of Heptad Repeats of gp41 of HIV have been explored in search of anti-HIV drugs acting by inhibition of the gp41 6-helix formation and subsequent cellular infection. These are classified under a distinct discipline called HIV fusion inhibitors. Resistance to HIV fusion inhibitors and their solutions have also been discussed in this review. PMID:19827030
Qadir, M I; Malik, S A
The HIV\\/AIDS epidemic is one of the major factors affecting women's health, with 20 million women living with HIV and more than two million pregnancies in HIV-positive women each year. Most HIV infections in women are in resource-constrained settings where the risk of maternal morbidity and mortality is also unacceptably high, and where most of the 529,000 deaths from complications
HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV) infections are major public health problems. Patients at risk for\\u000a HIV infection are likely also at risk for HCV and HBV because of shared routes of transmission. HIV and antiretroviral therapy\\u000a (ART) have a significant impact on HCV and HBV. HIV coinfection accelerates HCV and HBV natural history, leading to
Marie-Louise Vachon; Douglas T. Dieterich
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.
Noroozinejad, Gholamhossein; Yarmohmmadi Vasel, Mosaieb; Bazrafkan, Fatemeh; Sehat, Mahmoud; Rezazadeh, Majid; Ahmadi, Khodabakhsh
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
Noroozinejad, Gholamhossein; Yarmohmmadi Vasel, Mosaieb; Bazrafkan, Fatemeh; Sehat, Mahmoud; Rezazadeh, Majid; Ahmadi, Khodabakhsh
HIV is a devastating disease affecting millions of people worldwide despite the advent of successful antiretroviral therapy (ART). However, ART does not result in a cure and has to be taken for life. Accordingly, researchers are turning towards cure efforts, particularly in the light of two patients whose HIV has been seemingly eradicated. Numerous approaches and strategies have been considered for curing HIV, but no scalable and safe solution has yet been reached. With newly discovered difficulties in measuring the HIV reservoir, the main barrier to a cure, the only true test of cure is to stop ART and see whether the virus becomes detectable. However, it is possible that this treatment interruption may be associated with certain risks for patients. Here, we compare the current major approaches and recent advances for curing HIV, as well as discuss ways of evaluating HIV cure and the safety concerns involved. PMID:24745361
Pace, Matthew; Frater, John
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
Ofori, Leslie O; Hilimire, Thomas A; Bennett, Ryan P; Brown, Nathaniel W; Smith, Harold C; Miller, Benjamin L
Two-thirds of all HIV-infected individuals (about 25 million) live in Africa. AIDS causes more deaths in Africa than any other disease, including malaria. The prevalence of HIV varies widely across Africa: Southern Africa is worst affected, with seroprevalences in adults often exceeding 20%. Most adult HIV infections in Africa are acquired heterosexually. The epidemic is not static and trends are
Maarten F Schim van der Loeff
Dramatic improvement in the survival of the HIV population has occurred with the ascendance of highly active antiretroviral therapy (HAART). In the foreseeable future, HIV-infected women who acquired disease during the peak years of the epidemic are expected to survive to experience menopause and even years beyond. The HIV epidemic may be viewed as 'mature', as its earlier victims become part of the geriatric population. Research about the process of menopause in HIV-infected women and, conversely, about HIV infection in women undergoing menopause is currently limited. Existing research suggests that the process of menopause is affected by HIV infection, inasmuch as infected women appear to experience menopause at an earlier age, with greater symptomatology, and with different reproductive hormone profiles compared with HIV-uninfected women. HIV infection also appears to affect bone mineral density, cardiovascular disease and cognition, with some age-related interactions. Lifestyle and demographic factors have pervasive importance for both HIV infection and the menopause in women. This article reviews the current state of knowledge about the menopausal process in HIV-infected women, and the common conditions in postmenopausal women that are likely to be affected by HIV infection. Clinicians should appreciate the potential role of HIV infection in caring for menopause-aged women. PMID:19037065
Fan, Maria D; Maslow, Bat-Sheva; Santoro, Nanette; Schoenbaum, Ellie
Human immunodeficiency virus (HIV) afflicts an estimated 30 million people globally, making it a continuing pandemic. Despite major research efforts, the rate of new infections has remained relatively static over time. This article reviews an emerging strategy for the treatment of HIV, the inhibition of the co-receptors necessary for HIV entry, CCR5 and CXCR4. The aim of this article is to highlight potential therapeutics derived from peptides and proteins that show particular promise in HIV treatment. Molecules that act on CCR5, CXCR4 or on both receptors will be discussed herein. PMID:23856897
von Recum, Horst A; Pokorski, Jonathan K
Most approved drugs with activity against hepatitis B virus (HBV) have activity against human immunodeficiency virus type 1 (HIV-1), which precludes their use in patients who are coinfected with HBV and HIV-1 and who are not receiving antiretroviral therapy due to the risk of inducing resistance. The activity of telbivudine, a highly selective HBV inhibitor, against temporally and geographically distinct wild-type and multidrug-resistant HIV-1 clinical isolates was evaluated in vitro. No inhibition was observed with up to 600 ?M drug, which supports further exploration of telbivudine as a therapeutic option for the treatment of HBV infections in patients coinfected with HIV-1.
Lin, Kai; Karwowska, Sylwia; Lam, Eric; Limoli, Kay; Evans, Thomas G.; Avila, Claudio
Human immunodeficiency virus (HIV) afflicts an estimated 30 million people globally, making it a continuing pandemic. Despite major research efforts, the rate of new infections has remained relatively static over time. This article reviews an emerging strategy for the treatment of HIV, the inhibition of the co-receptors necessary for HIV entry, CCR5 and CXCR4. The aim of this article is to highlight potential therapeutics derived from peptides and proteins that show particular promise in HIV treatment. Molecules that act on CCR5, CXCR4 or on both receptors will be discussed herein.
von Recum, Horst A; Pokorski, Jonathan K
Since telomere integrity is required to guarantee the unlimited replicative potential of cancer cells, telomerase, the enzyme responsible for telomere length maintenance in most human tumors, and lately also telomeres themselves have become extremely attractive targets for new anticancer interventions. At the current status of knowledge, it is still not possible to define the best therapeutic target between telomerase and telomeres. It is noteworthy that interfering with telomeres, through direct targeting of telomeric DNA or proteins involved in the telosome complex, could negatively affect the proliferative potential not only of tumors expressing telomerase activity but also of those that maintain their telomeres through alternative lengthening or still unknown mechanisms. This review presents the different therapeutic approaches proposed thus far and developed in preclinical tumor models and discusses the perspectives for their use in the clinical setting. PMID:19419699
Folini, Marco; Gandellini, Paolo; Zaffaroni, Nadia
Orphans and vulnerable youth who live in group homes are at risk of poor mental health and sexual and drug-using behaviors that increase the risk of HIV transmission. This study explores factors related to this risk among youth living in group homes (“children’s homes”) for orphans and vulnerable children in South Africa, a country afflicted by high levels of parental loss due to HIV. The study explores 1) knowledge and attitudes about HIV, 2) social support, 3) communication with group home caregivers, and 4) the relevance of an existing evidence-based HIV prevention and mental health promotion program to situations where sexual and drug risk behaviors can occur. In-depth qualitative individual interviews were conducted with 20 youth (age 10 to 16 years) residing in two children’s homes in Durban, South Africa. Content analysis focused on critical themes related to coping and prevention of risk activities. Respondents exhibited inconsistent and incomplete knowledge of HIV transmission and prevention. They displayed positive attitudes toward people living with HIV, but reported experiencing or witnessing HIV-related stigma. Participants witnessed substance use and romantic/sexual relationships among their peers; few admitted to their own involvement. While relationships with childcare workers were central to their lives, youth reported communication barriers related to substance use, sex, HIV, and personal history (including parental loss, abuse, and other trauma). In conclusion, these qualitative data suggest that evidence-based HIV prevention programs that bring caregivers and youth together to improve communication, HIV knowledge, social support, youth self-esteem, and health care, reduce sexual and drug risk behaviors, and strengthen skills related to negotiating situations of sexual and substance use possibility could benefit youth and childcare workers in children’s homes.
Nestadt, D.F.; Alicea, S.; Petersen, I.; John, S.; Myeza, N.P.; Nicholas, S.W.; Cohen, L.G.; Holst, H.; Bhana, A.; McKay, M.M.; Abrams, E.J.; Mellins, C.A.
This article provides an overview of the issues surrounding the use of cannabis for therapeutic purposes. Examples of some of the ethical issues related to professional practice are discussed. The authors do not advocate legalising cannabis for all, but the therapeutic advantages and disadvantages of using cannabis are highlighted. PMID:11975210
Wall, J; Davis, S; Ridgway, S
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)
Aron, William S.; And Others
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.
Balan, Ivan C.; Carballo-Dieguez, Alex; Ventuneac, Ana; Remien, Robert H.; Dolezal, Curtis; Ford, Jordan
Introduction In South Africa where HIV prevalence is high, mentor mother programmes have been used to promote the health and wellbeing of women enrolled in government programmes preventing vertical transmission. The Masihambisane Project trained mentors to be educators and facilitators as “expert patients” in self-help groups. While this and other similar interventions demonstrate positive outcomes for mothers and their children, the long-term repercussions for mentors delivering the intervention are seldom considered. This article explores the personal impact of being a mentor, the potentially traumatizing effects of repeatedly sharing their experiences of living with HIV and the coping strategies they adopt. Results Towards the end of the Masihambisane intervention, 10 semi-structured qualitative interviews were conducted with locally recruited mentors living with HIV and were thematically analysed. Mentors found the repeated telling of their stories a painful reminder of adverse personal experiences. In some cases, retelling caused a physical reaction. Mentors relied on coping strategies like taking breaks, writing their experiences down and debriefing sessions. Despite the difficulties associated with their role, some mentors found being advisors and the group sessions therapeutic and empowering. Conclusions These findings indicate that the inclusion of peer mentors comes with certain responsibilities. While the mentors were resilient and some found the experience therapeutic and empowering found creative ways to cope with secondary trauma, the negative implications cannot be ignored. To effectively deliver a mentor-driven intervention to mothers enrolled in a programme to prevent vertical transmission, the possibilities of secondary trauma should be considered and mentors provided with ongoing counselling, training on coping skills and regular debriefing sessions.
Dhlamini, Lebohang; Knight, Lucia; van Rooyen, Heidi; van Heerden, Alastair; Rotheram-Borus, Mary Jane
Side Effects of HIV Medicines HIV and Lactic Acidosis (Last updated 9/30/2013; last reviewed 9/30/2013) Key Points Lactic acidosis is a ... side effect of some HIV medicines. Which HIV medicines can cause lactic acidosis? HIV medicines in the ...
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.
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.
Mousseau, Guillaume; Valente, Susana
The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13-21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics. PMID:24763408
Tamamis, Phanourios; Floudas, Christodoulos A
Although very inefficient, sexual transmission of HIV-1 is responsible for more than 80% of infections worldwide. Yet, the presence of HIV in spermatozoa has been a matter of debate. The aim of this study was to evaluate the presence of HIV nucleic acids and the distribution of mannose receptors in sperm cells, and to determine the semen parameters and cytokine levels in ejaculates from HIV-positive patients. The presence of non-seminal cells in purified sperm was revealed by light microscopy, flow cytometry and RT-PCR. HIV nucleic acids were evaluated by nested PCR; the distributions of mannose receptors on the surface of the sperm and cytokine levels in ejaculates were determined by fluorescence microscopy and flow cytometry respectively. Sperm characteristics were determined by conventional methods. HIV DNA was detected in 69.2% of purified sperm from HIV-positive men; in contrast all purified sperm were negative for HIV RNA. The distribution of mannose receptors and cytokine levels in HIV-1-positive men were similar to uninfected individuals. Using the Principal Component Analysis (PCA) method, it was possible to determine that semen parameters of HIV-positive men exhibit different distributions compared to HIV-negative individuals. Finally, these results indicate that viral DNA is present in purified sperm from HIV-positive men and that HIV infection of spermatozoa could be associated with lower seminal parameters as demonstrated by the PCA method. The similar distribution of mannose receptors between infected and uninfected individuals suggests that sperm cells from infected individuals interact normally with oocytes. PMID:19601777
Cardona-Maya, Walter; Velilla, Paula; Montoya, Carlos Julio; Cadavid, Angela; Rugeles, María T
Although the incidence of HIV in the United States is higher among men compared to women, the global proportion of women versus men who are infected has been approximately 50% since the late 1990s. Women have been under-represented in neuropsychological studies of HIV. A small number of studies have reported a significantly higher prevalence of neurocognitive impairment among HIV+ women compared to HIV? controls regardless of symptom status and with or without an AIDS diagnosis. Impairment was most evident on psychomotor tasks. The risk of neuropsychological impairment was increased among HIV+ women not on antiretroviral therapy. Age and depressive symptoms also increase neurocognitive risk. New neurocognitive studies of ovarian steroid hormones, PTSD and other psychiatric conditions are critical for addressing potential female-specific aspects of HIV-Associated Neurocognitive Disorder. Such studies will also address questions regarding involvement of the hippocampus and verbal memory, which may be of particular significance among HIV+ women.
Despite the extensive therapeutic arsenal currently available to treat HIV infection, new agents allowing long-term safety and tolerability, with novel mechanism of action and more convenient administration, would be desirable to fight this chronic infection. In this regard, news on this topic has been highlighted at the last CROI held in Boston at the beginning of March, 2014. PMID:24984767
Poveda, Eva; Pedreira, José D
OPINION STATEMENT: There is no specific treatment for Huntington's disease (HD). Its many symptoms of motor, psychiatric, and cognitive deterioration are managed with symptomatic relief, rehabilitation, and support. The only drug approved by the US Food and Drug Administration (FDA) for the treatment of HD is an antichoreic agent, tetrabenazine, but this drug is used sparingly because of uneasiness regarding its propensity to cause depression and suicidality in this population, which is already at risk for these complications. Neuroleptics are still first-line treatments for chorea accompanied by comorbid depression and/or behavioral or psychotic symptoms, as is often the case. Psychiatric features, which have a significant impact on a patient's professional and personal life, often become the major focus of management. In addition to neuroleptics, commonly used medications include antidepressants, mood stabilizers, anxiolytics, and psychostimulants. In contrast, few treatment options are available for cognitive impairment in HD; this remains an important and largely unmet therapeutic need. HD patients typically lack insight into their disease manifestations, failing to recognize their need for treatment, and possibly even arguing against it. Multipurpose medications are employed advantageously to simplify the medication regimen, so as to facilitate compliance and not overwhelm the patient. For example, haloperidol can be prescribed for a patient with chorea, agitation, and anorexia, rather than targeting each symptom with a different drug. This approach also limits the potential for adverse effects, which can be difficult to distinguish from the features of the disease itself. With HD's complexity, it is best managed with a multidisciplinary approach that includes a movement disorders specialist, a genetic counselor, a mental health professional, a physical therapist, and a social worker for support and coordination of services. As the disease progresses, there may be need for other specialists, such as a speech and occupational therapist, a nutritionist for weight loss, and ultimately, a palliative care specialist. PMID:22314929
Killoran, Annie; Biglan, Kevin M
Despite the high prevalence of hepatitis C virus (HCV) infection among injection drug users also infected with human immunodeficiency virus (HIV), and the synergistic adverse effect of the two diseases on patients' health and survival, research on the clinical management of these patients and particularly the low uptake of HCV therapy is limited. We conducted qualitative interviews with 17 HIV providers from two urban public hospitals. We discovered that the limitations of the current state of medical knowledge, the severe side effects of HIV and HCV therapies, and the psychosocial vulnerability of HIV/HCV-coinfected patients combined with their resistance to becoming informed about HCV posed significant challenges for providers. To contend with these challenges, providers incorporated key dimensions of patient-centered medicine in their practice, such as considering their patients' psychosocial profiles and the meaning patients assign to being coinfected, and finding ways to engage their patients in a therapeutic alliance. PMID:21825278
Lekas, Helen-Maria; Siegel, Karolynn; Leider, Jason
Liver disease is a major cause of mortality in individuals with HIV–HBV coinfection. The pathogenesis of liver disease in this setting is unknown, but is likely to involve drug toxicity, infection of hepatic cells with both HIV and HBV, and an altered immune response to HBV. The availability of therapeutic agents that target both HIV and HBV replication enable dual viral suppression, and assessment of chronic hepatitis B is important prior to commencement of antiretroviral therapy. Greater importance is now placed on HBV DNA levels and staging of liver fibrosis, either by liver biopsy or noninvasive measurement, such as transient elastography, since significant liver fibrosis may exist in the presence of normal liver function tests. Earlier treatment of both HIV and HBV is now generally advocated and treatment is usually lifelong.
Iser, David M; Lewin, Sharon R
In infected individuals, human immunodeficiency virus type 1 (HIV-1) exist as a "swarm" of quasi species compartmentalized in tissues where individual viral variants may interact locally. We have used human lymphoid tissue, where the critical events of HIV disease occur, to study local interactions in model HIV-1 binary swarms ex vivo. We infected tissue blocks with binary mixtures consisting either of CCR5-dependent and CXCR4-dependent variants or of 2 dual-tropic HIV-1 variants, of which one is skewed to utilization of CXCR4 and the other of CCR5. HIV-1 variants that use CXCR4 suppress replication of CCR5-dependent HIV-1 variants, whereas CCR5-dependent HIV-1 variants do not affect replication of CXCR4-dependent HIV-1. CC-chemokines that inhibit replication of CCR5-dependent HIV-1 variants were up-regulated by CXCR4-dependent HIV-1, thus possibly contributing to this suppression. Tissue-specific chemokine/cytokine network modulations triggered by individual HIV-1 variants may be an important mechanism of local interactions among HIV-1 quasi species in infected tissue. PMID:14745709
Ito, Yoshinori; Grivel, Jean-Charles; Chen, Silvia; Kiselyeva, Yana; Reichelderfer, Patricia; Margolis, Leonid
Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD?), using the Conners’ Continuous Performance Test–II (CPT–II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT–II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD? participants. When examining CPT–II performance over the six study blocks, both HIV+/BD+ and HIV+/BD? participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT–II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD? participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT–II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes.
Posada, Carolina; Moore, David J.; Deutsch, Reena; Rooney, Alexandra; Gouaux, Ben; Letendre, Scott; Grant, Igor; Atkinson, J. Hampton
Difficulties with sustained attention have been found among both persons with HIV infection (HIV+) and bipolar disorder (BD). The authors examined sustained attention among 39 HIV+ individuals with BD (HIV+/BD+) and 33 HIV-infected individuals without BD (HIV+/BD-), using the Conners' Continuous Performance Test-II (CPT-II). A Global Assessment of Functioning (GAF) score was also assigned to each participant as an overall indicator of daily functioning abilities. HIV+/BD+ participants had significantly worse performance on CPT-II omission errors, hit reaction time SE (Hit RT SE), variability of SE, and perseverations than HIV+/BD- participants. When examining CPT-II performance over the six study blocks, both HIV+/BD+ and HIV+/BD- participants evidenced worse performance on scores of commission errors and reaction times as the test progressed. The authors also examined the effect of current mood state (i.e., manic, depressive, euthymic) on CPT-II performance, but no significant differences were observed across the various mood states. HIV+/BD+ participants had significantly worse GAF scores than HIV+/BD- participants, which indicates poorer overall functioning in the dually-affected group; among HIV+/BD+ persons, significant negative correlations were found between GAF scores and CPT-II omission and commission errors, detectability, and perseverations, indicating a possible relationship between decrements in sustained attention and worse daily-functioning outcomes. PMID:22450615
Posada, Carolina; Moore, David J; Deutsch, Reena; Rooney, Alexandra; Gouaux, Ben; Letendre, Scott; Grant, Igor; Atkinson, J Hampton
NEW AGENTS: Among new treatments used for infectious dermatology diseases, new agents for genital herpes, valaciclovir and famciclovir, have greatly simplified therapeutic schemes. Cidofovir has also been shown to be effective against aciclovir-resistant cutaneous and mucosal herpetic lesions and for the treatment of molluscum contagiosum. NEW ADMINISTRATION ROUTES: For genital papillomavirus infections, trials using systemic or intralesional administered interferon have not provided conclusive evidence but imiquimode appears to be quite promising. Itaconazole and fluconazole are effective for onchomycoses. NEW POSSIBILITIES: Ivermectine is effective against scabies, but must be reserved for particularly severe forms. Finally, the emergence of Neisseria gonorrhoeae strains resistant to fluoroquinolones is disquieting. PMID:10874915
Lascaux, A S; Chosidow, O
A study was conducted to ascertain correlates of HIV high risk behaviors and attitudes toward HIV. A questionnaire was administered to 103 men living in a modified therapeutic community (TC) for homeless, chemically addicted and mentally ill men. The psychiatric diagnoses of the sample population included psychotic disorders (48%), depressive disorders (36%), and bipolar disorders (16%). Forty-two percent reported that
Petros Levounis; Marc Galanter; Helen Dermatis; Alexander Hamowy; George De Leon
Therapeutic intervention with highly active antiretroviral therapy (HAART) can lead to suppression of HIV-1 plasma viremia to undetectable levels for 3 or more years. However, adherence to complex drug regimens can prove problematic, and subjects may temporarily discontinue HAART for variable periods. We studied 6 HIV-1-infected individuals who stopped therapy. Off HAART, levels of viremia were suppressed to fewer than
Gabriel M. Ortiz; Douglas F. Nixon; Alexandra Trkola; James Binley; Xia Jin; Sebastian Bonhoeffer; Peter J. Kuebler; Sean M. Donahoe; Marie-Ange Demoitie; William M. Kakimoto; Tom Ketas; Brian Clas; Jonas J. Heymann; Linqi Zhang; Yunzhen Cao; Arlene Hurley; John P. Moore; David D. Ho; Martin Markowitz
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
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.
Bennett, Michael S.; Akkina, Ramesh
Previous studies have suggested the efficacy of foscarnet combined with thymidine analogues as salvage therapy in late-stage HIV-1 infection. Here, we report on the first case of foscarnet therapy in a patient infected with HIV-2 exhibiting virologic failure. The patient was known to be HIV-2-infected since 1992 and had received 11 sequential lines of combined antiretroviral therapy (cART) with almost all the available antiretroviral agents including raltegravir. A marked decrease in HIV-2 plasma viral load of 1.48 log(10)copies/ml was observed at day 14 of foscarnet induction therapy associated with zidovudine and failing cART. An optimized cART was then introduced with lamivudine, zidovudine, lopinavir/r, etravirine and maraviroc. Four months after the end of foscarnet therapy, HIV-2 plasma viral load remained undetectable. This case report suggests that foscarnet may represent a therapeutic option for HIV-2-infected patients exhibiting multidrug resistance. PMID:19962343
Stegmann, Sophie; Manea, Maria Elena; Charpentier, Charlotte; Damond, Florence; Karmochkine, Marina; Laureillard, Didier; Si-Mohamed, Ali; Weiss, Laurence; Piketty, Christophe
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.
Cohen, Myron S.; Muessig, Kathryn E.; Smith, M. Kumi; Powers, Kimberly A.; Kashuba, Angela D.M.
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.
Andrographolide, a diterpene lactone of the Andrographis paniculata, displays anti-HIV activity in vitro. A series of andrographolide derivatives have been synthesized and evaluated for their anti-HIV activity in a cell-free virus infectivity assay using TZM-bl cells. As compared to andrographolide, 3-nitrobenzylidene derivative 6 showed higher in vitro anti-HIV activity, whereas 2',6'-dichloro-nicotinoyl ester derivative 9 showed higher Therapeutic Index. The andrographolide and its derivatives, 6 and 9, inhibited gp120-mediated cell fusion of HL2/3 cells (expressing gp120 on its surface) with TZM-bl cells (expressing CD4 and co-receptors CCR5 & CXCR4). Further, computational studies revealed that these molecules bind to the important residues of V3 loop of gp120. These results suggest that andrographolide derivatives may be promising candidates for prevention of HIV infection. PMID:22858223
Uttekar, Mayur M; Das, Tiyasa; Pawar, Rohan S; Bhandari, Beena; Menon, Vidya; Nutan; Gupta, Satish K; Bhat, Sujata V
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.
Mastroianni, Claudio M.; Lichtner, Miriam; Mascia, Claudia; Zuccala, Paola; Vullo, Vincenzo
Since the discovery of CCR5 as a coreceptor for HIV entry, there has been interest in blockade of the receptor for treatment and prevention of HIV infection. Although several CCR5 antagonists have been evaluated in clinical trials, only maraviroc has been approved for clinical use in the treatment of HIV-infected patients. The efficacy, safety and resistance profile of CCR5 antagonists with a focus on maraviroc are reviewed here along with their usage in special and emerging clinical situations. Despite being approved for use since 2007, the optimal use of maraviroc has yet to be well-defined in HIV and potentially in other diseases. Maraviroc and other CCR5 antagonists have the potential for use in a variety of other clinical situations such as the prevention of HIV transmission, intensification of HIV treatment and prevention of rejection in organ transplantation. The use of CCR5 antagonists may be potentiated by other agents such as rapamycin which downregulate CCR5 receptors thus decreasing CCR5 density. There may even be a role for their use in combination with other entry inhibitors. However, clinical use of CCR5 antagonists may have negative consequences in diseases such as West Nile and Tick-borne encephalitis virus infections. In summary, CCR5 antagonists have great therapeutic potential in the treatment and prevention of HIV as well as future use in novel situations such as organ transplantation. Their optimal use either alone or in combination with other agents will be defined by further investigation. PMID:21284908
Gilliam, Bruce L; Riedel, David J; Redfield, Robert R
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.
Easley, Charles A.; Simerly, Calvin R.; Schatten, Gerald
The last decade has witnessed major advances in our understanding of the epidemiology and pathophysiology of HIV-related cardiovascular disease in sub-Saharan Africa. In this review, we summarise these and discuss clinically relevant advances in diagnosis and treatment. In the Heart of Soweto Study, 10% of patients with newly diagnosed cardiovascular disease were HIV positive, and the most common HIV-related presentations were cardiomyopathy (38%), pericardial disease (13%) and pulmonary arterial hypertension (8%). HIV-related cardiomyopathy is more common with increased immunosuppression and HIV viraemia. With adequate antiretroviral therapy, the prevalence is low. Contributing factors such as malnutrition and genetic predisposition are under investigation. In other settings, pericardial disease is the most common presentation of HIV-related cardiovascular disease (over 40%), and over 90% of pericardial effusions are due to Mycobacterium tuberculosis (TB) pericarditis. HIV-associated TB pericarditis is associated with a greater prevalence of myopericarditis, a lower rate of progression to constriction, and markedly increased mortality. The role of steroids is currently under investigation in the form of a randomised controlled trial. HIV-associated pulmonary hypertension is significantly more common in sub-Saharan Africa than in developed countries, possibly as a result of interactions between HIV and other infectious agents, with very limited treatment options. It has recently been recognised that patients with HIV are at increased risk of sudden death. Infection with HIV is independently associated with QT prolongation, which is more marked with hepatitis C co-infection and associated with a 4.5-fold higher than expected rate of sudden death. The contribution of coronary disease to the overall burden of HIV-associated cardiovascular disease is still low in sub-Saharan Africa. PMID:23680889
Syed, Faisal F; Sani, Mahmoud Umar
Endoscopic ultrasound (EUS) is a viable and often preferred alternative to interventional and radiologic procedures, and the therapeutic applications of EUS continue to evolve. This evolution was catalyzed by the introduction of linear echoendoscopes that provide continuous imaging and observation of needles and by therapeutic devices that pass through large-caliber working channels. In this paper, we will discuss the spectrum of EUS-guided interventions that are currently available and in development.
Abu Dayyeh, Barham K.
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.
Levin, B W; Krantz, D H; Driscoll, J M; Fleischman, A R
It is well established that infection with the human immunodeficiency virus (HIV) leads to immune suppression. Less well known is the fact that long-term, progressive HIV disease is associated with the development of cognitive deficits. Since the introduction of combined antiretroviral therapy (cART), the clinical presentation of HIV infection has evolved into a chronic illness with very low levels of viral replication and chronic immune activation, with compliant affected individuals surviving for decades with a high quality of life. Despite these advances, many HIV-infected individuals develop some degree of neurodegeneration and cognitive impairment. The underlying pathophysiological mechanisms are not well understood, and there are no effective treatments. Thus, there is an unmet need for animal models that enable the study of HIV-associated neurocognitive disorders (HAND) and the testing of new therapeutic approaches to combat them. Here, we review the pros and cons of existing mouse models of HIV infection for addressing these aims and propose a detailed strategy for developing a new mouse model of HIV infection.
Jaeger, Laura B.; Nath, Avindra
This paper addresses the growing phenomena of therapeutic community (TC) treatment approaches for women in correctional settings. Although rapidly increasing in number across the country, there is very little empirical research to support the effectiveness of TC treatment for women. Therefore, the literature on the efficacy and effectiveness of TC treatment for women is reviewed in relation to the literature on women's treatment issues. The literature review highlights the gaps where TC treatment ignores or exacerbates issues that are common to addicted women, or uses methods that may be contradictory to women's recovery.
Eliason, Michele J
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
Sherin, Kevin; Klekamp, Benjamin G; Beal, Jeffery; Martin, Nicolle
Treatment adherence is generally regarded as an important factor in achieving optimal outcomes across many disease states; in the treatment of HIV, poor adherence to treatment has the potential to impact outcomes on multiple levels. Poor adherence to antiretroviral therapy (ART) is associated with less effective viral suppression, which risks the immediate health of the patient, but also risks creating permanent treatment resistance to that particular agent or group of agents within a given combination therapy regimen. This may have downstream effects on treatment costs as well as therapeutic options. The causes of poor adherence to ART are extremely diverse, and include complexity of therapeutic regimens (eg, pill burden and dosing frequency), treatment side effects, poor health literacy, poor patient-physician relationship, and limited access to ART as a result of formulary restrictions or copayment costs. Treatment approaches, such as the use of fixed-dose combinations of ART agents to reduce dosing complexity, as well as educational interventions, such as medication therapy management initiatives, have been shown to improve adherence to therapy in HIV. It is important that all members of the healthcare team address potential barriers to adherence in order to achieve viral suppression and optimize outcomes in patients with HIV. PMID:24495293
Schaecher, Kenneth L
Although therapeutic alliance in schizophrenia has been linked with treatment adherence and outcome, less is known about its clinical correlates. This study explored neurocognition as a possible predictor of perceived therapeutic alliance among people with schizophrenia in cognitive behavior therapy. Twenty-four participants with schizophrenia spectrum disorders and their therapists were administered the Working Alliance Inventory, Short Form after 3 months of therapy. Totals for clients and therapists were correlated with measures of verbal memory, premorbid intelligence, visual spatial reasoning, executive function, and attention, all obtained before beginning therapy. Poorer performance on verbal memory was significantly related to client report of stronger alliance, whereas better performance on visual spatial reasoning was significantly related to therapist report of stronger alliance. Client and therapist ratings of therapeutic alliance were significantly and positively related. Clients' abilities may differentially affect therapist and client perception of therapeutic alliance in schizophrenia. PMID:15232322
Davis, Louanne W; Lysaker, Paul H
HIV-1 represents an elusive target for therapeutic compounds due to its high rate of mutation. Targeting structural patterns instead of a constantly changing specific three-dimensional structure may represent an approach that is less sensitive to viral mutations. The V3 loop of gp120 of HIV-1, which is responsible for binding of viral gp120 to CCR5 or CXCR4 coreceptors, has already been identified as an effective target for the inhibition of viral entry. The peptide derived from the V3 loop of gp120 specifically interacts with the lipid A moiety of LPS, as does the full gp120 protein. NMR analysis of V3 in complex with LPS shows formation of an amphipathic turn. The interaction between LPS and V3 relies on the structural pattern, comprising a combination of hydrophobic and charge interactions, similar to the interaction between antimicrobial peptides and LPS. LPS inhibited binding of gp120 to the surface of target T cells. Nonendotoxic LPS antagonists inhibited viral infection, demonstrating the possibility for the development of an inhibitor of HIV-1 attachment to T cells based on the recognition of a conserved structural pattern. PMID:21636577
Majerle, Andreja; Pristovsek, Primoz; Mancek-Keber, Mateja; Jerala, Roman
Background Visceral leishmaniasis has now emerged as an important opportunistic disease in patients coinfected with human immunodeficiency virus type-1 (HIV-1). Although the effectiveness of HIV-1 protease inhibitors, such as nelfinavir, in antiretroviral therapies is well documented, little is known of the impact of these drugs on Leishmania in coinfected individuals. Methodology and Principal Findings Here, we show that nelfinavir generates oxidative stress in the parasite, leading to altered physiological parameters such as an increase in the sub-G1 DNA content, nuclear DNA fragmentation and loss of mitochondrial potential, which are all characteristics of apoptosis. Pretreatment of axenic amastigotes with the caspase inhibitor z-VAD-fmk did not inhibit the increase in sub-G1 DNA content in nelfinavir-treated parasites, suggesting therefore that this antiviral agent does not kill Leishmania amastigotes in a caspase-dependent manner. Furthermore, we observed that the mitochondrial resident protein endonuclease G is involved. We also demonstrate that parasites overexpressing GSH1 (the rate limiting enzyme of glutathione biosynthesis) were more resistant to nelfinavir when compared to untransfected controls. Conclusions and Significance These data suggest that nelfinavir induces oxidative stress in Leishmania amastigotes, culminating in caspase-independent apoptosis, in which DNA is degraded by endonuclease G. This study provides a rationale for future, long-term design of new therapeutic strategies to test nelfinavir as a potential antileishmanial agent as well as for possible future use in Leishmania/HIV-1 coinfections.
Kumar, Pranav; Lodge, Robert; Trudel, Nathalie; Ouellet, Michel; Ouellette, Marc; Tremblay, Michel J.
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.
Peripheral nerve disorders are frequent complications of HIV disease. Distal symmetrical polyneuropathy (DSP) is the most common peripheral nerve disorder associated with HIV and occurs in over one third of infected patients but may occur in up to 67% if asymptomatic patients are included. Risk factors for DSP include increased age, advanced HIV disease, and history of "d-drugs" or other neurotoxic drugs. The primary manifestations of polyneuropathy are slowly progressive numbness and paresthesias, with burning sensations in the feet usually in a symmetrical pattern. The etiology of HIV-associated DSP is unknown, although neurotoxic effects of cytokines, toxicity of HIV proteins, and mitochondrial damage have been implicated. The current treatment for HIV-associated DSP is symptomatic, with pain modifying medications, including anti-inflammatory agents, opioids, antidepressants, antiepileptics, topical anesthetics, and capsaicin. Sustained virologic control may improve DSP. Novel therapies such as -acetyl-l-carnitine or neurotrophic factors are being studied for treatment of DSP. PMID:17883996
Gonzalez-Duarte, Alejandra; Cikurel, Katia; Simpson, David M