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1

[Hemoglobinopathies. Current therapeutic possibilities].  

PubMed

In recent years, the number of immigrants has increased considerably in Denmark. Consequently, a series of new clinical pictures has appeared in the Danish health care system. Typical examples are the genetic diseases, the haemoglobinopathies. Most of the immigrants come from areas, where the gene frequency of these disorders is widely distributed, for instance the Mediterranean countries, the Middle East, Southeast Asia and Africa. Most frequent are the heterozygous thalassaemias, but also the number of patients with severe thalassaemia and other clinically important haemoglobinopathies such as sickle cell anaemia has also increased in recent years. The clinical problems concerning these patients focus on two important topics, namely genetic counselling of heterozygous individuals (in some cases combined with prenatal diagnostics) and the treatment of patients with clinically severe haemoglobinopathy. The only curative treatment of the haemoglobinopathies is allogeneic bone marrow transplantation, but this treatment can only be offered to a few of these patients. However, a variety of therapeutic options exist which can improve their prognosis and quality of life. Since the number of patients with these diseases will probably increase over the next years we find it relevant, based on typical case stories, to give a review of the present therapeutic possibilities for these disorders. PMID:7770980

Birgens, H S; Karle, H

1995-05-29

2

Therapeutic vaccination reduces HIV sequence variability  

Microsoft Academic Search

With HIV persisting lifelong in infected persons, therapeutic vaccination is a novel alternative concept to control virus replication. Even though CD8 and CD4 cell responses to such immunizations have been demonstrated, their effects on virus replication are still unclear. In view of this fact, we studied the impact of a therapeutic vaccination with HIV nef deliv- ered by a recombinant

Dieter Hoffmann; Judith Seebach; Antonio Cosma; Frank D. Goebel; Korbinian Strimmer; Hermann M. Schatzl; Volker Erfle

2008-01-01

3

Is an HIV vaccine possible?  

PubMed

Although many new prevention modalities that include the use of antiretroviral drugs show promise, there is no question that a global solution to the HIV epidemic will not be economically or logistically feasible without the development of vaccine that provides durable protection. In the best case scenario, the vaccine has to protect against acquisition of infection, likely mediated by Env-specific B-cell responses combined with CD4+ T-cell responses to evoke full maturation and maintenance of protective antibodies. But HIV-specific CD8+ T-cell responses are also likely to be a key element, particularly for those inevitable situations in which full vaccine-induced protection from acquisition is not achieved, in which case durable control of established infection will be required. Although there is reason to be optimistic that an effective HIV vaccine is possible, one of the major constraints moving forward will likely be constraint on funding to support a diversity of concepts at a time that the correlates of protection from acquisition and disease progression are still unknown. Given the scope of the epidemic and the economic climate, we must strive to do much more with less and seek to access additional resources, both scientific and monetary, from every possible source. PMID:22772390

McElrath, M Juliana; Walker, Bruce D

2012-08-01

4

[Therapeutic possibilities after traumatic experiences].  

PubMed

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

Kapfhammer, Hans-Peter

2008-12-01

5

Personalized Therapeutics: HIV Treatment in Adolescents  

PubMed Central

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

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

2009-01-01

6

TB and HIV Therapeutics: Pharmacology Research Priorities  

PubMed Central

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

2012-01-01

7

Novel therapeutic strategies targeting HIV integrase.  

PubMed

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

Quashie, Peter K; Sloan, Richard D; Wainberg, Mark A

2012-04-12

8

[Novel therapeutic possibilities in systemic lupus erythematosus].  

PubMed

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving different organs and organ systems with consequent characteristic clinical and serologic symptoms. Despite of the improvement in lupus survival, approximately 10-20% of patients do not respond to traditional immune suppressive therapies. Relapses are more frequent; e.g. after cyclophosphamide therapy diffuse proliferative nephritis flares in 1/3 of patients. Different immune competent cells and inflammatory mediators participate in the pathogenesis of SLE involving both the adaptive and innate immunity. Several pathogenic elements and mechanisms may serve as therapeutic targets, consequently. Authors summarize novel therapeutic possibilities and their mechanisms regarding the pathogenesis of SLE. Immune modulation of B and T cells, co-stimulatory pathways, cytokine network, soluble mediators and autologous hemopoietic stem cell transplantation are discussed. PMID:20410000

Bazsó, Anna; Poór, Gyula; Gergely, Péter; Kiss, Emese

2010-05-01

9

Contributions of HIV-1 Nef to immune dysregulation in HIV-infected patients: a therapeutic target?  

PubMed

Introduction: HIV accessory protein Nef is a factor responsible for many of the viral pathogenic effects. Progression to AIDS is dramatically delayed and in some well-documented cases completely abolished on infection with naturally occurring HIV strains lacking intact nef sequences in their genomes. The topic of this review is the contribution of Nef to the immune pathology as a possible target in HIV-infected patients. Areas covered: An overview of known Nef functions accounting for its role in pathogenesis is presented, emphasizing interactions with dendritic cells and macrophages, and Nef-induced exosome secretion, all involved in immune dysregulation during the course of HIV infection. Current approaches to Nef inhibition by different classes of compounds are reviewed. Expert opinion: Blocking Nef for therapeutic purposes is a challenging endeavor mainly due to intrinsic properties of this HIV accessory protein. Nef has multiple interfaces to interact with host proteins and lacks a catalytic domain. Potential benefits arising from the development of successful inhibitors could however prove beneficial for reducing gradual deterioration of immune system in chronically infected patients in absence of functional cure. PMID:23967871

Witkowski, Wojciech; Verhasselt, Bruno

2013-08-23

10

Possible additional therapeutic uses of aromatase inhibitors  

Microsoft Academic Search

Several excellent chapters in this book describe the clinical utility of aromatase inhibitors in the treatment of breast cancer.\\u000a It is true to say that use of third-generation aromatase inhibitors has had a major therapeutic impact: emerging clinical\\u000a evidence for some of them shows that they can achieve superior efficacy to tamoxifen, the gold standard of endocrine care\\u000a for more

Barrington J. A. Furr

11

Monoclonal antibody-based candidate therapeutics against HIV type 1.  

PubMed

Treatment of HIV-1 infection has been highly successful with small molecule drugs. However, resistance still develops. In addition, long-term use can lead to toxicity with unpredictable effects on health. Finally, current drugs do not lead to HIV-1 eradication. The presence of the virus leads to chronic inflammation, which can result in increased morbidity and mortality after prolonged periods of infection. Monoclonal antibodies (mAbs) have been highly successful during the past two decades for therapy of many diseases, primarily cancers and immune disorders. They are relatively safe, especially human mAbs that have evolved in humans at high concentrations to fight diseases and long-term use may not lead to toxicities. Several broadly neutralizing mAbs (bnmAbs) against HIV-1 can protect animals but are not effective when used for therapy of an established infection. We have hypothesized that HIV-1 has evolved strategies to effectively escape neutralization by full-size antibodies in natural infections but not by smaller antibody fragments. Therefore, a promising direction of research is to discover and exploit antibody fragments as potential candidate therapeutics against HIV-1. Here we review several bnmAbs and engineered antibody domains (eAds), their in vitro and in vivo antiviral efficacy, mechanisms used by HIV-1 to escape them, and strategies that could be effective to develop more powerful mAb-based HIV-1 therapeutics. PMID:21827278

Chen, Weizao; Dimitrov, Dimiter S

2011-09-23

12

Monoclonal Antibody-Based Candidate Therapeutics Against HIV Type 1  

PubMed Central

Abstract Treatment of HIV-1 infection has been highly successful with small molecule drugs. However, resistance still develops. In addition, long-term use can lead to toxicity with unpredictable effects on health. Finally, current drugs do not lead to HIV-1 eradication. The presence of the virus leads to chronic inflammation, which can result in increased morbidity and mortality after prolonged periods of infection. Monoclonal antibodies (mAbs) have been highly successful during the past two decades for therapy of many diseases, primarily cancers and immune disorders. They are relatively safe, especially human mAbs that have evolved in humans at high concentrations to fight diseases and long-term use may not lead to toxicities. Several broadly neutralizing mAbs (bnmAbs) against HIV-1 can protect animals but are not effective when used for therapy of an established infection. We have hypothesized that HIV-1 has evolved strategies to effectively escape neutralization by full-size antibodies in natural infections but not by smaller antibody fragments. Therefore, a promising direction of research is to discover and exploit antibody fragments as potential candidate therapeutics against HIV-1. Here we review several bnmAbs and engineered antibody domains (eAds), their in vitro and in vivo antiviral efficacy, mechanisms used by HIV-1 to escape them, and strategies that could be effective to develop more powerful mAb-based HIV-1 therapeutics.

Dimitrov, Dimiter S.

2012-01-01

13

[Therapeutic possibilities for the handicapped child].  

PubMed

This article reviews the papers on therapies for handicapped children which were delivered at the 20th annual "Fortbildungskurs der Osterreichischen Gesellschaft für Kinderheilkunde", Obergurgl, 1987. Central topic was the oral region. J. P. Guggenbichler, Innsbruck (pathogenesis) and Sieglinde Zschiesche, Erlangen (The Erlangen interdisciplinary treatment approach) covered genesis and treatment of cheilo-gnatho-palato-schisis. Background and therapy-principles for dysfunctions of the facial, oral and pharyngeal region were discussed by H. Haberfellner, Innsbruck. He also described therapy by use of modified orthodontic devices (ISMAR: Innsbruck sensori-motor activators and regulators) and Schönherr's vestibular screen. The same was done for Castillo-Morales' palatal plates by J. Limbrock, München. Essence and changing features were described for Bobath concept and Petö's Conductive Education by H. Haberfellner and for Vojta's and Castillo-Morales' therapy by J. Limbrock. This part was concluded by a survey on therapeutic sports (H. Haberfellner): Riding on horseback, swimming, skiing and cross-country skiing, also for spinally injured patients. PMID:2970055

Haberfellner, H

1988-01-01

14

Therapeutic potential of HIV protease-activable CASP3  

PubMed Central

Development of a therapeutic application of CASP3/caspase 3/CPP32, an executor of apoptosis, has been challenging because regulation of its activation is complicated. This study aimed to inhibit cancer cell growth and human immunodeficiency virus type 1 (HIV-1) propagation through a CASP3 mutant, CASP3*, activable by HIV-1-encoded aspartate protease. Active CASP3* was delivered to leukemic cells using a protein transduction vehicle, the lentivirus-like nanoparticle (LENA), which should contain thousands of CASP3*-Gag protein molecules and release the activated CASP3* into the target cell cytoplasm. CASP3*-LENA induced apoptosis in various types of leukemic cells. In addition to being effective against leukemic cells, constitutive expression of CASP3* restricted HIV-1 propagation in SUP-T1 cells. The attenuation of HIV-1 replication in SUP-T1/CASP3* cells was attributed to the elimination of HIV-1-infected cells by apoptosis. These data suggest that CASP3* has therapeutic potential against both lymphoid malignancies and HIV-1 infection.

Miyauchi, Kosuke; Urano, Emiko; Takizawa, Mari; Ichikawa, Reiko; Komano, Jun

2012-01-01

15

Therapeutic antibodies in HIV treatment--classical approaches to novel advances.  

PubMed

Therapeutic antibodies have evolved into an important drug class and have achieved considerable success in combating cancers and autoimmune diseases. Although their potential in the treatment of viral infections has not yet been fully explored, recently established approaches have the potential to aid the development of HIV specific antibody therapies. Antibody engineering has led to improvements in antibody isolation and increases in antibody efficacy and potency. Strategies have been developed to tailor Fc recruitment of effector functions, and conjugation of monoclonals to toxins endows them with the ability to mediate destruction of specific target cells. These technical advances introduce the possibility of designing a therapy to target and clear cells infected with a broad range of HIV strains and recommend some hypothetical clinical settings in which advanced antibody therapeutics could be employed in prophylaxis or therapy for HIV infection. PMID:21128888

Abela, Irene A; Reynell, Lucy; Trkola, Alexandra

2010-01-01

16

[Fournier's gangrene in an HIV-positive patient. Therapeutic options].  

PubMed

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

17

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

PubMed Central

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

2013-01-01

18

Pancreatic insufficiency in HIV: is it possible?  

PubMed

Pancreatic involvement in AIDS is very important and common, but there are few studies in the literature concerning the pancreas in AIDS. Therefore, our research involves an important issue in the pancreatic field. The objective of the study was to evaluate the profile of HIV-infected patients with probable exocrine pancreatic insufficiency and its relation to the degree of human immunodeficiency virus (HIV) infection. This is a cross-sectional study carried out at Faculdade de Medicina do ABC in partnership with the basic health care unit Vila Guiomar in Santo André. We selected 118 individuals divided into four groups (a control group and three other groups composed of AIDS patients, separated according to CD4 levels); participants had an interview, completed a questionnaire, and had laboratory and imaging tests. The only clinical variables with significant differences among the studied groups were the use of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections, the administration of chemoprophylaxis, and weight loss. There were no differences in the amylase, lipase, and steatocrit dosages among the groups. Levels of fecal elastase 1 were lower in the HIV patient groups (2, 3, and 4) when compared with the control group, although all of them showed average levels that were much higher than the cutoff point (200??g/g). Only nonalcoholic individuals showed a relationship between diarrhea and alterations in elastase levels. A relationship between the use of HAART and exocrine pancreatic insufficiency in different phases of HIV infection could not be verified. PMID:23088671

Chehter, Ethel Zimberg; Bacci, Marcelo Rodrigues; Alessi, Ruda; D'Oria, Pedro; Chicoli, Felipe; Salloto, Nicole; Maximiano, Fabio Luiz; Fonseca, Fernando Luiz Afonso

2012-11-21

19

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

PubMed

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

Spear, Mark; Guo, Jia; Wu, Yuntao

2013-11-01

20

HIV-1 Accessory Protein Vpr: Relevance in the pathogenesis of HIV and potential for therapeutic intervention  

PubMed Central

The HIV protein, Vpr, is a multifunctional accessory protein critical for efficient viral infection of target CD4+ T cells and macrophages. Vpr is incorporated into virions and functions to transport the preintegration complex into the nucleus where the process of viral integration into the host genome is completed. This action is particularly important in macrophages, which as a result of their terminal differentiation and non-proliferative status, would be otherwise more refractory to HIV infection. Vpr has several other critical functions including activation of HIV-1 LTR transcription, cell-cycle arrest due to DCAF-1 binding, and both direct and indirect contributions to T-cell dysfunction. The interactions of Vpr with molecular pathways in the context of macrophages, on the other hand, support accumulation of a persistent reservoir of HIV infection in cells of the myeloid lineage. The role of Vpr in the virus life cycle, as well as its effects on immune cells, appears to play an important role in the immune pathogenesis of AIDS and the development of HIV induced end-organ disease. In view of the pivotal functions of Vpr in virus infection, replication, and persistence of infection, this protein represents an attractive target for therapeutic intervention.

2011-01-01

21

Developing Novel Conjugate HIV-1 Subunit Therapeutic Vaccines.  

National Technical Information Service (NTIS)

Highly pure, native preparations of recombinant gp120 have been obtained from the T-tropic HIV-l(LAI) and the macrophage-tropic HIV-l(JR-FL) isolates. Conjugates of these HIV-l gp120 preparations were prepared with tetanus toxoid (TT) and keyhole limpet h...

L. D. Giavedoni

1997-01-01

22

Predictors of HIV-specific lymphocyte proliferative immune responses induced by therapeutic vaccination  

PubMed Central

We treated a cohort of 38 HIV-infected individuals with a therapeutic vaccine (Remune, HIV-1 Immunogen) in an open label study. We then determined whether baseline parameters, such as CD4 cell count, viral load and IgG levels, were predictive of the magnitude of the HIV-specific lymphocyte proliferative responses (LPRs). We demonstrate herein that there is a significant enhancement from baseline for both HIV and p24 antigen-stimulated LPRs after immunization. Using a responder definition of a stimulation index of >5 on at least two post-immunization time-points, 29/38 (76%) responded to HIV-1 antigen while 27/38 (71%) responded to native p24 antigen. Viral load and total IgG were negatively correlated, while CD4 cell counts were positively associated with the magnitude of the HIV antigen LPR. In a multivariable analysis, baseline CD4 was the best predictor of HIV antigen LPR post-immunization.

MOSS, R B; WALLACE, M R; STEIGBIGEL, R T; MORRISON, S A; GIERMAKOWSKA, W K; NARDO, C J; DIVELEY, J P; CARLO, D J

2002-01-01

23

[Childhood asthma and viral infection: interactions and therapeutic possibilities].  

PubMed

Rhinovirus infections are the main cause of wheezing in children and adults. Studies carried out with experimental infections report that at least in certain conditions, this infection may spread to the lower respiratory tract as the virus acts on the respiratory epithelium. In vitro experiments with cells from the immune system and lower respiratory tract suggest that the mechanisms of action are directly linked to the production of pro-inflammatory cytokines. Both in vivo and in vitro evidence shows that rhinoviruses may stimulate bronchial epithelial cells to produce cytokines and pro-inflammatory chemokines. They may also stimulate the cholinergic and non-cholinergic nervous system, increasing the production of ICAM-1 and may give rise to a T-lymphocyte non-specific response or to T-lymphocyte replication in direct relation with viral infection. In addition, greater production of cysteinyl leukotrienes has been observed in the secretions of patients with bronchospasm. Experimental infection with Rhinovirus increases clinical symptomatology and bronchial hyperreactivity. The latter is associated with increased eosinophils and cationic proteins in sputum. The above findings suggest that multiple cellular pathways are involved in the induction of exacerbations of asthma induced by the virus. In addition, the possible stimulating role of exposure to allergens in sensitized patients would also increase allergic inflammation. Because of the limited therapeutic efficacy of steroids in reducing exacerbations, new treatment strategies based on greater insight into the physiopathology of the role of viruses in asthma are needed. PMID:11434888

Boquete, M; Carballada, F

24

Affect Management for HIV Prevention with Adolescents in Therapeutic Schools: The Immediate Impact of Project Balance.  

PubMed

Adolescents in therapeutic schools are at greater risk for HIV and other STIs than their peers due to earlier higher rates of sexual risk and difficulty managing strong emotions. HIV prevention programs that incorporate techniques for affect management (AM) during sexual situations may be beneficial. This paper determined the immediate impact of such an intervention, AM, compared to a standard, skills-based HIV prevention intervention and a general health promotion intervention (HP) for 377 youth, ages 13-19, in therapeutic schools in two cities. 1 month after the intervention, analyses that adjusted for the baseline scores found adolescents in AM were more likely to report condom use at last sex than those in HP (0.89 vs. 0.67, p = 0.02) and that their HIV knowledge was significantly greater. These data suggest that AM techniques might improve the impact of standard skills-based prevention programs for adolescents in therapeutic schools. PMID:23975475

Brown, Larry K; Houck, Christopher; Donenberg, Geri; Emerson, Erin; Donahue, Kelly; Misbin, Jesse

2013-10-01

25

Developing Novel Conjugate HIV-1 Subunit Therapeutic Vaccines.  

National Technical Information Service (NTIS)

Highly pure preparations of recombinant gp120 were obtained from two different HIV-1 isolates. Conjugates of these HIV-1 gp120 proteins were prepared with tetanus toxoid (TT) and keyhole limpet hemocyanin (KHL) with the hypothesis that very immunogenic ca...

L. D. Giavedoni

1999-01-01

26

Therapeutic Vaccination Using Cationic Liposome-Adjuvanted HIV Type 1 Peptides Representing HLA-Supertype-Restricted Subdominant T Cell Epitopes: Safety, Immunogenicity, and Feasibility in Guinea-Bissau.  

PubMed

Abstract We have designed a therapeutic HIV-1 vaccine concept based on peptides together with the adjuvant CAF01. Peptides represented 15 HLA-supertype-restricted subdominant and conserved CD8 T cell epitopes and three CD4 T-helper cell epitopes. In this phase I clinical trial, safety and immunogenicity were assessed in untreated HIV-1-infected individuals in Guinea-Bissau, West Africa. Twenty-three HIV-1-infected individuals were randomized to receive placebo (n=5) or vaccine (n=18). Safety was appraised by clinical follow-up combined with monitoring of biochemistry, hematology, CD4 T cell counts, and HIV-1 viral loads. T cell immunogenicity was monitored longitudinally by interferon (IFN)-? ELISpot. New vaccine-specific T cell responses were induced in 6/14 vaccinees for whom ELISpot data were valid. CD4 T cell counts and viral loads were stable. The study shows that therapeutic immunization is feasible and safe in Guinea-Bissau and that it is possible to redirect T cell immunity with CAF01-adjuvanted HIV-1 peptide vaccine during untreated HIV-1 infection in some patients. However, relatively few preexisting and vaccine-induced HIV-1 T cell responses to CD8 T cell epitopes were detected against HIV-1 using IFN-? ELISpot in this chronically infected African population. PMID:23634822

Román, Victor Raúl Gómez; Jensen, Kristoffer Jarlov; Jensen, Sanne Skov; Leo-Hansen, Christian; Jespersen, Sanne; Té, David da Silva; Rodrigues, Candida Medina; Janitzek, Christoph Mikkel; Vinner, Lasse; Katzenstein, Terese Lea; Andersen, Peter; Kromann, Ingrid; Andreasen, Lars Vibe; Karlsson, Ingrid; Fomsgaard, Anders

2013-06-21

27

Soluble mediators of inflammation in HIV and their implications for therapeutics and vaccine development.  

PubMed

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. PMID:22743035

Keating, Sheila M; Jacobs, Evan S; Norris, Philip J

2012-06-27

28

Viral infectivity factor: a novel therapeutic strategy to block HIV-1 replication.  

PubMed

The HIV-1 viral infectivity factor (Vif), one of the six accessory proteins, is essential for viral replication and pathogenesis. Its main function is to form Vif-Cullin5-ElonginBC complex and then is able to ubiquitinate and degrade the human anti-viral factor APOBEC3G, which markedly enhances the virus infectivity. Delete Vif leads to the loss of the infectivity of HIV-1; therefore, Vif is a potentially new attractive target for therapeutic intervention in AIDS. This review describes the structure, function and especially inhibitors of HIV-1 Vif. PMID:23621690

Yang, Guliang; Xiong, Xujie

2013-06-01

29

Targeting persistent HIV infection: Where and how, if possible?  

Microsoft Academic Search

Sanctuaries of persistent human immunodeficiency virus (HIV) infection, which are diverse and still-incompletely resolved, account for the incomplete clearance of HIV among infected persons with a long-standing history of highly active antiretroviral therapy-HAART use. Specifically, sanctuaries of both actively replicating, and latent-virus make-up a source of rebound-viremia in persons living with HIV\\/AIDS (PLWHA) who, either stop or default-from HAART, even

Misaki Wayengera

2011-01-01

30

Therapeutic compliance methodologies in HIV-infection treatment: A comparative study  

Microsoft Academic Search

Compliance with HIV treatment has been studied extensively. Following the introduction of tritherapy, its importance and implications have changed. Antiretroviral treatments entail taking up to 20 pills a day at set hours, for which there are often numerous undesirable and even toxic side effects. These therapeutic constraints lead to what is labeled greater or lesser compliance. Certain factors such as

Cyril Tarquinio; Gustave Nicolas Fischer

2001-01-01

31

Rational design of highly potent HIV-1 fusion inhibitory proteins: Implication for developing antiviral therapeutics  

SciTech Connect

Recombinant protein containing one heptad-repeat 1 (HR1) segment and one HR2 segment of the HIV-1 gp41 (HR1-HR2) has been shown to fold into thermally stable six-helix bundle, representing the fusogenic core of gp41. In this study, we have used the fusogenic core as a scaffold to design HIV-1 fusion inhibitory proteins by linking another HR1 to the C terminus of HR1-HR2 (HR121) or additional HR2 to the N terminus of HR1-HR2 (HR212). Both recombinant proteins could be abundantly and solubly expressed and easily purified, exhibiting high stability and potent inhibitory activity on HIV-1 fusion with IC{sub 50} values of 16.2 {+-} 2.8 and 2.8 {+-} 0.63 nM, respectively. These suggest that these rationally designed proteins can be further developed as novel anti-HIV-1 therapeutics.

Ni Ling [Department of Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Graduate School of the Chinese Academy of Sciences (China); Gao, George F. [Department of Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China)]. E-mail: ggao66@yahoo.com; Tien Po [Department of Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China)]. E-mail: tienpo@sun.im.ac.cn

2005-07-08

32

NTPDase activity in human lymphocytes is not affected by therapeutic doses of anti-HIV drugs.  

PubMed

NTPDase (EC 3.6.1.5) is an enzyme that hydrolyzes extracellular nucleoside tri- and/or diphoshates forming AMP that can serve as a substrate for an ecto-5'-nucleotidase (EC 3.1.3.5) with liberation of adenosine, a modulator of vascular tone and inhibitor of platelet aggregation. These enzymes also occur in lymphocytes playing an important role in immune function. In this study, it was investigated if anti-HIV therapy could affect NTPDase activity in human lymphocytes. Samples of lymphocytes were incubated with different concentrations of anti-HIV drugs and NTPDase activity was determined by colorimetric assay with quantification of inorganic phosphate released. There is not significant difference of NTPDase activity among samples with therapeutic doses of anti-HIV drugs tested when compared with controls. NTPDase activity in peripheral human lymphocytes is not altered by anti-HIV therapy. PMID:21306861

Leal, Daniela B R; Schetinger, Maria R C; Leal, Claudio A M; Bertoncheli, Claudia de M; Morsch, Vera M

2011-01-19

33

Indian Herbal Medicines: Possible Potent Therapeutic Agents for Rheumatoid Arthritis  

PubMed Central

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

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

2007-01-01

34

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

PubMed Central

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

2013-01-01

35

HIV-1 Induces Telomerase Activity in Monocyte-Derived Macrophages, Possibly Safeguarding One of Its Reservoirs  

PubMed Central

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

2012-01-01

36

Sang Froid in a time of trouble: is a vaccine against HIV possible?  

Microsoft Academic Search

Since the announcement of the STEP trial results in the past months, we have heard many sober pronouncements on the possibility of an HIV vaccine. On the other hand, optimistic quotations have been liberally used, from Shakespeare's Henry V's \\

Stanley A Plotkin

2009-01-01

37

Generation and Characterization of a Defective HIV-1 Virus as an Immunogen for a Therapeutic Vaccine  

PubMed Central

Background The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. Results Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/?RT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine ?-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/?RT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/?RT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. Conclusions We propose that immature HIV-1 virions generated from NL4-3/?RT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles.

Garcia-Perez, Javier; Garcia, Felipe; Blanco, Julia; Escriba-Garcia, Laura; Gatell, Jose Maria; Alcami, Jose; Plana, Montserrat; Sanchez-Palomino, Sonsoles

2012-01-01

38

Nuclear localization signal of HIV-1 as a novel target for therapeutic intervention.  

PubMed Central

BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) is a lentivirus and shares with other members of this retroviral subfamily the ability to replicate in nondividing cells, in particular, cells of the monocyte/macrophage lineage. This feature relies on the presence of a specific nuclear localization signal (NLS) within the viral matrix protein (MA p17), which to some degree can be complemented by the activity of the viral vpr gene product. The MA p17 NLS ensures efficient transportation of the viral preintegration complex into the nucleus of an infected macrophage and confers persistence of HIV-1 in quiescent T cells, and therefore presents an attractive target for therapeutic intervention. MATERIALS AND METHODS: Nuclear localization signals (NLS) in general and the HIV-1 MA p17 NLS in particular are characterized by a stretch of positively charged amino acids including one or more lysine residues. A series of compounds potentially capable of binding and reacting with lysine by forming Schiff base adducts was synthesized. Our special consideration was to make compounds that would preferentially bind to two closely contiguous amino functions, as opposed to isolated single lysine residues. We assumed that this approach might specifically target the compound to NLS while affecting other regions less, thus reducing nonspecific cytotoxicity. Antiviral activity was assessed in primary monocytes and in peripheral blood lymphocytes (PBL) infected with HIV-1ADA strain. Viral replication was monitored by reverse transcriptase (RT) activity in the supernatant. Efficiency of nuclear importation of the viral preintegration complex was estimated by the formation of 2-LTR circle forms of HIV-1 DNA and also by in situ PCR techniques. RESULTS: Arylene bis(methyl ketone) compounds with a nitrogenous third subsituent, especially a pyrimidinic side-chain, inhibited HIV-1 replication in human monocytes at an IC50 as low as 1 nM. These compounds did not block HIV-1 replication in peripheral blood lymphocyte cultures. The inhibitory effect observed in monocyte cultures appeared in the context of markedly reduced nuclear importation of viral DNA in the presence of the drug. No cytotoxic effects of the compounds was observed in vitro at concentrations as high as 10 microM. An amidinohydrazone derivative of the most active compound was about 100 times less active than the parent, indicating that carbonyl groups were instrumental in the antiviral effect. CONCLUSIONS: These early results suggest that retroviral replication in nondividing cells is susceptible to pharmaceutical intervention targeted against the NLS activity of HIV-1 proteins in the viral preintegration complex. The compounds described efficiently block translocation of viral DNA to the nuclei of infected primary monocytes, and inhibit viral replication. This inhibition is effective only in nondividing cells and is not seen in proliferating cultures, such as activated PBLs. Thus, drugs that target HIV-1 NLS may be useful to specifically block the macrophage arm of HIV infection and could thereby be of value in treating macrophage-specific manifestations of HIV disease, such as HIV-1 dementia. In combination with other drugs, potential therapeutics exploiting this target may also help to control the progression of HIV-1 infection and disease. Images FIG. 3 FIG. 4 FIG. 5 FIG. 6

Dubrovsky, L.; Ulrich, P.; Nuovo, G. J.; Manogue, K. R.; Cerami, A.; Bukrinsky, M.

1995-01-01

39

Safe Thinking and Affect Regulation (STAR): HIV Prevention in Alternative/Therapeutic Schools  

PubMed Central

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

2011-01-01

40

Associated actinomycosis and rhinopharyngeal adenocarcinoma during HIV infection: diagnostic and therapeutic issues.  

PubMed

An extremely infrequent episode of nasopharyngeal actinomycosis associated with squamous adenocarcinoma occurred in an HIV-infected male patient with a previous diagnosis of AIDS, treated with combined antiretroviral therapy taken with insufficient adherence, such that a satisfactory immune system recovery (as expressed by a CD4 lymphocyte count persistently above 400 cells/mcl), contrasted with a low-level persistence of detectable HIV viraemia, and enlarged genotypic resistance mutations. Interestingly, a number of local and specific risk factors for both infectious and neoplastic disorders were recognized by healthcare staff (tobacco smoke, long-term inhalatory substance abuse, in particular cocaine, and semi-professional mushroom-truffle hunting, including evaluation by systematic smelling). Despite appropriate and timely diagnostic assessment carried out with repeated, combined computerized tomography, magnetic resonance imaging, and fiberoptic rhinoscopy with biopsy and histopathologic studies, the final diagnosis of a combined dual infectious-neoplastic pathology occurred only after a demolishing surgical intervention and subsequent pathology studies. Despite proper antimicrobial therapy, and an associated radiotherapy and cytotoxic chemotherapy schedule, rapid dissemination of multiple secondary lesions to the brain rapidly led to our patient's death. The imaging and histopathological diagnostics of the dual illnesses of our HIV-infected patient, and its therapeutic and outcome features, are presented and discussed on the basis of the evidence from the available literature. To the best of our knowledge, this is the first described case of actinomycosis associated with a local, underlying squamous cell adenocarcinoma of the same ear, nose, and throat district in either HIV-infected or HIV-non-infected subjects. PMID:18843216

Sabbatani, Sergio; Fulgaro, Ciro; Latini, Gino; Burzi, Marcellino; Manfredi, Roberto

2008-09-01

41

Communication, recruitment and enrolment in the preventative and therapeutic phase I clinical trial against HIV\\/AIDS based on the recombinant HIV1 Tat protein  

Microsoft Academic Search

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

2011-01-01

42

Roles for Biological Membranes in Regulating Human Immunodeficiency Virus Replication and Progress in the Development of HIV Therapeutics that Target Lipid Metabolism  

PubMed Central

Infection by the human immunodeficiency virus (HIV) involves a number of important interactions with lipid components in host membranes that regulate binding, fusion, internalization, and viral assembly. Available data suggests that HIV actively modifies the sphingolipid content of cellular membranes to create focal environments that are favorable for infection. In this review, we summarize the roles that membrane lipids play in HIV infection and discuss the current status of therapeutics that attempt to modify biological membranes to inhibit HIV.

Haughey, Norman J.; Tovar-y-Romo, Luis B.; Bandaru, Veera Venkata Ratnam

2012-01-01

43

Antiretroviral therapeutic possibilities for human immunodeficiency virus\\/acquired immunodeficiency syndrome  

Microsoft Academic Search

In human immunodeficiency virus (HIV)\\/acquired immunodeficiency syndrome (AIDS) illness, the reverse transcriptase and protease (PRT) enzymes of HIV are currently the targets of antiretroviral (ARV) therapy. Nucleoside analogues were the first group of ARV drugs that exerted antiviral activity in patients. More recently, PRT inhibitors have provided new approaches in the treatment of HIV infection and AIDS. Impressive clinical results

G. A Balint

2001-01-01

44

Lower HIV Prevalence Among Asian\\/Pacific Islander Men Who Have Sex with Men: A Critical Review for Possible Reasons  

Microsoft Academic Search

We conducted a critical literature review for possible reasons that may explain the lower HIV prevalence observed among API\\u000a MSM compared to MSM of other races\\/ethnicities. Trends emerging from the literature suggest that traditional individual-level\\u000a factors—unprotected anal intercourse, substance use, STD prevalence, rates and frequency of HIV testing, and utilization of\\u000a HIV prevention services—do not appear to be related to

Chongyi Wei; H. Fisher Raymond; Frank Y. Wong; Anthony J. Silvestre; Mark S. Friedman; Patricia Documét; Willi McFarland; Ron Stall

2011-01-01

45

Endotoxin release in cardiac surgery with cardiopulmonary bypass: pathophysiology and possible therapeutic strategies. An update.  

PubMed

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

2011-04-01

46

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

ERIC Educational Resources Information Center

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

Rule, Peter

2011-01-01

47

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

ERIC Educational Resources Information Center

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

Rule, Peter

2011-01-01

48

Boosters of a therapeutic HIV-1 vaccine induce divergent T cell responses related to regulatory mechanisms.  

PubMed

Therapeutic human immunodeficiency virus (HIV) vaccines aim to reduce disease progression by inducing HIV-specific T cells. Vacc-4x are peptides derived from conserved domains within HIV-1 p24 Gag. Previously, Vacc-4x induced T cell responses in 90% of patients which were associated with reduced viral loads. Here we evaluate the effects of Vacc-4x boosters on T cell immunity and immune regulation seven years after primary immunization. Twenty-five patients on effective antiretroviral therapy received two Vacc-4x doses four weeks apart and were followed for 16 weeks. Vacc-4x T cell responses were measured by proliferation (CFSE), INF-?, CD107a, Granzyme B, Delayed-Type Hypersensitivity test (DTH) and cytokines and chemokines (Luminex). Functional regulation of Vacc-4x-specific T cell proliferation was estimated in vitro using anti-IL-10 and anti-TGF-ß monoclonal antibodies. Vacc-4x-specific CD8(+) T cell proliferation increased in 80% after either the first (64%) or second (16%) booster. Only 40% remained responders after two boosters with permanently increased Vacc-4x-specific proliferative responses (p=0.005) and improved CD8(+) T cell degranulation, IFN-? production and DTH. At baseline, responders had higher CD8(+) T cell degranulation (p=0.05) and CD4(+) INF-? production (p=0.01), whereas non-responders had higher production of proinflammatory TNF-?, IL-1? and IL-1ß (p<0.045) and regulatory IL-10 (p=0.07). Notably, IL-10 and TGF-ß mediated downregulation of Vacc-4x-specific CD8(+) T cell proliferation increased only in non-responders (p<0.001). Downregulation during the study correlated to higher PD-1 expression on Vacc-4x-specific CD8(+) T cells (r=0.44, p=0.037), but was inversely correlated to changes in Vacc4x-specific CD8(+) T cell proliferation (r=-0.52, p=0.012). These findings show that Vacc-4x boosters can improve T cell responses in selected patients, but also induce vaccine-specific downregulation of T cell responses in others. Broad surveillance of T cell functions during immunization may help to individualize boosting, where assessment of vaccine-related immune regulation should be further explored as a potential new parameter. PMID:23906886

Lind, Andreas; Brekke, Kristin; Sommerfelt, Maja; Holmberg, Jens O; Aass, Hans Christian D; Baksaas, Ingebjørg; Sørensen, Birger; Dyrhol-Riise, Anne Ma; Kvale, Dag

2013-07-30

49

HIV-1 vaccine antibody induction against a variable region of HIV-1: a possible link to protective immunity?  

PubMed

Evaluation of: Liao H, Bonsignori M, Alam M et al. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity 38, 176-186 (2013). In 2009, results from the Phase III HIV-1 vaccine clinical trial RV144 applying a prime/boost regimen with a canarypox vaccine vector ALVAC-HIV plus the AIDSVAX B/E subunit envelope vaccine conducted in Thailand were reported. The priming canarypox vector carried the HIV-1 vaccine genes gp120 linked to the transmembrane-anchoring portion of subtype B gp41, HIV-1 Gag and protease; the boosting vaccine was composed of clades B and E of HIV-1 gp120. A 31.2% vaccine efficacy could be seen in this trial, an encouraging result in HIV-1 vaccine research that had been previously plagued with little clinical efficacy. In this paper, results from tests of four monoclonal antibodies isolated from RV144 vaccinees are reported. The antibodies recognize a certain HIV-1 envelope residue (169), neutralize laboratory-adapted HIV-1 strains and mediate killing of CD4(+) cells infected with HIV-1 laboratory isolates. Crystal structure analysis suggests that the recognized HIV-1 envelope epitope can exist in different conformations. It is thought that the immune pressure elicited by the monoclonal antibodies targets a HIV-1 envelope region with variable sequence structure. PMID:23638741

Bauer, Gerhard

2013-05-01

50

Heart rate as a possible therapeutic guide for the prevention of cardiovascular disease.  

PubMed

Epidemiologic evidence indicates that an elevated heart rate (HR) is an independent predictor of all-cause and cardiovascular (CV) mortality. Ivabradine, a pure HR-lowering agent, reduces CV events in patients with coronary artery disease (CAD) and chronic heart failure, and indicate that an HR greater than 70 b.p.m. is hazardous. These findings demonstrate not only that an elevated HR is an epiphenomenon of CV risk status but also that an elevated HR itself should be a therapeutic target. In addition, recent epidemiologic evidence demonstrates that the in-treatment HR or HR change predicts subsequent all-cause and CV mortality, independent of the HR-lowering strategy. Characteristics of the in-treatment HR or HR change are also important as possible therapeutic guides for risk management. However, there have been concerns regarding deleterious effects on CV event prevention owing to ?-blocker-derived pharmacologic HR reduction. The potential role of HR and its modulation should be considered in future guidance documents. PMID:23966053

Inoue, Taku; Iseki, Kunitoshi; Ohya, Yusuke

2013-08-22

51

Possible therapeutic targets among the molecules involved in the Warburg effect in tumor cells.  

PubMed

The majority of human tumors display a high rate of glycolysis under aerobic conditions. This phenomenon was recognized approximately seven decades ago and is known as the Warburg effect. Several key enzymes required to maintain this high level of glucose metabolism are found in tumor cells. The effects of the glycolytic enzymes are known to be directly or indirectly regulated by various signaling pathways, oncogenes, suppressor genes and transcription factors. Recent molecular biology studies have shown that multiple genetic alterations are related to tumor development. Therefore, these factors may be rational targets for cancer therapy. In this short review, we describe several important molecules that affect aerobic glycolysis and discuss their possible use as therapeutic targets for cancer. PMID:23780970

Nam, Sung Ouk; Yotsumoto, Fusanori; Miyata, Kohei; Shirasu, Naoto; Miyamoto, Shingo; Kuroki, Masahide

2013-07-01

52

Sang Froid in a time of trouble: is a vaccine against HIV possible?  

PubMed Central

Since the announcement of the STEP trial results in the past months, we have heard many sober pronouncements on the possibility of an HIV vaccine. On the other hand, optimistic quotations have been liberally used, from Shakespeare's Henry V's "Once more unto the breach, dear friends" to Winston Churchill's definition of success as "going from one failure to another with no loss of enthusiasm". I will forgo optimistic quotations for the phrase "Sang Froid", which translates literally from the French as "cold blood"; what it really means is to avoid panic when things look bad, to step back and coolly evaluate the situation. This is not to counsel easy optimism or to fly in face of the facts, but I believe that while the situation is serious, it is not desperate. I should stipulate at the outset that I am neither an immunologist nor an expert in HIV, but someone who has spent his life in vaccine development. What I will try to do is to provide a point of view from that experience. There is no doubt that the results of STEP were disappointing: not only did the vaccine fail to control viral load, but may have adversely affected susceptibility to infection. But HIV is not the only vaccine to experience difficulties; what lessons can we glean from prior vaccine development?

2009-01-01

53

[Oral candidiasis in HIV-seropositive patients and AIDS cases. Clinical, mycological and therapeutical aspects].  

PubMed

A prospective study to identify clinical and mycological aspects of oral candidiasis including a therapeutic trial for 4 drugs-2 topical (chlotrimazole and nistatine) and 2 systemic (itraconale and ketoconazole) was performed on 97 HIV adult patients from March 2003 to June 2004. Average age was 34.97 years, being males and heterosexual behaviour predominant. The pseudomembranous clinical form of presentation prevailed in 93.8% of cases, with accompanying symptoms like pain, burning sensation and difficult swallowing in addition to extensive lesions. Candida albicans was the most frequently isolated species both in swabs taken at the beginning (92%) and at the end of the treatment schedules applied to patients who did not succeed in mycological cure (89.4%). Treatment schemes had positive results from the clinical viewpoint in 91.8% of cases with improvement or total remission of symptoms and signs, and in 51.6% of mycological curing. There were no statistically significant differences of clinical and mycological responses between topical and systemic treatments. The above-mentioned allowed recommending a more extensive use of local treatment in the studied population because of their benefits for the patients. PMID:23424783

Prieto Santa Anna, Luz Marina; Illnait Zaragozi, Maria Teresa; Ramos Rodallegas, Edna G; Lazcano Herrero, Bonfilio; Márquez Sánchez, Norma; Cantelar de Francisco, Nereyda; Manzur Katriba, Julián; Martínez Machin, Gerardo

54

A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy?,??  

PubMed Central

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 <5000 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.

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.

2010-01-01

55

A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy.  

PubMed

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

2009-05-29

56

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

PubMed Central

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.

2011-01-01

57

Systemic and Mucosal Differences in HIV Burden, Immune and Therapeutic Responses  

PubMed Central

Background Mucosal tissues represent major targets for HIV transmission, but differ in susceptibility and reservoir function by unknown mechanisms. Methods In a cross-sectional study, HIV RNA and infectious virus were compared between oral and genital compartments and blood in HIV-infected women, in association with clinical parameters, co-pathogens and putative innate and adaptive HIV inhibitors. Results HIV RNA was detectable in 24.5% of women from all 3 compartments, whereas 45% had RNA in only one or two sites. By comparison, infectious HIV, present in blood of the majority, was rare in mucosal sites. Innate mediators, SLPI and TSP, were highest in mucosae. Highly active antiretroviral therapy (HAART) was associated with an 80% decreased probability of shedding. Multivariate logistic regression models revealed that mucosal HIV RNA was associated with higher plasma RNA, infectious virus, and total mucosal IgA, but not IgG. There was a 37-fold increased probability of detecting RNA in both genital and oral specimens (P=0.008;P=0.02, respectively) among women in highest vs lowest IgA tertiles. Conclusions Mucosal sites exhibit distinct characteristics of infectious HIV, viral shedding and responses to therapy, dependent upon both systemic and local factors. Of the putative innate and adaptive mucosal defense factors examined, only IgA was associated with HIV RNA shedding. However, rather than being protective, there was a striking increase in probability of detectable HIV RNA shedding in women with highest total IgA.

Wahl, Sharon M.; Redford, Maryann; Christensen, Shawna; Mack, Wendy; Cohn, Jon; Janoff, Edward N.; Mestecky, Jiri; Jenson, Hal B.; Navazesh, Mahvash; Cohen, Mardge; Reichelderfer, Patricia; Kovacs, Andrea

2011-01-01

58

Direct Effects of HIV-1 Tat on Excitability and Survival of Primary Dorsal Root Ganglion Neurons: Possible Contribution to HIV-1-Associated Pain  

PubMed Central

The vast majority of people living with human immunodeficiency virus type 1 (HIV-1) have pain syndrome, which has a significant impact on their quality of life. The underlying causes of HIV-1-associated pain are not likely attributable to direct viral infection of the nervous system due to the lack of evidence of neuronal infection by HIV-1. However, HIV-1 proteins are possibly involved as they have been implicated in neuronal damage and death. The current study assesses the direct effects of HIV-1 Tat, one of potent neurotoxic viral proteins released from HIV-1-infected cells, on the excitability and survival of rat primary dorsal root ganglion (DRG) neurons. We demonstrated that HIV-1 Tat triggered rapid and sustained enhancement of the excitability of small-diameter rat primary DRG neurons, which was accompanied by marked reductions in the rheobase and resting membrane potential (RMP), and an increase in the resistance at threshold (RTh). Such Tat-induced DRG hyperexcitability may be a consequence of the inhibition of cyclin-dependent kinase 5 (Cdk5) activity. Tat rapidly inhibited Cdk5 kinase activity and mRNA production, and roscovitine, a well-known Cdk5 inhibitor, induced a very similar pattern of DRG hyperexcitability. Indeed, pre-application of Tat prevented roscovitine from having additional effects on the RMP and action potentials (APs) of DRGs. However, Tat-mediated actions on the rheobase and RTh were accelerated by roscovitine. These results suggest that Tat-mediated changes in DRG excitability are partly facilitated by Cdk5 inhibition. In addition, Cdk5 is most abundant in DRG neurons and participates in the regulation of pain signaling. We also demonstrated that HIV-1 Tat markedly induced apoptosis of primary DRG neurons after exposure for longer than 48 h. Together, this work indicates that HIV-1 proteins are capable of producing pain signaling through direct actions on excitability and survival of sensory neurons.

Byrd, Daniel; Chang, Kuei-Hua; Shah, Kavita; Hu, Ningjie; Grantham, Ayslinn; Hu, Sishun; Duan, Jianhong; Tao, Feng; Nicol, Grant; Yu, Qigui

2011-01-01

59

NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities.  

PubMed

Reactive oxygen species (ROS) influence many physiological processes including host defense, hormone biosynthesis, fertilization, and cellular signaling. Increased ROS production (termed "oxidative stress") has been implicated in various pathologies, including hypertension, atherosclerosis, diabetes, and chronic kidney disease. A major source for vascular and renal ROS is a family of nonphagocytic NAD(P)H oxidases, including the prototypic Nox2 homolog-based NAD(P)H oxidase, as well as other NAD(P)H oxidases, such as Nox1 and Nox4. Other possible sources include mitochondrial electron transport enzymes, xanthine oxidase, cyclooxygenase, lipoxygenase, and uncoupled nitric oxide synthase. NAD(P)H oxidase-derived ROS plays a physiological role in the regulation of endothelial function and vascular tone and a pathophysiological role in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis, and rarefaction, important processes underlying cardiovascular and renal remodeling in hypertension and diabetes. These findings have evoked considerable interest because of the possibilities that therapies against nonphagocytic NAD(P)H oxidase to decrease ROS generation and/or strategies to increase nitric oxide (NO) availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress target organ damage associated with hypertension and diabetes. Here we highlight current developments in the field of reactive oxygen species and cardiovascular disease, focusing specifically on the recently identified novel Nox family of NAD(P)H oxidases in hypertension. We also discuss the potential role of targeting ROS as a therapeutic possibility in the management of hypertension and cardiovascular disease. PMID:18227481

Paravicini, Tamara M; Touyz, Rhian M

2008-02-01

60

HIV-1 infection and alcohol abuse: Neurocognitive impairment, mechanisms of neurodegeneration and therapeutic interventions  

PubMed Central

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

2011-01-01

61

Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases.  

PubMed

Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives. PMID:23688272

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

2013-08-01

62

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

PubMed

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

Pertwee, Roger G

2012-12-01

63

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

ERIC Educational Resources Information Center

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

2006-01-01

64

Performance of Clinical Criteria for Screening of Possible Antiretroviral Related Mitochondrial Toxicity in HIV-Infected Children in Accra.  

PubMed

Mitochondrial damage is implicated in highly active antiretroviral therapy (HAART) toxicity. HIV infection also causes mitochondrial toxicity (MT). Differentiating between the two is critical for HIV management. Our objective was to test the utility of the Mitochondrial Disease Criteria (MDC) and the Enquête Périnatale Française (EPF) to screen for possible HAART related MT in HIV-infected children in Ghana. The EPF and MDC are compilations of clinical symptoms, or criteria, of MT: a (+) score indicates possible MT. We applied these criteria retrospectively to 403 charts of HIV-infected children. Of those studied, 331/403 received HAART. Comparing HAART exposed and HAART naïve children, the difference in EPF score, but not MDC, approached significance (P = 0.1). Young age at HIV diagnosis or at HAART initiation was associated with (+) EPF (P ? 0.01). Adherence to HAART trended toward an association with (+) EPF (P = 0.09). Exposure to nevirapine, abacavir, or didanosine increased risk of (+) EPF (OR = 3.55 (CI = 1.99-6.33), 4.76 (2.39-9.43), 4.93 (1.29-18.87)). Neither EPF nor MDC identified a significant difference between HAART exposed or naïve children regarding possible MT. However, as indicators of HAART exposure are associated with (+) EPF, it may be a candidate for prospective study of possible HAART related MT in resource-poor settings. PMID:23533730

Langs-Barlow, Allison; Renner, Lorna; Katz, Karol; Northrup, Veronika; Paintsil, Elijah

2013-03-07

65

Do Men who have Sex with Men (MSM) in the United States Understand that HIV Serodiscordance is Possible?  

PubMed Central

Background Little is currently known about the extent to which US MSM understand the possibility that a long-term sex partner can have an HIV status different than one’s own status. This information is important in the adaptation of Couples Voluntary HIV Counseling and Testing (CVCT) for US MSM. Methods 428 US MSM completed an online survey using MySpace.com from March-April, 2009. Results Of 426 MSM with complete data, 21.1% (90) were not definitively aware that serodiscordance is possible. Factors associated with a lack of understanding that serodiscordance is possible were: never having tested for HIV (OR: 2.0; CI: 1.1, 3.8), compared to testing 0-6 months previously and having a high school education or less (OR: 2.2; CI: 1.1, 4.5), compared to men who had completed at least some college. Conclusions A large proportion of young, internet-using MSM in the United States may not understand that HIV serodiscordance is possible within sexual partnerships. Based on these results, we recommend that CVCT provided to male couples in the United States should include education on HIV serodiscordance.

Wagenaar, Bradley H.; Grabbe, Kristina L.; Stephenson, Rob; Khosropour, Christine M.; Sullivan, Patrick S.

2013-01-01

66

Impact of the number of failed therapeutic regimes on the development of resistance mutations to HIV-1 in northeast Brazil.  

PubMed

Highly-potent antiretroviral therapy is necessary to avoid viral replication in HIV patients; however, it can favor the appearance of resistance mutations. The mutations 41L, 67N, 70R, 210W, 215Y/F, 219E/Q, 44D and 118I are defined as nucleoside analogous mutations (NAMs), because they affect the efficacy of all nucleoside reverse transcriptase inhibitors (NRTI). The mutation most frequently associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) is 103N. 33W/F, 82A/F/L/T, 84V and 90M are called protease inhibitor resistance-associated mutations (PRAM), because they are associated with resistance to several protease inhibitors (PI). This study evaluated the development of resistance mutations and examine the susceptibility of HIV with these mutations to antiretrovirals in HIV-1 patients who have failed one or more therapy regimes. Analyses were made of 101 genotypic tests of patients with therapeutic failure to 2 or 3-drug regimens with NRTI, NNRTI or PI. We used the Stanford database to define the susceptibility profile of the viruses. The samples were divided into three treatment-failure groups: first (F), second (S) and multi-failure (MF) to antiretroviral regimens, and we correlated these groups with resistance profiles and principal mutations. There was a significant increase in resistance mutations V82A/F/L/T, I84V, L90M, M41L, K70R, L210W, T215Y/F and K219Q/E in MF. We also found significantly higher resistance to zidovudine, didanosine, stavudine and abacavir in MF. There was no increase in resistance to tenofovir (p=0.28) and lopinavir (p=0.079) in MF. A high degree of resistance to NNRTIs was observed in all groups. Increased resistance mutations will affect future therapeutic options for HIV patients in Brazil because it results in a significant increase in resistance to antiretroviral drugs. PMID:17962868

Medeiros, Melissa Soares; Arruda, Erico Antônio Gomes; Guerrant, Richard Littleton; Brown, Christopher Cooley; Lima, Aldo Angelo Moreira

2007-10-01

67

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

PubMed

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. J. Med. Virol. 85:2057-2064, 2013. © 2013 Wiley Periodicals, Inc. 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

2013-08-19

68

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

PubMed

Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. PMID:23806280

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

2013-06-24

69

Is gene therapy a good therapeutic approach for HIV-positive patients?  

PubMed Central

Despite advances and options available in gene therapy for HIV-1 infection, its application in the clinical setting has been challenging. Although published data from HIV-1 clinical trials show safety and proof of principle for gene therapy, positive clinical outcomes for infected patients have yet to be demonstrated. The cause for this slow progress may arise from the fact that HIV is a complex multi-organ system infection. There is uncertainty regarding the types of cells to target by gene therapy and there are issues regarding insufficient transduction of cells and long-term expression. This paper discusses state-of-the-art molecular approaches against HIV-1 and the application of these treatments in current and ongoing clinical trials.

Marathe, Jai G; Wooley, Dawn P

2007-01-01

70

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

PubMed Central

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

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

2010-01-01

71

HIV\\/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic Technologies  

Microsoft Academic Search

World-wide, hepatitis C virus (HCV) accounts for approximately 130 million chronic infections, with an overall 3% prevalence.\\u000a Four to 5 million persons are co-infected with HIV. It is well established that HIV has a negative impact on the natural history\\u000a of HCV, including a higher rate of viral persistence, increased viral load, and more rapid progression to fibrosis, end-stage\\u000a liver

Eva A. Operskalski; Andrea Kovacs

2011-01-01

72

In Vitro Downregulation of Matrix Metalloproteinase-9 in Rat Glial Cells by CCR5 Antagonist Maraviroc: Therapeutic Implication for HIV Brain Infection  

Microsoft Academic Search

BackgroundMatrix metalloproteinases (MMPs) released by glial cells are important mediators of neuroinflammation and neurologic damage in HIV infection. The use of antiretroviral drugs able to combat the detrimental effect of chronic inflammation and target the exaggerated MMP activity might represent an attractive therapeutic challenge. Recent studies suggest that CCR5 antagonist maraviroc (MVC) exerts immunomodulant and anti-inflammatory activity beyond its anti-HIV

Pasqua Gramegna; Tiziana Latronico; Maria Teresa Branà; Gaetano Di Bari; Fabio Mengoni; Valeria Belvisi; Maria T. Mascellino; Miriam Lichtner; Vincenzo Vullo; Claudio M. Mastroianni; Grazia M. Liuzzi

2011-01-01

73

Treatment of torture survivors - influences of the exile situation on the course of the traumatic process amd therapeutic possibilities.  

PubMed

Traumatized refugees often suffer from complex posttraumatic disorders with a high tendency of chronicity. This is due to severe and often repeated traumatization in the course of political persecution on one hand and uprooting and ongoing stress caused by leaving their home country and society and living under an adverse situation in exile on the other hand. This article shows how positive and negative factors going along with migration interfere with the course of the traumatic process and the therapeutic possibilities and how the therapeutic process can be adjusted to the situation. PMID:17728486

Wenk-Ansohn, Mechthild

2007-01-01

74

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

PubMed Central

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

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

2011-01-01

75

The ischemic heart disease life stress monitoring program: Possible therapeutic mechanisms  

Microsoft Academic Search

This paper attempts to identify the therapeutic components responsible for the mortality-reducing impact of the Ischemic Heart Disease Life Stress Monitoring Program. Designed to break the link between stress and illness, this one-year intervention program for patients recovering from myocardial infarctions included monthly telephone monitoring of psychological symptoms of stress and home nursing visits for high stress patients. Nursing interventions

Nancy Frasure-smith; Raymond H. Prince

1987-01-01

76

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

ERIC Educational Resources Information Center

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

Kagotho, Njeri

2012-01-01

77

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

ERIC Educational Resources Information Center

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

Kagotho, Njeri

2012-01-01

78

Possible benefits of micronutrient supplementation in the treatment and management of HIV infection and AIDS  

Microsoft Academic Search

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

2009-01-01

79

Theoretical Assessment of Public Health Impact of Imperfect Prophylactic HIV1 Vaccines with Therapeutic Benefits  

Microsoft Academic Search

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

2006-01-01

80

To cure chronic HIV infection, a new therapeutic strategy is needed  

Microsoft Academic Search

With the advent of highly active anti-retroviral therapy (HAART) in 1997, most investigators felt that HIV infection would be cured with a few years of antiviral therapy. It is now clear that antiviral drugs alone cannot cure the infection, even when applied within a few weeks of initial symptoms. There are now several reports of the discontinuation of HAART after

Kendall A Smith

2001-01-01

81

[Modern possibilities of therapeutic aid in the time of mass sanitary losses of radiation profile].  

PubMed

Modern concept of medical-prophylactic measures in the time of mass radiation affection is presented in the present article. Moreover the past changes in organization-regular structure of medical service of the Armed Forces of the Russian Federation and appearance of new time-board equipment were taken into account. Recommendations about the rendering of all types of therapeutic aid on all stages of medical evacuation--first, premedical, medical assistance, qualified and specialized--are given. PMID:22558849

Khalimov, Iu Sh; Grebeniuk, A N; Karamullin, M A; Matveev, S Iu; Vlasenko, A N

2012-02-01

82

Rethinking deprivations of liberty: possible contributions from therapeutic and ecological jurisprudence.  

PubMed

In place of the police and parens patriae powers, this article proposes three distinct justifactory models for government-sponsored deprivations of liberty. The punishment model authorizes deprivation of liberty as a sanction for blameworthy behavior. The prevention model authorizes deprivation of liberty to prevent harm, either through deterrence or restraint. The protection model authorizes liberty deprivation to ensure autonomous decisionmaking. The article compares these models to the purposes traditionally advanced as justification for punishment, and explores their strengths and weaknesses. Using therapeutic jurisprudence and ecological jurisprudence as organizing frameworks, it then describes a range of empirical issues raised by each of the models. PMID:11018782

Slobogin, C; Fondacaro, M

2000-01-01

83

Recent therapeutic strategies for spinal cord injury treatment: possible role of stem cells.  

PubMed

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

2012-04-27

84

Possible therapeutic effects of myxobacterial metabolites on type I Gaucher disease.  

PubMed

Gaucher disease (GD) is the most prevalent lysosomal storage disorder caused by an inherited deficiency of glucocerebrosidase. In the present study, we aimed to determine whether myxobacterial metabolites exhibit a potential therapeutic effect in the cells from a patient with type I GD. We screened 288 bioactive compounds of myxobacteria in the skin fibroblasts from a patient with type I GD. MTT assays were performed to determine their effects on cell viability. The expression levels of Bcl-2-associated X protein (Bax), ATP-citrate synthase (ATP-CS), E3-binding protein (E3BP), and acetyl-coenzyme A acetyltransferase 1 (ACAT1) were determined by western blotting to understand the molecular mechanisms of myxobacterial metabolites in cells. Thin-layer chromatography (TLC) was carried out to measure changes in glucosylceramide levels in the cultured fibroblasts. This screening process identified 4 compounds that increased cell viability more than 1.45 times. After exposure to these compounds, the expression level of Bax decreased, whereas those of ATP-CS, E3BP, and ACAT1 increased. TLC revealed reduced amounts of intracellular glucosylceramides in patient cells. Here we suggest that myxobacterial metabolites can relieve the stress due to glucosylceramide accumulation, and that it may be utilized as a new therapeutic approach. PMID:22634098

Kim, Sung-Jo; Kang, Sunyang; Kim, June-Bum

2012-05-24

85

Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications  

PubMed Central

The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.

Louboutin, Jean-Pierre; Strayer, David S.

2012-01-01

86

A Randomized Trial of Therapeutic Drug Monitoring of Protease Inhibitors in Antiretroviral-Experienced, HIV-1-Infected Patients  

PubMed Central

Objective Whether therapeutic drug monitoring of protease inhibitors (PIs) improves outcomes in HIV-infected patients is controversial. We evaluated this strategy in a randomized, open-label clinical trial, using a normalized inhibitory quotient (NIQ), which incorporates drug exposure and viral drug resistance. NIQs?1 may predict poor outcome and identify patients who could benefit from dose escalation. Design/Methods Eligible patients had a viral load ?1,000 copies/mL on a failing regimen, and began a new PI-containing regimen at entry. All FDA-approved PIs available during study recruitment (June 2002-May 2006) were allowed. One-hundred-eighty-three participants with NIQ?1, based on their week 2 PI trough concentration and pre-entry drug resistance test, were randomized at week 4 to standard of care (SOC) or PI dose escalation (TDM). The primary endpoint was change in log10 plasma HIV-1 RNA concentration from randomization to 20 weeks later. Results Ninety-one subjects were randomized to SOC, 92 to TDM. NIQs increased more in the TDM arm compared to SOC (+69% versus +25%, p=0.01). Despite this, TDM and SOC arms showed no difference in outcome (+0.09 versus +0.02 log10, p=0.17). In retrospective subgroup analyses, patients with less HIV resistance to their PIs benefited from TDM (p=0.002), as did black and Hispanic patients (p=0.035 and 0.05, respectively). Differences between black and white patients persisted when accounting for PI susceptibility. Conclusions There was no overall benefit of TDM. In post-hoc, subgroup analyses, TDM appeared beneficial in black and Hispanic patients, and in patients whose virus retained some susceptibility to the PIs in their regimen.

Demeter, Lisa M.; Jiang, Hongyu; Mukherjee, A. Lisa; Morse, Gene D.; DiFrancesco, Robin; Dykes, Carrie; Sista, Prakash; Bacheler, Lee; Klingman, Karin; Rinehart, Alex; Albrecht, Mary

2009-01-01

87

Prevention of HIV infection in primary care: current practices, future possibilities.  

PubMed

More than a decade has passed since the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome (AIDS) epidemic began; our failure to develop an effective vaccine and adequate medical treatments indicates that future research and practice must work to prevent the spread of HIV. We review the literature on the current HIV-prevention practices of primary care physicians and highlight opportunities for clinical prevention. Prevention is hindered in four ways: 1) by narrow conceptions of medical care and of the role of the physician; 2) by physicians' discomfort with discussing human sexuality and illicit drug use and their attitudes toward persons with HIV or AIDS; 3) by constraints on time and resources; and 4) by the ambiguity of HIV prevention messages. We suggest strategies to overcome these barriers, including modifications in public policy, health care delivery systems, and medical education. These strategies support a nonhierarchical physician-patient relationship, with attention to culture and values, that will help physicians to identify and work with persons at increased risk for HIV infection. PMID:7574227

Makadon, H J; Silin, J G

1995-11-01

88

SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers.  

PubMed

DNA methylation is a major contributor to epigenetic alterations and as such is a potential biomarker and therapeutic target in gastrointestinal malignancies. DNA methylation is commonly observed in several Gastrointestinal (GI) malignancies including pancreatic and colorectal cancer. Methylation results in decreased expression of tumor suppressor genes. Secreted protein acidic and rich in cysteine (SPARC) is a tumor suppressor gene that can be functionally inactivated through methylation. SPARC is commonly dysregulated in GI malignancies. Inhibition of DNA methylation can reverse the silencing of SPARC. In the present review, we will discuss recent advances in our understanding of the features of DNA methylation that pertain to SPARC, focusing on their functional and clinical relevance in GI carcinogenesis. PMID:22939997

Nagaraju, Ganji Purnachandra; El-Rayes, Bassel F

2012-08-29

89

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

PubMed

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

2013-09-01

90

Natural products as anti-glycation agents: possible therapeutic potential for diabetic complications.  

PubMed

Diabetes mellitus is characterised by hyperglycaemia, lipidaemia and oxidative stress and predisposes affected individuals to long-term complications afflicting the eyes, skin, kidneys, nerves and blood vessels. Increased protein glycation and the subsequent build-up of tissue advanced glycation endproducts (AGEs) contribute towards the pathogenesis of diabetic complications. Protein glycation is accompanied by generation of free radicals through autoxidation of glucose and glycated proteins and via interaction of AGEs with their cell surface receptors (referred to as RAGE). Glycationderived free radicals can damage proteins, lipids and nucleic acids and contribute towards oxidative stress in diabetes. There is interest in compounds with anti-glycation activity as they may offer therapeutic potential in delaying or preventing the onset of diabetic complications. Although many different compounds are under study, only a few have successfully entered clinical trials but none have yet been approved for clinical use. Whilst the search for new synthetic inhibitors of glycation continues, little attention has been paid to anti-glycation compounds from natural sources. In the last few decades the traditional system of medicine has become a topic of global interest. Various studies have indicated that dietary supplementation with combined anti-glycation and antioxidant nutrients may be a safe and simple complement to traditional therapies targeting diabetic complications. Data for forty two plants/constituents studied for anti-glycation activity is presented in this review and some commonly used medicinal plants that possess anti-glycation activity are discussed in detail including their active ingredients, mechanism of action and therapeutic potential. PMID:22268395

Elosta, Abdulhakim; Ghous, Tahseen; Ahmed, Nessar

2012-03-01

91

Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: Possible therapeutic targets?  

PubMed

Nitric oxide (NO) is synthetized enzymatically from l-arginine (l-Arg) by three NO synthase isoforms, iNOS, eNOS and nNOS. The synthesis of NO is selectively inhibited by guanidino-substituted analogs of l-Arg or methylarginines such as asymmetric dimethylarginine (ADMA), which results from protein degradation in cells. Many disease states, including cardiovascular diseases and diabetes, are associated with increased plasma levels of ADMA. The N-terminal catalytic domain of these NOS isoforms binds the heme prosthetic group as well as the redox cofactor, tetrahydrobiopterin (BH4) associated with a regulatory protein, calmodulin (CaM). The enzymatic activity of NOS depends on substrate and cofactor availability. The importance of BH4 as a critical regulator of eNOS function suggests that BH4 may be a rational therapeutic target in vascular disease states. BH4 oxidation appears to be a major contributor to vascular dysfunction associated with hypertension, ischemia/reperfusion injury, diabetes and other cardiovascular diseases as it leads to the increased formation of oxygen-derived radicals due to NOS uncoupling rather than NO. Accordingly, abnormalities in vascular NO production and transport result in endothelial dysfunction leading to various cardiovascular disorders. However, some disorders including a wide range of functions in the neuronal, immune and cardiovascular system were associated with the over-production of NO. Inhibition of the enzyme should be a useful approach to treat these pathologies. Therefore, it appears that both a lack and excess of NO production in diseases can have various important pathological implications. In this context, NOS modulators (exogenous and endogenous) and their therapeutic effects are discussed. PMID:23859953

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

2013-07-13

92

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

PubMed Central

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.

2011-01-01

93

Novel Recombinant Engineered gp41 N-terminal Heptad Repeat Trimers and Their Potential as Anti-HIV-1 Therapeutics or Microbicides*  

PubMed Central

Peptides derived from N-terminal heptad repeat (NHR) of the HIV-1 gp41 are generally poor inhibitors of HIV-1 entry, because they tend to aggregate and do not form a trimeric coiled-coil. In this study, we have fused portions of gp41 NHR, e.g. N36 or N28, to the T4 fibritin trimerization domain, Foldon (Fd), thus constructing novel NHR trimers, designated N36Fd or N28Fd, which could be expressed in Escherichia coli cells. The purified N36Fd and N28Fd exhibited SDS-resistant trimeric coiled-coil conformation with improved ?-helicity compared with the corresponding N-peptides. They could interact with a C-peptide (e.g. C34) to form stable six-helix bundle and possessed potent anti-HIV-1 activity against a broad spectrum of HIV-1 strains. N28Fd was effective against T20-resistant HIV-1 variants and more resistant to proteinase K compared with T20 (enfuvirtide), a C-peptide-based HIV fusion inhibitor. Therefore, N28Fd trimer has great potentials for further development as an affordable therapeutic or microbicide for treatment and prevention of HIV-1 infection.

Chen, Xi; Lu, Lu; Qi, Zhi; Lu, Hong; Wang, Ji; Yu, Xiaoxia; Chen, Yinghua; Jiang, Shibo

2010-01-01

94

Warfarin Therapy in the HIV Medical Home Model: Low Rates of Therapeutic Anticoagulation Despite Adherence and Differences in Dosing Based on Specific Antiretrovirals  

PubMed Central

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.

2012-01-01

95

The nurses'experience of possible HIV infection after injury and/or exposure on duty.  

PubMed

The purpose of the research was to describe the experience of nurses in the studied hospital who had been exposed to possible HIV infection during injury or exposure on duty. A qualitative phenomenological descriptive study was used to describe the emotions and non-verbal reactions of the twelve participants during two subsequent in-depth interviews. These were conducted post-exposure, and after counselling and prophylactic treatment took place. The nursing staffs from a selected private hospital were included in the study after exposure of blood and/or human body fluid. After completion of the study, it was found that the exposed staff's experience had two main categories. Firstly, they were grieving for the loss of the concept of being healthy and invincible, blessed with nursing skills and definite goals in life. The bereavement process included phases of denial, anger, anxiety and fear, with recurring thoughts regarding the adverse events, as well as acceptance which developed with time. The bereavement process and shock of the exposure had wider consequences to the family, as well as an impact on the working environment. Most participants reported that they experienced genuine support and compassion from colleagues, at home and in the community. The second category of experience was the physical side effects which participant's developments developed due to the prophylactic antiretroviral therapy. Some participants experienced severe difficulties due to the treatment, while other had fewer problems. Some proposals to adjust and possibly improve the hospital's exposure surveillance system were developed from the research results, including that a 24-hour crisis management system be implemented for exposed staff members; that support groups be started for staff, colleagues and family members; that all staff receive orientation and support during unfamiliar procedures or placement in unknown departments; that all exposures-on-duty be investigated and studied so that pro-active or preventive measures may be devised; and that problems with staffing and working climate be resolved. All the findings and proposals were subsequently addressed to the relevant members of the Hospital Management. If healthcare services wish to retain nursing staff in future, more will need to be done to prevent all types of exposure-on-duty and, if they do occur, to anticipate, manage and shorten the subsequent period of the professional nurse or learner's bereavement. PMID:19653533

Roets, L; Ziady, L E

2008-12-01

96

Glucagon-like peptide 1 (GLP-1): a potent gut hormone with a possible therapeutic perspective.  

PubMed

Glucagon-like peptide 1 (GLP-1) is a physiological incretin hormone from the lower gastrointestinal tract, partially explaining the augmented insulin response after oral compared to intravenous glucose administration in normal humans. In addition, GLP-1 also lowers glucagon concentrations, slows gastric emptying, stimulates (pro)insulin biosynthesis, and reduces food intake upon intracerebroventricular administration in animals. Therefore, GLP-1 offers some interesting perspective for the treatment of type 2, and perhaps also for type 1 diabetic patients. The other incretin hormone, gastric inhibitory polypeptide (GIP), has lost almost all its activity in type-2 diabetic patients. In contrast, GLP-1 glucose-dependently stimulates insulin secretion in type-2 diabetic patients and exogenous administration of GLP-1 ([7-37] or [7-36 amide]) in doses elevating plasma concentrations to approximately three to four times physiological postprandial levels fully normalizes fasting hyperglycaemia and reduces postprandial glycaemic increments. Due to rapid proteolytic cleavage, which results in an inactive or even antagonistic fragment. GLP-1 [9-36 amide], and to rapid elimination, the half-life of GLP-1 is too short to maintain therapeutic plasma levels for sufficient periods by subcutaneous injections of the natural peptide hormone. Current research aims to characterize GLP-1 analogues with more suitable pharmacokinetic properties than the original peptide. Given the large amount of GLP-1 present in L cells, it also appears worthwhile to search for more agents that could 'mobilize' this endogenous pool of GLP-1. PMID:9840447

Nauck, M A

1998-10-01

97

Therapeutic Immunization with Human Immunodeficiency Virus Type 1 (HIV1) Peptide-Loaded Dendritic Cells Is Safe and Induces Immunogenicity in HIV1Infected Individuals  

Microsoft Academic Search

Treatments for human immunodeficiency virus type 1 (HIV-1)-positive individuals that augment HIV-1 suppression and have potential for achieving long-term control of HIV-1 viremia in the absence of antiretro- viral therapy (ART) are urgently needed. We therefore conducted a phase I, clinical safety trial of a dendritic cell (DC)-based vaccination strategy as immunotherapy for HIV-1-positive individuals on ART. We studied 18

Nancy C. Connolly; Theresa L. Whiteside; Cara Wilson; Venkatswarlu Kondragunta; Charles R. Rinaldo; Sharon A. Riddler

2008-01-01

98

Communication, recruitment and enrolment in the preventative and therapeutic phase I clinical trial against HIV/AIDS based on the recombinant HIV-1 Tat protein.  

PubMed

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 support both the sponsor and the volunteers during trial enrolment and conduction. This process, which is an integrated, multidisciplinary, biomedical and psycho-socio-behavioural network, represented a novel and important aspect for the conduction and success of the clinical study. A specific flow of information from the sponsor to the population was developed through the SCP which started from the national announcement of the trials (through a press conference and a press release) to the enrolment of the volunteers. To this aim a telephone counselling intervention was performed to supply the scientific information translated in personalised message, allowing to select potential participants prior to the first contact with the clinical sites. Furthermore, the multi-step procedure contributed in reinforcing the motivation to participation and trial retention, providing important hints for the design of standardised enrolment procedures to be used in clinical studies. Indeed, this methodological approach, which foresees the joined participation of researchers and expert of communication, could be followed in future vaccine trials in order to improve the effectiveness of enrolment procedures. PMID:21390884

Luzi, Anna Maria; Gallo, Pietro; Colucci, Anna; Marcotullio, Simone; Bellino, Stefania; Longo, Olimpia; Ensoli, Barbara

2011-07-07

99

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

ERIC Educational Resources Information Center

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

Ramrathan, P.

2003-01-01

100

Influence of naturally occurring antioxidants on magnetic nanoparticles: risks, benefits, and possible therapeutic applications.  

PubMed

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

2013-03-11

101

Minority report: hidden memory genomes in HIV-1 quasispecies and possible clinical implications.  

PubMed

The RNA viruses replicate as complex distributions of closely related genomes termed viral quasispecies. The behavior of the evolving quasispecies and its response to selective pressures such as antiviral treatment is influenced by the ensemble of mutants that compose the viral population. One such influence is the presence of minority subpopulations in the mutant spectra of viral quasispecies. Biologically relevant mutants have long been known to be present as minority components of replicating viral populations. However, experiments designed with specific mutants of the animal pathogen foot-and-mouth disease virus in cell culture explained the presence of a class of minority genomes termed memory genomes. They descend from those variants that were dominant at an earlier phase of quasispecies evolution, and arise as a consequence of quasispecies dynamics, when viral populations are subjected to discontinuous selective pressures. The presence of memory genomes has also been documented during intrahost evolution of HIV-1 in vivo. The analysis of sequential viral samples of different HIV-1-infected patients showed that two distinct types of memory can operate in retroviruses: a replicative memory analogous to that observed in foot-and-mouth disease virus, as well as a reservoir memory derived from the integrative phase of the retroviral lifecycle. Despite being hidden as minority components of the HIV-1 viral population (ranging from about 0.1 to 20% of the total number of genomes in the quasispecies analyzed), memory genomes can drive the evolution of the virus during HIV-1 infections under antiviral therapy. The limited availability of current experimental data on minority HIV-1 subpopulations in vivo implies that further studies are required in order to define the cutoffs of clinically relevant minority genomes. Nevertheless, it is already evident that such low-abundance genomes remain undetectable by traditional genotyping methods such as consensus sequencing or conventional hybridization techniques. Several experimental systems are currently available for the detection and characterization of minority components of the mutant spectra of viral quasispecies including HIV, hepatitis C virus and hepatitis B virus. Some of these biotechnological approaches could, in the near future, be taken over and exploited in the clinical setting as useful biosensors with which to improve the management of HIV-infected patients. PMID:18615120

Briones, Carlos; Domingo, Esteban

102

Development and preclinical safety evaluation of a new therapeutic HIV-1 vaccine based on 18 T-cell minimal epitope peptides applying a novel cationic adjuvant CAF01.  

PubMed

Therapeutic immunization of HIV-1-infected individuals with or without anti-retroviral therapy is a new promising disease prevention. To induce a new cytotoxic T(CD8) lymphocyte (CTL) immunity during chronic HIV-1 infection 15 infrequently targeted but conserved HLA-supertype binding CTL epitopes from Gag, Pol, Nef, Env, Vpu and Vif were identified. The 15 T(CD8) and three T(CD4) helper peptides were GMP synthesised and formulated with a new adjuvant CAF01 which is a synthetic two-component liposomic adjuvant comprising the quaternary ammonium dimethyl-dioctadecyl-ammonium (DDA) and the immune modulator trehalose 6,6'-dibehenate (TDB). Using IFN-? ELISPOT assay, T-cell immune induction by the vaccine was found to both CD4 and CD8 T-cell restricted peptides in HLA-A2 transgenic mice. Comprehensive toxicity studies of the CAF01 adjuvant-alone and together with different vaccines showed that CAF01 when tested at human dose levels was safe and well tolerated with only local inflammation at the site of injection and no systemic reactions. No pharmacological safety issues were observed in Beagle dogs. The HIV-1 vaccine toxicity study in the Göttingen Minipig(®) showed no systemic toxicity from five repetitive i.m. injections, each with a 2-week interval, of either the 18 HIV-1 peptide antigen solution (AFO18) or the AFO18-CAF01, in which the 18 HIV-1 peptides were formulated with the CAF01 adjuvant. Distinct inflammatory responses were observed in the injected muscles of the AFO18-CAF01 vaccine treated animals as a result of the immune stimulating effect of the adjuvant on the vaccine. The results of the toxicity studies provide optimism for phase I clinical trials evaluating the therapeutic HIV-1 T-cell vaccination approach using multiple subdominant minimal epitope peptides applying the novel cationic adjuvant CAF01. PMID:21767590

Fomsgaard, Anders; Karlsson, Ingrid; Gram, Gregers; Schou, Christian; Tang, Sheila; Bang, Peter; Kromann, Ingrid; Andersen, Peter; Andreasen, Lars Vibe

2011-07-19

103

Modified therapeutic community aftercare for clients triply diagnosed with HIV\\/AIDS and co-occurring mental and substance use disorders  

Microsoft Academic Search

This clinical trial evaluated a modified therapeutic community aftercare (MTC-A) program for a population triply diagnosed with HIV\\/AIDS, a substance use disorder, and a mental disorder. After six months of MTC residential treatment (MTC-R), subjects were randomly assigned to MTC-A (n=42) or to standard aftercare (C; n=34). Follow-up interviews at six and 12 months assessed eight outcome domains and adherence

Stanley Sacks; Karen McKendrick; Peter Vazan; JoAnn Y. Sacks; Charles M. Cleland

2011-01-01

104

Acceptability and effectiveness of chickpea sesame-based ready-to-use therapeutic food in malnourished HIV-positive adults  

PubMed Central

Objective: A prospective descriptive study to assess acceptability and effectiveness of a locally made ready-to-use therapeutic food (RUTF) in HIV-infected chronically sick adults (CSA) with mid-upper-arm circumference (MUAC) <210 mm or pitting edema. Methods: Sixty-three wasted AIDS adults were prescribed 500 g representing ~2600 kcal/day of locally made RUTF for three months and routine cotrimoxazole. Weight, height, MUAC, Karnofsky score and morbidity were measured at admission and at monthly intervals. The amount of RUTF intake and acceptability were assessed monthly. Results: Ninety-five percent (60/63) of the CSA that were invited to join the study agreed to participate. Mean daily intake in these 60 patients was 300 g/person/day (~1590 Kcal and 40 g of protein). Overall, 73.3% (44/60) gained weight, BMI, and MUAC. The median weight, MUAC and BMI gains after three months were 3.0 kg, 25.4 mm, and 1.1 kg/m2, respectively. The intervention improved the physical activity performance of participants and 78.3% (47/60) regained sufficient strength to walk to the nearest health facility. Mortality at three months was 18.3% (11/60). Conclusion: Locally made RUTF was acceptable to patients and was associated with a rapid weight gain and physical activity performance. The intervention is likely to be more cost effective than nutritional support using usual food-aid commodities.

Bahwere, Paluku; Sadler, Kate; Collins, Steve

2009-01-01

105

A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential.  

PubMed

Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area. We report the properties of the first mGlu4-selective orthosteric agonist, derived from a virtual screening hit, LSP4-2022 using cell-based assays with recombinant mGlu receptors [EC(50): 0.11 ± 0.02, 11.6 ± 1.9, 29.2 ± 4.2 ?M (n>19) in calcium assays on mGlu4, mGlu7, and mGlu8 receptors, respectively, with no activity at the group I and -II mGlu receptors at 100 ?M]. LSP4-2022 inhibits neurotransmission in cerebellar slices from wild-type but not mGlu4 receptor-knockout mice. In vivo, it possesses antiparkinsonian properties after central or systemic administration in a haloperidol-induced catalepsy test, revealing its ability to cross the blood-brain barrier. Site-directed mutagenesis and molecular modeling was used to identify the LSP4-2022 binding site, revealing interaction with both the glutamate binding site and a variable pocket responsible for selectivity. These data reveal new approaches for developing selective, hydrophilic, and brain-penetrant mGlu receptor agonists, offering new possibilities to design original bioactive compounds with therapeutic potential. PMID:22223752

Goudet, Cyril; Vilar, Bruno; Courtiol, Tiphanie; Deltheil, Thierry; Bessiron, Thomas; Brabet, Isabelle; Oueslati, Nadia; Rigault, Delphine; Bertrand, Hugues-Olivier; McLean, Heather; Daniel, Hervé; Amalric, Marianne; Acher, Francine; Pin, Jean-Philippe

2012-01-05

106

Trends of HIV1 and HIV2 prevalence among pregnant women in Guinea-Bissau, West Africa: possible effect of the civil war 1998–1999  

Microsoft Academic Search

Objectives: Sentinel surveys in Bissau, the capital of Guinea-Bissau, have shown low prevalence of HIV-1 but high HIV-2 prevalence before 1998. Guinea-Bissau experienced a civil war in 1998–1999. To examine specifically the trends of HIV prevalence from antenatal surveys in Bissau, Guinea-Bissau in 1987–2004, and whether the civil war in 1998–1999 could have an effect on HIV prevalence levels after

Fredrik Ma?nsson; Alfredo Alves; Zacarias Jose? da Silva; Francisco Dias; So?ren Andersson; Gunnel Biberfeld; Eva Maria Fenyo?; Hans Norrgren

2007-01-01

107

Modified therapeutic community aftercare for clients triply diagnosed with HIV/AIDS and co-occurring mental and substance use disorders.  

PubMed

This clinical trial evaluated a modified therapeutic community aftercare (MTC-A) program for a population triply diagnosed with HIV/AIDS, a substance use disorder, and a mental disorder. After six months of MTC residential treatment (MTC-R), subjects were randomly assigned to MTC-A (n=42) or to standard aftercare (C; n=34). Follow-up interviews at six and 12 months assessed eight outcome domains and adherence to prescribed HIV medication. A propensity model was used to re-balance the retrieved sample. At the six-month follow-up, High stratum MTC-A clients (those with greater psychological functioning and stable physical health at baseline) had greater improvement overall and for substance use and mental health than C clients in the same stratum. In contrast, C clients in the Low/Medium stratum (those with poorer psychological functioning and improved physical health) had more favorable outcomes overall and for substance use than their MTC-A counterparts; however, this stratum was not re-balanced effectively. Differences in HIV medication adherence were not detected. Clients with greater psychological functioning and stable health at treatment entry benefit more from the MTC-A program. In view of the potentially progressive nature of HIV, measuring physical and mental health during treatment and controlling for changes could be important in future research. PMID:21711215

Sacks, Stanley; McKendrick, Karen; Vazan, Peter; Sacks, Joann Y; Cleland, Charles M

2011-06-29

108

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

PubMed Central

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.

2012-01-01

109

Ready to Use Therapeutic Foods (RUTF) improves undernutrition among ART-treated, HIV-positive children in Dar es Salaam, Tanzania  

PubMed Central

Background HIV/AIDS is associated with an increased burden of undernutrition among children even under antiretroviral therapy (ART). To treat undernutrition, WHO endorsed the use of Ready to Use Therapeutic Foods (RUTF) that can reduce case fatality and undernutrition among ART-naïve HIV-positive children. However, its effects are not studied among ART-treated, HIV-positive children. Therefore, we examined the association between RUTF use with underweight, wasting, and stunting statuses among ART-treated HIV-positive children in Dar es Salaam, Tanzania. Methods This cross-sectional study was conducted from September-October 2010. The target population was 219 ART-treated, HIV-positive children and the same number of their caregivers. We used questionnaires to measure socio-economic factors, food security, RUTF-use, and ART-duration. Our outcome variables were underweight, wasting, and stunting statuses. Results Of 219 ART-treated, HIV-positive children, 140 (63.9%) had received RUTF intervention prior to the interview. The percentages of underweight and wasting among non-RUTF-receivers were 12.4% and 16.5%; whereas those of RUTF-receivers were 3.0% (P?=?0.006) and 2.8% (P?=?0.001), respectively. RUTF-receivers were less likely to have underweight (Adjusted Odd Ratio (AOR) =0.19, CI: 0.04, 0.78), and wasting (AOR?=?0.24, CI: 0.07, 0.81), compared to non RUTF-receivers. Among RUTF receivers, children treated for at least four months (n?=?84) were less likely to have underweight (P?=?0.049), wasting (P?=?0.049) and stunting (P?HIV-positive children under ART, the provision of RUTF for at least four months was associated with low proportions of undernutrition status. RUTF has a potential to improve undernutrition among HIV-positive children under ART in the clinical settings in Dar es Salaam, Tanzania.

2012-01-01

110

GI side-effects of a possible therapeutic GRF analogue in monkeys are likely due to VIP receptor agonist activity.  

PubMed

Growth hormone (GH) is used or is being evaluated for efficacy in treatment of short stature, aspects of aging, cardiac disorders, Crohn's disease, and short bowel syndrome. Therefore, we synthesized several stable growth hormone-releasing factor (GRF) analogues that could be therapeutically useful. One potent analog, [D-Ala(2),Aib(8, 18,)Ala(9, 15, 16, 22, 24-26,)Gab(27)]hGRF(1-27)NH(2) (GRF-6), with prolonged infusion caused severe diarrhea in monkeys; however, it had no side-effects in rats. Because GRF has similarity to VIP/PACAP and VIPomas cause diarrhea, this study investigated the ability of this and other GRF analogues to interact with the VIP/PACAP receptors. Rat VPAC(1)-R (rVPAC(1)-R), human VPAC(1)-R (hVPAC(1)-R), rVPAC(2)-R and hVPAC(2)-R stably transfected CHO and PANC 1 cells were made and T47D breast cancer cells containing native human VPAC(1)-R and AR4-2J cells containing PAC(1)-R were used. hGRF(1-29)NH(2) had low affinity for both rVPAC(1)-R and rVPAC(2)-R while VIP had a high affinity for both receptors. GRF-6 had a low affinity for both rVPAC(1)-R and rVPAC(2)-R and very low affinity for the rPAC(1)-R. VIP had a high affinity, whereas hGRF(1-29)NH(2) had a low affinity for both hVPAC(1)-R and hVPAC(2)-R. In contrast GRF-6, while having a low affinity for hVPAC(2)-R, had relatively higher affinity for the hVPAC(1)-R. In guinea pig pancreatic acini, all GRF analogues were full agonists at the VPAC(1)-R causing enzyme secretion. These results demonstrate that in contrast to native hGRF(1-29)NH(2,) GRF-6 has a relatively high affinity for the human VPAC(1)-R but not for the human VPAC(2)-R, rat VPAC(1)-R, rat VPAC(2)-R or rat PAC(1)-R. These results suggest that the substituted GRF analog, GRF-6, likely causes the diarrheal side-effects in monkeys by interacting with the VPAC(1)-R. Furthermore, they demonstrate significant species differences can exist for possible therapeutic peptide agonists of the VIP/PACAP/GRF receptor family and that it is essential that receptor affinity assessments be performed in human cells or from a closely related species. PMID:11445245

Ito, T; Igarashi, H; Pradhan, T K; Hou, W; Mantey, S A; Taylor, J E; Murphy, W A; Coy, D H; Jensen, R T

2001-07-01

111

A Low-Molecular-Weight Compound K7174 Represses Hepcidin: Possible Therapeutic Strategy against Anemia of Chronic Disease.  

PubMed

Hepcidin is the principal iron regulatory hormone, controlling the systemic absorption and remobilization of iron from intracellular stores. The expression of the hepcidin gene, HAMP, is increased in patients with anemia of chronic disease. Previously, the synthetic compound K7174 was identified through chemical screening as a novel inhibitor of the adhesion of monocytes to cytokine-stimulated endothelial cells. K7174 also ameliorated anemia induced by inflammatory cytokines in mice, which suggests a possible involvement of hepcidin regulation. The present study was performed to assess the impact of K7174 on hepcidin expression in a human hematoma cell line and in mice in vivo. We first demonstrated that K7174 treatment in HepG2 cells significantly decreased HAMP expression. Then, we conducted microarray analysis to determine the molecular mechanism by which K7174 inhibits HAMP expression. Transcriptional profiling confirmed the downregulation of HAMP. Surprisingly, we found that K7174 strongly induced GDF15, known as a negative regulator of HAMP expression. Western blotting analysis as well as ELISA confirmed the induction of GDF15 by K7174 treatment. Furthermore, K7174-mediated HAMP suppression was rescued by the silencing of GDF15 expression. Interestingly, we found that K7174 also upregulates CEBPB. Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. Subsequently, we also examined whether K7174 inhibits hepcidin expression in mice. Quantitative RT-PCR analysis with liver samples from K7174-treated mice demonstrated significant upregulation of Gdf15 and downregulation of Hamp expression, as compared to control mice. Furthermore, serum hepcidin concentration was also significantly decreased in K7174-treated mice. In conclusion, K7174 inhibits hepcidin expression partly by inducing GDF15. K-7174 may be a potential therapeutic option to treat anemia of chronic disease. PMID:24086573

Fujiwara, Tohru; Ikeda, Takashi; Nagasaka, Yuki; Okitsu, Yoko; Katsuoka, Yuna; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Ichinohasama, Ryo; Tomosugi, Naohisa; Harigae, Hideo

2013-09-27

112

A Low-Molecular-Weight Compound K7174 Represses Hepcidin: Possible Therapeutic Strategy against Anemia of Chronic Disease  

PubMed Central

Hepcidin is the principal iron regulatory hormone, controlling the systemic absorption and remobilization of iron from intracellular stores. The expression of the hepcidin gene, HAMP, is increased in patients with anemia of chronic disease. Previously, the synthetic compound K7174 was identified through chemical screening as a novel inhibitor of the adhesion of monocytes to cytokine-stimulated endothelial cells. K7174 also ameliorated anemia induced by inflammatory cytokines in mice, which suggests a possible involvement of hepcidin regulation. The present study was performed to assess the impact of K7174 on hepcidin expression in a human hematoma cell line and in mice in vivo. We first demonstrated that K7174 treatment in HepG2 cells significantly decreased HAMP expression. Then, we conducted microarray analysis to determine the molecular mechanism by which K7174 inhibits HAMP expression. Transcriptional profiling confirmed the downregulation of HAMP. Surprisingly, we found that K7174 strongly induced GDF15, known as a negative regulator of HAMP expression. Western blotting analysis as well as ELISA confirmed the induction of GDF15 by K7174 treatment. Furthermore, K7174-mediated HAMP suppression was rescued by the silencing of GDF15 expression. Interestingly, we found that K7174 also upregulates CEBPB. Promoter analysis and chromatin immunoprecipitation analysis revealed that CEBPB could contribute to K7174-mediated transcriptional activation of GDF15. Subsequently, we also examined whether K7174 inhibits hepcidin expression in mice. Quantitative RT-PCR analysis with liver samples from K7174-treated mice demonstrated significant upregulation of Gdf15 and downregulation of Hamp expression, as compared to control mice. Furthermore, serum hepcidin concentration was also significantly decreased in K7174-treated mice. In conclusion, K7174 inhibits hepcidin expression partly by inducing GDF15. K-7174 may be a potential therapeutic option to treat anemia of chronic disease.

Fujiwara, Tohru; Ikeda, Takashi; Nagasaka, Yuki; Okitsu, Yoko; Katsuoka, Yuna; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Ichinohasama, Ryo; Tomosugi, Naohisa; Harigae, Hideo

2013-01-01

113

Influence of perfusion and ventilation scans on therapeutic decision making and outcome in cases of possible embolism  

SciTech Connect

The authors examined the influence of perfusion (Q) and ventilation (V) scans on therapeutic decision making and outcome among 229 patients referred for lung scans because embolism was suggested and found that specific V/Q scan patterns strongly influenced postscan decisions regarding initiation, maintenance or cessation of heparin therapy. These therapeutic decisions bore a relationship to outcome (recurrences and death) and disclosed decision-making deficits that need remedy by future investigational and educational efforts. 25 references, 5 tables.

Mercandetti, A.J.; Kipper, M.S.; Moser, K.M.

1985-02-01

114

An Initial In Vitro Investigation into the Potential Therapeutic Use of SupT1 Cells to Prevent AIDS in HIV-Seropositive Individuals  

PubMed Central

HIV infection usually leads to a progressive decline in number and functionality of CD4+ T lymphocytes, resulting in AIDS development. In this study, I investigated the strategy of using inoculated SupT1 cells to move infection from HIV-1 X4 strains toward the inoculated cells, which should theoretically prevent infection and depletion of normal CD4+ T cells, preventing the development of AIDS-related pathologies. Interestingly, the persistent in vitro replication in SupT1 cells renders the virus less cytopathic and more sensitive to antibody-mediated neutralization, suggesting that replication of the virus in the inoculated SupT1 cells may have a vaccination effect in the long run. In order to mimic the scenario of a therapy in which SupT1 cells are inoculated in an HIV-seropositive patient, I used infected SupT1/PBMC cocultures and a series of control experiments. Infections were done with equal amounts of the wild type HIV-1 LAI virus. The SupT1 CD4+CD8+ T cell population was distinguished from the PBMC CD4+CD8? T cell population by FACS analysis. The results of this study show that the virus-mediated killing of primary CD4+ T cells in the SupT1/PBMC cocultures was significantly delayed, suggesting that the preferential infection of SupT1 cells can induce the virus to spare primary CD4+ T cells from infection and depletion. The preferential infection of SupT1 cells can be explained by the higher viral tropism for the SupT1 cell line. In conclusion, this study demonstrates that it's possible in an in vitro system to use SupT1 cells to prevent HIV infection of primary CD4+ T cells, suggesting that further exploration of the SupT1 cell line as a cell-based therapy against HIV-1 may prove worthwhile.

Fior, Jonathan

2012-01-01

115

[Prevalence of hepatitis B, hepatitis C and HIV among injecting drug users treated outpatiently and in therapeutic community in Brod-Posavina County, Croatia].  

PubMed

Blood transmitted diseases (hepatitis B, hepatitis C, HIV) are major public health problems. Drug users, especially injecting drug users (IDU), are by nature of their illness, a risk population for these diseases. The aim of the study was to determine the prevalence of blood transmitted diseases among IDU in the Brod-Posavina County due to shared use of needle/syringe in outpatients and those treated in a therapeutic community, and to compare the results obtained. First, we analyzed data separately for hepatitis B and C, and then we selected patients with coinfection. The prevalence of HBsAg positive patients in both groups was significantly lower than the prevalence among drug addicts in Croatia (1.16% and 3.28% vs. 13.2%). Significant correlation was found in outpatients with anti-HBs+anti-HBc antibody (p < 0.05) between those who shared needles/syringes and those who did not. Significant correlation was also found among patients treated at therapeutic community (p < 0.01). Comparing the patients treated as outpatients and in therapeutic community, significant correlation was only found between vaccinated patients. HCV positive outpatients had lower and drug addicts in therapeutic communities significantly higher prevalence as compared with the prevalence of HCV among addicts in Croatia (41.86% and 60.66% vs. 44.6%). A significant correlation between those who shared needles/syringes and those who did not was found in both outpatients and patients treated in therapeutic community (P < 0.01). Comparison of HCV positive patients treated as outpatients and those in therapeutic community also yielded significant correlation (p < 0.05). The prevalence of HBV/HCV coinfection was similar in both groups of patients. Significant correlation (P < 0.05) was only found in the group of patients with anti HBC/anti HCV antibodies. There was no HIV-positive patient in any group. We also found a low prevalence of HBsAg/anti-HCV in both groups of patients (1.16% and 2.46%). Upon establishing a network of centers for the treatment of addicts, constant work on prevention and education, systematic testing and vaccination, and implementation of harm reduction programs, we noticed a trend of reducing the number of people with HBV and HCV in the younger population of addicts. PMID:21688612

Kolovrat, Ana; Jurisi?, Irena; Mari?, Zorana; Cvitkovi?, Ante

2010-10-01

116

Rhabdomyolysis: a case study exploring the possible side effect of lipid lowering medication by a HIV positive patient taking a protease inhibitor  

PubMed Central

This case study explores the incidence of rhabdomyolysis in a HIV positive patient that was taking a lipid lowering drug and a protease inhibitor concurrently while under chiropractic treatment for generalized muscular soreness. Dyslipidemia is a very common problem both in the general and HIV population, with many patients being prescribed lipid lowering drugs. While extremely rare, adverse effects of lipid lowering drugs have been documented to include myopathy such as rhabdomyolysis. It is imperative that chiropractors are aware of the possible adverse side effect of lipid lowering drug therapy in their patients complaining of musculoskeletal pain. It is even more important that chiropractors treating the HIV population are aware of the potential interactions between these medications and protease inhibitors to cause myopathy.

De Carvalho, Diana; Citro, Mark; Tibbles, Anthony

2008-01-01

117

HIV chemotherapy  

NASA Astrophysics Data System (ADS)

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.

2001-04-01

118

Blocking Type I Interferon Production: A New Therapeutic Option to Reduce the HIV-1-Induced Immune Activation  

PubMed Central

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

2012-01-01

119

Humanized Mouse Models of HIV Infection  

PubMed Central

Because of the limited tropism of HIV, in vivo modeling of this virus has been almost exclusively limited to other lentiviruses such as SIV that reproduce many important characteristics of HIV infection. However, there are significant genetic and biological differences among lentiviruses and some HIV-specific interventions are not effective against other lentiviruses in non-human hosts. For these reasons much emphasis has recently been placed on developing alternative animal models that support HIV replication and recapitulate key aspects of HIV infection and pathogenesis in humans. Humanized mice, CD34+ hematopoietic progenitor cell transplanted immunodeficient mice and in particular mice also implanted with human thymic/liver tissue (BLT mice) that develop a functional human immune system, have been the focus of a great deal of attention as possible models to study virtually all aspects of HIV biology and pathogenesis. Humanized mice are systemically reconstituted with human lymphoid cells offering rapid, reliable and reproducible experimental systems for HIV research. Peripheral blood of humanized mice can be readily sampled longitudinally to assess reconstitution with human cells and to monitor HIV replication permitting the evaluation of multiple parameters of HIV infection such as viral load levels, CD4+ T cell depletion, immune activation, as well as the effects of therapeutic interventions. Of high relevance to HIV transmission is the extensive characterization and validation of the reconstitution with human lymphoid cells of the female reproductive tract and of the gastrointestinal tract of humanized BLT mice that renders them susceptible to both vaginal and rectal HIV infection. Other important attributes of all types of humanized mice include: 1) their small size and cost that make them broadly accessible; 2) multiple cohorts of humanized mice can be made from multiple human donors and each cohort has identical human cells, permitting control of intragenetic variables; 3) continuous de novo production of human immune cells from the transplanted CD34+ cells within each humanized mouse facilitates long term experiments; 4) both primary and laboratory HIV isolates can be used for experiments; and 5) in addition to therapeutic interventions, rectal and vaginal HIV prevention approaches can be studied. In summary, humanized mice can have an important role in virtually all aspects of HIV research including the analysis of HIV replication, the evaluation of HIV restriction factors, the characterization of successful biomedical HIV prevention strategies, the evaluation of new treatment regimens and the evaluation of novel HIV eradication strategies.

Denton, Paul W.; Garcia, J. Victor

2013-01-01

120

Studies on processing, particle formation, and immunogenicity of the HIV1 gag gene product: a possible component of a HIV vaccine  

Microsoft Academic Search

Summary Antigens in a particulate conformation were shown to be highly immunogenic in mammals. For this reason, the particle forming capacity of derivatives of the HIV-1 group specific core antigen p 55gag was assayed and compared dependent on various expression systems: recombinant bacteria, vaccinia-and baculoviruses were established encoding the entire core protein p 55 either in its authentic sequence or

R. Wagner; H. Fließbach; G. Wanner; M. Motz; M. Niedrig; Gabriele Deby; A. von Brunn; H. Wolf

1992-01-01

121

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

PubMed Central

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

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

2013-01-01

122

[Is the GIRK channel a possible target in the development of a novel therapeutic drug of urinary disturbance?].  

PubMed

Clinically, both overactive bladder (OAB) and dysuria are known to occur in patients with cerebral infarction (CI). A few anticholinergic drugs are used to treat OAB in such patients, although the effect is not satisfactory. On the other hand, little or no therapeutic drug is available for dysuria after CI. We previously reported that dextromethorphan (DM) and cloperastine (CP), centrally acting antitussives, reduce the frequency of micturition reflex and increase the threshold pressure in anesthetized rats. In this article, we describe the effects of DM and CP on urinary disturbances at 24 h after CI, induced by occlusion of the left middle cerebral artery in conscious rats. We also briefly review the structure, function, and distribution of G-protein-coupled inwardly rectifying K(+) (GIRK) channels in the brain, since both drugs have potent inhibitory effect on GIRK channel-activated currents in brain neurons. Of the two drugs, CP at antitussive-effective doses ameliorated both OAB and dysuria 24 h after CI in rats. On the other hand, DM aggravated the dysuria, although it significantly ameliorated the OAB. These results suggest that CP may have some therapeutic value for the treatment of OAB and dysuria after CI. At the present time, mechanisms of the effect of CP are unknown. However, several lines of evidence including pharmacological findings support the idea that the effects of CP may be produced at least partly by an increase in the level of 5-HT in the brain through an inhibitory effect on GIRK channel-activating currents. PMID:21467791

Yamamoto, Gen; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

2011-04-01

123

Uptake of HIV testing and outcomes within a Community-based Therapeutic Care (CTC) programme to treat Severe Acute Malnutrition in Malawi: a descriptive study  

Microsoft Academic Search

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

2008-01-01

124

Enteric Pathogens, Immune Status and Therapeutic Response in Diarrhea in HIV/AIDS Adult Subjects from North India.  

PubMed

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

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

2013-06-01

125

Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease.  

PubMed

Parkinson's disease (PD) is an age-associated and progressive movement disorder that is characterized by dopaminergic neuronal loss in the substantia nigra and, at autopsy, by fibrillar alpha-synuclein inclusions, or Lewy bodies. Despite the qualitative correlation between alpha-synuclein fibrils and disease, in vitro biophysical studies strongly suggest that prefibrillar alpha-synuclein oligomers, or protofibrils, are pathogenic. Consistent with this proposal, transgenic mice that express human alpha-synuclein develop a Parkinsonian movement disorder concurrent with nonfibrillar alpha-synuclein inclusions and the loss of dopaminergic terminii. Double-transgenic progeny of these mice that also express human beta-synuclein, a homologue of alpha-synuclein, show significant amelioration of all three phenotypes. We demonstrate here that beta- and gamma-synuclein (a third homologue that is expressed primarily in peripheral neurons) are natively unfolded in monomeric form, but structured in protofibrillar form. Beta-synuclein protofibrils do not bind to or permeabilize synthetic vesicles, unlike protofibrils comprising alpha-synuclein or gamma-synuclein. Significantly, beta-synuclein inhibits the generation of A53T alpha-synuclein protofibrils and fibrils. This finding provides a rationale for the phenotype of the double-transgenic mice and suggests a therapeutic strategy for PD. PMID:12667059

Park, June-Young; Lansbury, Peter T

2003-04-01

126

Individual phenotype predicts nicotine-haloperidol interaction in catalepsy: possible implication for the therapeutic efficacy of nicotine in Tourette's syndrome.  

PubMed

In individuals with Tourette's syndrome, the therapeutic efficacy of haloperidol can be augmented by nicotine. In laboratory rats, the dopamine antagonist haloperidol produces catalepsy and nicotine can potentiate it, although this effect is variable and not always observed. Our aim was to understand this variability. In rats, the locomotor response to a novel environment predicts the magnitude of the locomotor response to nicotine. Since the psychostimulant effect of nicotine might counter catalepsy, we hypothesized that rats with a high locomotor response to novelty would show reduced vulnerability to nicotine potentiation of haloperidol catalepsy. First, we administered haloperidol (0, 0.1 or 0.3mg/kg, ip) and found stronger catalepsy in rats with low reactivity to novelty. Second, we administered haloperidol (0.3mg/kg) or haloperidol plus nicotine (0.1mg/kg, ip) and found that nicotine indeed potentiated haloperidol catalepsy but only in rats with low reactivity to novelty. Nicotine did not induce catalepsy on its own. Thus, previously reported inconsistencies in the catalepsy potentiating effect of nicotine may have been due to differential vulnerability to its stimulant actions. As previously observed, the potentiation of haloperidol catalepsy was greatest 4h after injection. Given the short half-life of nicotine, the mechanism(s) underlying the delayed expression of its pro-cataleptic capacity remains obscure. PMID:22947904

Boye, Sandra M

2012-08-28

127

Emergency double balloon enteroscopy: a feasible and promising diagnostic as well as possible therapeutic option in recurrent midgut bleeding.  

PubMed

Gastrointestinal (GI) tract bleeding, in particular originating within the long segment of the small intestine, remains a diagnostic and therapeutic challenge. The authors describe the potential utility of emergency double balloon enteroscopy (DBE) for small bowel bleeding. An elderly woman was admitted because of a hypertensive crisis to the medical department of a regional hospital. Her medical history was significant for non-steroidal anti-inflammatory drug (NSAID) abuse. While in hospital she had massive obscure GI bleeding. Upper GI endoscopy and colonoscopy for recurrent bleeding showed only thrombotic residuals in two sigmoid diverticuli, which led to segmental resection of the sigmoid colon. However, postoperatively, bleeding recurred leading to transfer to our university hospital. Immediate angiography only revealed a vascular malformation at the upper jejunum but no ongoing bleeding. Subsequent emergency DBE detected an oozing jejunal ulcer, which was coagulated using a argon beamer. Because of recurrent falls in haemoglobin with the need for repeated transfusion, the patient underwent surgical reintervention including segmental resection of the ulcerated upper jejunum with subsequent end-to-end anastomosis. Histopathology revealed NSAID-induced ulcerous jejunopathy. Postoperatively, there was no further bleeding and the patient was discharged home in a stable condition. In conclusion, this is one of the first reports of successful emergency use of DBE in a case of recurrent and occult bleeding within the small bowel which successfully located the source of bleeding and facilitated successful superficial ulcer coagulation with an argon beamer to prevent further bleeding. PMID:22700075

Büschel, Philip; Mönkemüller, Klaus; von Falkenhausen, Uwe; Fry, Lucia C; Malfertheiner, Peter; Lippert, Hans; Meyer, Frank

2011-03-25

128

A possible homology between immunodeficiency virus p24 core protein and picornaviral VP2 coat protein: prediction of HIV p24 antigenic sites.  

PubMed Central

With the use of a sensitive sequence comparison algorithm, a homology has been suggested between the primary structures of simian immunodeficiency virus (SIV) p24 core protein and foot-and-mouth disease virus (FMD) VP2 coat protein. Since the FMD sequence is homologous to picornaviral VP2 sequences with known three-dimensional architecture and since the SIV p24 sequence can be convincingly aligned with that from human immunodeficiency virus (HIV), it was possible to predict an eight-stranded beta-barrel fold for the HIV core protein. From analogy with the known environments of the picornaviral coats, p24 sequence spans could be predicted as likely candidates for antibody attachment. These suggestions may be important for development of an AIDS vaccine.

Argos, P

1989-01-01

129

Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen--ANRS 111 trial  

PubMed Central

Due to high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir or lopinavir/ritonavir or nelfinavir containing therapy, protease inhibitor dose was modified when plasma trough concentrations (Ctrough) at week 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/ml from week 24 to 48 and/or experiencing grade 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last Ctrough measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39% CI95%: 29.4–50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r or lopinavir/r treated patients (8/51; CI95% 7.0–28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; CI95%: 24.4–65.1; virological failure: 10; adverse event: 1); Ctrough concentrations outside the range were less frequent at the last measurement than at W2 (41% versus 66%; p < 0.05) with proportions of 35% for indinavir/r or lopinavir/r treated patients, but 57% for nelfinavir treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r and lopinavir/r-treated patients, but for nelfinavir failed to move concentrations into the predefined range and to produce the expected virological success.

Duval, Xavier; Mentre, France; Rey, Elisabeth; Auleley, Solange; Peytavin, Gilles; Biour, Michel; Metro, Annie; Goujard, Cecile; Taburet, Anne-Marie; Lascoux, Cecile; Panhard, Xaviere; Treluyer, Jean-Marc; Salmon-Ceron, Dominique

2009-01-01

130

Benefit of therapeutic drug monitoring of protease inhibitors in HIV-infected patients depends on PI used in HAART regimen--ANRS 111 trial.  

PubMed

As a result of high inter-patient variability, and efficacy-concentration and toxicity-concentration relationships, optimization of HIV-protease inhibitor (PI) doses based on plasma concentrations could be beneficial. During a 48-week open prospective non-randomized interventional study of 115 protease inhibitor-naïve patients initiating an indinavir/ritonavir- or lopinavir/ritonavir-, or nelfinavir-containing therapy, protease inhibitor dose was modified when plasma trough concentrations (C(trough)) at weeks 2, 8, 16 and 24 were outside predefined optimal concentration ranges. Failure of the strategy was defined as the proportions of patients with HIV-RNA above 200 copies/mL from weeks 24 to 48 and/or experiencing grades 2, 3 or 4 PI-related adverse events during the study; proportion of patients with last C(trough) measurement outside the concentration range was determined at each visit. Virological failure and/or occurrence of adverse event were observed in 37/94 assessable patients (39%; 95% CI: 29.4-50.0). In the on-treatment analysis, failure of the strategy was noted in 16% of indinavir/r- or lopinavir/r-treated patients (8/51; 95% CI: 7.0-28.6; virological failure: 2; adverse event: 6) but in 44% of nelfinavir-treated patients (11/25; 95% CI: 24.4-65.1; virological failure: 10; adverse event: 1); C(trough) concentrations outside the range were less frequent at the last measurement than at W2 (41% vs. 66%; P < 0.05), with proportions of 35% for indinavir/r- or lopinavir/r-treated patients, but 57% for nelfinavir-treated patients. The proposed strategy of therapeutic drug monitoring may be beneficial to indinavir/r- and lopinavir/r-treated patients, but failed to move concentrations into the predefined range and to produce the expected virological success for nelfinavir-treated patients. PMID:19709326

Duval, Xavier; Mentré, France; Rey, Elisabeth; Auleley, Solange; Peytavin, Gilles; Biour, Michel; Métro, Annie; Goujard, Cecile; Taburet, Anne-Marie; Lascoux, Cecile; Panhard, Xaviere; Tréluyer, Jean-Marc; Salmon-Céron, Dominique

2009-08-01

131

Adherence profiles and therapeutic responses of treatment-naive HIV-infected patients starting boosted atazanavir-based therapy in the ANRS 134-COPHAR 3 trial.  

PubMed

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.). PMID:23459496

Parienti, Jean-Jacques; Barrail-Tran, Aurélie; Duval, Xavier; Nembot, Georges; Descamps, Diane; Vigan, Marie; Vrijens, Bernard; Panhard, Xavière; Taburet, Anne-Marie; Mentré, France; Goujard, Cécile

2013-03-04

132

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

NASA Astrophysics Data System (ADS)

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

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

2010-02-01

133

Morphine and HIV-Tat Increase Microglial Free Radical Production and Oxidative Stress: Possible Role in Cytokine Regulation  

PubMed Central

Opiate abuse alters the progression of HIV and may increase the risk of neuroAIDS. As neuroAIDS is associated with altered microglial reactivity, the combined effects of HIV-Tat and morphine were determined in cultured microglia. Specifically, experiments determined the effects of Tat and morphine on microglial free radical production and oxidative stress, and on cytokine release. Data show that combined Tat and morphine cause early and synergistic increases in reactive oxygen species, with concomitant increases in protein oxidation. Furthermore, combined Tat and morphine, but not Tat or morphine alone, cause reversible decreases in proteasome activity. The effects of morphine on free radical production and oxidative stress are prevented by pretreatment with naloxone, illustrating the important role of opioid receptor activation in these phenomena. While Tat is well-known to induce cytokine release from cultured microglia, morphine decreases Tat-induced release of the cytokines TNF? and IL-6, as well as the chemokine MCP-1. Finally, experiments using the reversible proteasome inhibitor MG115 show that temporary, non-cytotoxic decreases in proteasome activity increase protein oxidation and decrease TNF?, IL-6, and MCP-1 release from microglia. Taken together, these data suggest that oxidative stress and proteasome inhibition may be involved in the immunomodulatory properties of opioid receptor activation in microglia.

Turchan-Cholewo, Jadwiga; Dimayuga, Filomena O.; Gupta, Sunita; Keller, Jeffrey N.; Knapp, Pamela E.; Hauser, Kurt F.; Bruce-Keller, Annadora J.

2009-01-01

134

Trofile HIV co-receptor usage assay.  

PubMed

Background: The introduction of CCR5 antagonists increases the options available for constructing therapeutic drug regimens for HIV-positive patients. However, as these drugs do not inhibit HIV variants that use the CXCR4 co-receptor, a pretreatment test is required to determine accurately HIV co-receptor usage (tropism) before initiating CCR5 antagonist-based therapy. Objective/method: To discuss the Monogram Trofile assay as a diagnostic tool for determining HIV tropism by critically reviewing reported literature and available data. Conclusions: Monogram Trofile has become, largely by default, the de facto standard for HIV tropism assay. However, there is significant room for improvement in the speed, cost and availability of the test. Furthermore, the test is not quantitative, requires high-input HIV RNA viral loads, and produces results that are less biologically stable than expected. These technical considerations may limit the use of CCR5 antagonists in therapy. Nevertheless, this test is likely to remain the most widely used tropism diagnostic for the short term. We expect that a more practical and possibly more accurate method for measuring HIV tropism can be developed. PMID:23485164

Low, Andrew J; McGovern, Rachel A; Harrigan, P Richard

2009-03-01

135

INTERACTIONS OF DIFFERENT INHIBITORS WITH ACTIVE-SITE ASPARTYL RESIDUES OF HIV-1 PROTEASE AND POSSIBLE RELEVANCE TO PEPSINS  

PubMed Central

The importance of the active site region aspartyl residues 25 and 29 of the mature HIV-1 protease (PR) for the binding of five clinical and three experimental protease inhibitors (symmetric cyclic urea inhibitor DMP323, non-hydrolysable substrate analog (RPB) and the generic aspartic protease inhibitor acetyl-pepstatin (Ac-PEP)) was assessed by differential scanning calorimetry. ?Tm values, defined as the difference in Tm for a given protein in the presence and absence of inhibitor, for PR with DRV, ATV, SQV, RTV, APV, DMP323, RPB and Ac-PEP are 22.4, 20.8, 19.3, 15.6, 14.3, 14.7, 8.7, and 6.5 °C, respectively. Binding of APV and Ac-PEP is most sensitive to the D25N mutation, as shown by ?Tm ratios [?Tm(PR)/?Tm(PRD25N)] of 35.8 and 16.3, respectively, whereas binding of DMP323 and RPB (?Tm ratios of 1-2) is least affected. Binding of the substrate-like inhibitors RPB and Ac-PEP is nearly abolished (?Tm(PR)/?Tm(PRD29N) ? 44) by the D29N mutation, whereas this mutation only moderately affects binding of the smaller inhibitors (?Tm ratios of 1.4-2.2). Of the 9 FDA approved clinical HIV-1 protease inhibitors screened, APV, RTV and DRV competitively inhibit porcine pepsin with Ki values of 0.3, 0.6 and 2.14 ?M, respectively. DSC results were consistent with this relatively weak binding of APV (?Tm 2.7 °C) compared with the tight binding of AcPEP (?Tm ?17 °C). Comparison of superimposed structures of the PR/APV complex with those of PR/Ac-PEP and pepsin/pepstatin A complexes suggests a role for Asp215, Asp32 and Ser219 in pepsin, equivalent to Asp25, Asp25? and Asp29 in PR, in the binding and stabilization of the pepsin/APV complex.

Sayer, Jane M.; Louis, John M.

2008-01-01

136

Antitumor therapeutic and antimetastatic activity of electroporation-delivered human papillomavirus 16 E7 DNA vaccines: a possible mechanism for enhanced tumor control.  

PubMed

DNA vaccines are known to be lacking in immunogenicity in humans. Presently, electroporation (EP) is thought to overcome this limitation. Here, we investigate whether human papillomavirus 16 E7 DNA vaccines delivered by EP might elicit potent antitumor activity in animal cervical cancer models, with a focus on the underlying mechanism(s). Intramuscular (IM)-EP delivery of E7 DNA vaccines induced more potent antitumor therapeutic and antimetastatic activity compared with IM delivery. Moreover, the tumor-controlled animals by IM-EP possessed long-term memory responses to parental tumor cells. This improved antitumor effect was concomitant with augmented Ag-specific CTL activities. IM-EP also induced IgG and Th-cell responses higher than IM delivery. Finally, IM-EP resulted in more antigen production in and more attraction of immune cells into the site of DNA injection, suggesting that these biological and immunological changes made by IM-EP might be responsible for enhanced CTL activities and antitumor resistance. Thus, this study shows that IM-EP can induce more potent antitumor activity by augmenting CTL responses possibly through more antigen production in and more attraction of immune cells into the muscle sites. This study also suggests that IM-EP of E7 DNA vaccines might be a potential approach toward treating patients with cervical cancer. PMID:21649506

Lee, In Hee; Park, Jae-Bok; Cheong, Minseon; Choi, Youn Seok; Park, Daehan; Sin, Jeong-Im

2011-06-07

137

Macrophage colony-stimulating factor antagonists inhibit replication of HIV-1 in human macrophages.  

PubMed

Macrophages infected with HIV-1 produce high levels of M-CSF and macrophage-inflammatory protein-1alpha (MIP-1alpha). M-CSF facilitates the growth and differentiation of macrophages, while the chemotactic properties of MIP-1alpha attract both T lymphocytes and macrophages to the site of HIV infection. Studies described in this work indicate M-CSF may function in an autocrine/paracrine manner to sustain HIV replication, and data suggest possible therapeutic strategies for decreasing viral load following HIV infection. We show that macrophage infection with measles virus or respiratory syncytial virus, in contrast to HIV-1, results in production of MIP-1alpha, but not M-CSF. Thus, M-CSF appears to be specifically produced upon infection of macrophages with HIV-1. Furthermore, addition of M-CSF antagonists to HIV-1-infected macrophages, including anti-M-CSF monoclonal or polyclonal Abs or soluble M-CSF receptors, dramatically inhibited HIV-1 replication and reduced production of MIP-1alpha. Our results suggest that biologic antagonists for M-CSF may represent novel strategies for inhibiting the spread of HIV-1 by 1) blocking virus replication in macrophages, 2) reducing recruitment of HIV-susceptible T cells and macrophages by MIP-1alpha, and 3) preventing the establishment and maintenance of infected macrophages as a reservoir for HIV. PMID:10779806

Kutza, J; Crim, L; Feldman, S; Hayes, M P; Gruber, M; Beeler, J; Clouse, K A

2000-05-01

138

Differential cellular FGF2 upregulation in the rat facial nucleus following axotomy, functional electrical stimulation and corticosterone: a possible therapeutic target to Bell's palsy  

Microsoft Academic Search

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

Karen F Coracini; Caio J Fernandes; Almir F Barbarini; César M Silva; Rodrigo T Scabello; Gabriela P Oliveira; Gerson Chadi

2010-01-01

139

Therapeutic Immunization with HIV1 Tat Reduces Immune Activation and Loss of Regulatory T-Cells and Improves Immune Function in Subjects on HAART  

Microsoft Academic Search

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

Barbara Ensoli; Stefania Bellino; Antonella Tripiciano; Olimpia Longo; Vittorio Francavilla; Simone Marcotullio; Aurelio Cafaro; Orietta Picconi; Giovanni Paniccia; Arianna Scoglio; Angela Arancio; Cristina Ariola; Maria J. Ruiz Alvarez; Massimo Campagna; Donato Scaramuzzi; Cristina Iori; Roberto Esposito; Cristina Mussini; Florio Ghinelli; Laura Sighinolfi; Guido Palamara; Alessandra Latini; Gioacchino Angarano; Nicoletta Ladisa; Fabrizio Soscia; Vito S. Mercurio; Adriano Lazzarin; Giuseppe Tambussi; Raffaele Visintini; Francesco Mazzotta; Massimo di Pietro; Massimo Galli; Stefano Rusconi; Giampiero Carosi; Carlo Torti; Giovanni di Perri; Stefano Bonora; Fabrizio Ensoli; Enrico Garaci; Kim J. Hasenkrug

2010-01-01

140

Yeast Genetic Analysis Reveals the Involvement of Chromatin Reassembly Factors in Repressing HIV-1 Basal Transcription  

PubMed Central

Rebound of HIV viremia after interruption of anti-retroviral therapy is due to the small population of CD4+ T cells that remain latently infected. HIV-1 transcription is the main process controlling post-integration latency. Regulation of HIV-1 transcription takes place at both initiation and elongation levels. Pausing of RNA polymerase II at the 5? end of HIV-1 transcribed region (5?HIV-TR), which is immediately downstream of the transcription start site, plays an important role in the regulation of viral expression. The activation of HIV-1 transcription correlates with the rearrangement of a positioned nucleosome located at this region. These two facts suggest that the 5?HIV-TR contributes to inhibit basal transcription of those HIV-1 proviruses that remain latently inactive. However, little is known about the cell elements mediating the repressive role of the 5?HIV-TR. We performed a genetic analysis of this phenomenon in Saccharomyces cerevisiae after reconstructing a minimal HIV-1 transcriptional system in this yeast. Unexpectedly, we found that the critical role played by the 5?HIV-TR in maintaining low levels of basal transcription in yeast is mediated by FACT, Spt6, and Chd1, proteins so far associated with chromatin assembly and disassembly during ongoing transcription. We confirmed that this group of factors plays a role in HIV-1 postintegration latency in human cells by depleting the corresponding human orthologs with shRNAs, both in HIV latently infected cell populations and in particular single-integration clones, including a latent clone with a provirus integrated in a highly transcribed gene. Our results indicate that chromatin reassembly factors participate in the establishment of the equilibrium between activation and repression of HIV-1 when it integrates into the human genome, and they open the possibility of considering these factors as therapeutic targets of HIV-1 latency.

Respaldiza, Inaki; Rodriguez-Gil, Alfonso; Gomez-Herreros, Fernando; Jimeno-Gonzalez, Silvia; Jordan, Albert; Chavez, Sebastian

2009-01-01

141

Visceral leishmaniasis - current therapeutic modalities  

Microsoft Academic Search

Major therapeutic obstacles in the treatment of visceral leishmaniasis (VL) include the alarming increase in antimonial unresponsiveness especially in Bihar, India and relapses in HIV- Leishmania co-infected patients. The therapeutic armamentarium for VL is currently plagued with several limitations as the available drugs are toxic, majority are effective only parenterally and need to be administered for extended periods. The first

Shyam Sundar; Mitali Chatterjee

2006-01-01

142

Intracerebroventricular administration of HIV1 Tat induces brain cytokine and indoleamine 2,3-dioxygenase expression: A possible mechanism for AIDS comorbid depression  

Microsoft Academic Search

Human immunodeficiency virus (HIV) remains a major public health concern despite a large education effort during the past 25 years. A persistent problem with HIV infection is the high comorbity rate of clinical depression. We previously established that increasing proinflammatory cytokines within the brain of mice induces sickness that can culminate in depressive-like behavior. Here we investigated the role of

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

2011-01-01

143

Impaired Infectivity of Ritonavir-resistant HIV Is Rescued by Heat Shock Protein 90AB1*  

PubMed Central

Certain ritonavir resistance mutations impair HIV infectivity through incomplete Gag processing by the mutant viral protease. Analysis of the mutant virus phenotype indicates that accumulation of capsid-spacer peptide 1 precursor protein in virus particles impairs HIV infectivity and that the protease mutant virus is arrested during the early postentry stage of HIV infection before proviral DNA synthesis. However, activation of the target cell can rescue this defect, implying that specific host factors expressed in activated cells can compensate for the defect in ritonavir-resistant HIV. This ability to rescue impaired HIV replication presented a unique opportunity to identify host factors involved in postentry HIV replication, and we designed a functional genetic screen so that expression of a given host factor extracted from activated T cells would lead directly to its discovery by rescuing mutant virus replication in nonactivated T cells. We identified the cellular heat shock protein 90 kDa ? (cytosolic), class B member 1 (HSP90AB1) as a host factor that can rescue impaired replication of ritonavir-resistant HIV. Moreover, we show that pharmacologic inhibition of HSP90AB1 with 17-(allylamino)-17-demethoxygeldanamycin (tanespimycin) has potent in vitro anti-HIV activity and that ritonavir-resistant HIV is hypersensitive to the drug. These results suggest a possible role for HSP90AB1 in postentry HIV replication and may provide an attractive target for therapeutic intervention.

Joshi, Pheroze; Stoddart, Cheryl A.

2011-01-01

144

HIV/AIDS: a minority health issue.  

PubMed

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

2005-07-01

145

Creating genetic resistance to HIV.  

PubMed

HIV/AIDS remains a chronic and incurable disease, in spite of the notable successes of combination 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. PMID:22985479

Burnett, John C; Zaia, John A; Rossi, John J

2012-09-15

146

Cationic host defence peptides: potential as antiviral therapeutics.  

PubMed

There is a pressing need to develop new antiviral treatments; of the 60 drugs currently available, half are aimed at HIV-1 and the remainder target only a further six viruses. This demand has led to the emergence of possible peptide therapies, with 15 currently in clinical trials. Advancements in understanding the antiviral potential of naturally occurring host defence peptides highlights the potential of a whole new class of molecules to be considered as antiviral therapeutics. Cationic host defence peptides, such as defensins and cathelicidins, are important components of innate immunity with antimicrobial and immunomodulatory capabilities. In recent years they have also been shown to be natural, broad-spectrum antivirals against both enveloped and non-enveloped viruses, including HIV-1, influenza virus, respiratory syncytial virus and herpes simplex virus. Here we review the antiviral properties of several families of these host peptides and their potential to inform the design of novel therapeutics. PMID:23649937

Gwyer Findlay, Emily; Currie, Silke M; Davidson, Donald J

2013-10-01

147

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

PubMed

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

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

2013-01-01

148

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

PubMed Central

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

2013-01-01

149

Standardised in vitro susceptibility testing of Borrelia burgdorferi against well-known and newly developed antimicrobial agents — Possible implications for new therapeutic approaches to Lyme disease  

Microsoft Academic Search

Lyme disease represents a disorder of potentially chronic proportions, and relatively little is known about the in vivo pharmacodynamic interactions of antimicrobial agents with borreliae. So far, evidence-based drug regimens for the effective treatment of Lyme disease have not been definitively established. Moreover, therapeutic failures have been reported for almost every suitable antimicrobial agent currently available. Resistance to treatment and

Klaus-Peter Hunfeld; Peter Kraiczy; Elena Kekoukh; Volker Schäfer; Volker Brade

2002-01-01

150

Estimation of “needs” and “probable uptake” for HIV\\/AIDS preventive vaccines based on possible policies and likely acceptance (a WHO\\/UNAIDS\\/IAVI study)  

Microsoft Academic Search

Once an effective HIV vaccine is discovered, a major challenge will be to ensure its world wide access. A preventive vaccine with low or moderate efficacy (30–50%) could be a valuable prevention tool, especially if targeted to populations at higher risk of HIV infection. High efficacy vaccines (80–90%) could be used in larger segments of the population.Estimated “needs” for future

José Esparza; Marie-Louise Chang; Roy Widdus; Yvette Madrid; Neff Walker; Peter D. Ghys

2003-01-01

151

Mechanism of gamma sigma T-cell-mediated inhibition of stem cell differentiation in vitro: possible relevance for myelosuppression in HIV-infected individuals.  

PubMed

We investigated whether gamma delta T cells contribute to the suppression of myelopoiesis in HIV infection. Freshly isolated gamma delta T cells from HIV seropositive patients suppressed CFU-GM growth in vitro. Preactivation of gamma delta T cells with IL-2 and/or IL-15 further reduced the number of CFU-GM. Natural killer cells and to a lower extent CD4+ and CD8+ cells also inhibited CFU-GM growth. In contrast to gamma delta T cells, this effect was not dependent on IL-15 or IL-2 preactivation. Moreover, no enhanced inhibitory effect of CD56+ and CD4+ cells was observed in HIV+ subjects compared to HIV- donors. The myelosuppressive effect of supernatants of gamma delta T cells could be inhibited by antibodies against IFN-gamma or TNF-alpha. Accordingly, we found increased numbers of TNF-alpha or IFN-gamma-secreting CD8+ gamma delta T cells in HIV+ patients. We conclude that the increased fraction of activated gamma delta T cells producing myelosuppressive cytokines might contribute to the dyshematopoiesis frequently observed in HIV-infected individuals. PMID:9626332

Dobmeyer, T S; Dobmeyer, J M; Klein, S A; Wesch, D; Wagner, S; Helm, E B; Hoelzer, D; Rossol, R; Kabelitz, D

1998-02-25

152

HIV associated eosinophilic folliculitis--differential diagnosis and management  

PubMed Central

Eosinophilic folliculitis (EF) is a chronic, intensely pruritic condition of unknown pathogenesis that causes marked morbidity in those HIV patients whom it affects. There is a wide differential diagnosis of itchy skin conditions in HIV which are amenable to different treatments. It is therefore essential to take a biopsy of each suspected case and examine multiple sections of the biopsy to confirm or refute a diagnosis of EF. Treatment of EF can be difficult but we hope that by suggesting a rational approach to this and considering possible therapeutic options more patients may be helped with this troublesome dermatosis. ???

Simpson-Dent, S.; Fearfield, L. A.; Staughton, R. C.

1999-01-01

153

Differential cellular FGF-2 upregulation in the rat facial nucleus following axotomy, functional electrical stimulation and corticosterone: a possible therapeutic target to Bell's palsy  

PubMed Central

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.

2010-01-01

154

HIV-1 Nef: at the crossroads  

PubMed Central

The development of anti-virals has blunted the AIDS epidemic in the Western world but globally the epidemic has not been curtailed. Standard vaccines have not worked, and attenuated vaccines are not being developed because of safety concerns. Interest in attenuated vaccines has centered on isolated cases of patients infected with HIV-1 containing a deleted nef gene. Nef is a multifunctional accessory protein that is necessary for full HIV-1 virulence. Unfortunately, some patients infected with the nef-deleted virus eventually lose their CD4+ T cells to levels indicating progression to AIDS. This renders the possibility of an attenuated HIV-1 based solely on a deleted nef remote. In this review we discuss the knowledge gained both from the study of these patients and from in vitro investigations of Nef function to assess the possibility of developing new anti-HIV-1 drugs based on Nef. Specifically, we consider CD4 downregulation, major histocompatibility complex I downregulation, Pak2 activation, and enhancement of virion infectivity. We also consider the recent proposal that simian immunodeficiency viruses are non-pathogenic in their hosts because they have Nefs that downregulate CD3, but HIV-1 is pathogenic because its Nef fails to downregulate CD3. The possibility of incorporating the CD3 downregulation function into HIV-1 Nef as a therapeutic option is also considered. Finally, we conclude that inhibiting the CD4 downregulation function is the most promising Nef-targeted approach for developing a new anti-viral as a contribution to combating AIDS.

Foster, John L; Garcia, J Victor

2008-01-01

155

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  

PubMed Central

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.

2012-01-01

156

A Randomised, Placebo-Controlled, First-In-Human Study of a Novel Clade C Therapeutic Peptide Vaccine Administered Ex Vivo to Autologous White Blood Cells in HIV Infected Individuals  

PubMed Central

Background Preclinical studies of overlapping 15mer peptides, spanning SIV, SHIV or HIV, pulsed on autologous PBMC ex vivo have demonstrated high level, virus-specific T cell responses and viral suppression in non-human primates (NHP). Opal-HIV-Gag(c) consists of 120 synthetic 15mer peptides spanning Clade C, consensus Gag, manufactured to current good manufacturing practice; having been evaluated in a good laboratory practice toxicology study in Macaca mulatta. We evaluated the safety and preliminary immunogenicity of such peptides administered intravenously after short-duration ex vivo incubation, to HIV-positive adults on suppressive antiretroviral therapy. Methods and Findings A first-in-human, placebo-controlled, double-blind, dose escalation study was conducted. Twenty-three patients with virus suppressed by antiretroviral therapy were enrolled in four groups 12 mg (n?=?6), 24 mg (n?=?6), 48 mg (n?=?2) or matching placebo (n?=?8). Treatment was administered intravenously after bedside enrichment of 120 mL whole blood for white cells using a closed system (Sepax S-100 device), with ex vivo peptide admixture (or diluent alone) and 37°C incubation for one hour prior to reinfusion. Patients received 4 administrations at monthly intervals followed by a 12-week observation post-treatment. Opal-HIV-Gag(c) was reasonably tolerated at doses of 12 and 24 mg. There was an increased incidence of temporally associated pyrexia, chills, and transient/self-limiting lymphopenia in Opal-HIV-Gag(c) recipients compared to placebo. The study was terminated early, after two patients were recruited to the 48 mg cohort; a serious adverse event of hypotension, tachycardia secondary to diarrhoea occurred following a single product administration. An infectious cause for the event could not be identified, leaving the possibility of immunologically mediated product reaction. Conclusions A serious, potentially life-threatening event of hypotension led to early, precautionary termination of the study. In the absence of a clearly defined mechanism or ability to predict such occurrence, further development of Opal-HIV-Gag(c) will not be undertaken in the current form. Registration ClinicalTrials.gov NCT01123915; EudraCT: 2008-005142-23

Jackson, Akil; Kl?verpris, Henrik N.; Boffito, Marta; Handley, Amanda; Atkins, Mark; Hayes, Peter; Gilmour, Jill; Riddel, Lynn; Chen, Fabian; Bailey-Tippets, Melanie; Walker, Bruce; Ackland, Jim; Sullivan, Mark; Goulder, Philip

2013-01-01

157

Cell-associated viral burden provides evidence of ongoing viral replication in aviremic HIV-2-infected patients.  

PubMed

Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1(+)) and HIV-2(+) individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2(+) patients, despite the reduced viremia (undetectable to 2.6 × 10(4) RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2(+) patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2(+) patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2(+) patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection. PMID:21159859

Soares, Rui S; Tendeiro, Rita; Foxall, Russell B; Baptista, António P; Cavaleiro, Rita; Gomes, Perpétua; Camacho, Ricardo; Valadas, Emília; Doroana, Manuela; Lucas, Margarida; Antunes, Francisco; Victorino, Rui M M; Sousa, Ana E

2010-12-15

158

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients?  

PubMed Central

Viremia is significantly lower in HIV-2 than in HIV-1 infection, irrespective of disease stage. Nevertheless, the comparable proviral DNA burdens observed for these two infections indicate similar numbers of infected cells. Here we investigated this apparent paradox by assessing cell-associated viral replication. We found that untreated HIV-1-positive (HIV-1+) and HIV-2+ individuals, matched for CD4 T cell depletion, exhibited similar gag mRNA levels, indicating that significant viral transcription is occurring in untreated HIV-2+ patients, despite the reduced viremia (undetectable to 2.6 × 104 RNA copies/ml). However, tat mRNA transcripts were observed at significantly lower levels in HIV-2+ patients, suggesting that the rate of de novo infection is decreased in these patients. Our data also reveal a direct relationship of gag and tat transcripts with CD4 and CD8 T cell activation, respectively. Antiretroviral therapy (ART)-treated HIV-2+ patients showed persistent viral replication, irrespective of plasma viremia, possibly contributing to the emergence of drug resistance mutations, persistent hyperimmune activation, and poor CD4 T cell recovery that we observed with these individuals. In conclusion, we provide here evidence of significant ongoing viral replication in HIV-2+ patients, further emphasizing the dichotomy between amount of plasma virus and cell-associated viral burden and stressing the need for antiretroviral trials and the definition of therapeutic guidelines for HIV-2 infection.

Soares, Rui S.; Tendeiro, Rita; Foxall, Russell B.; Baptista, Antonio P.; Cavaleiro, Rita; Gomes, Perpetua; Camacho, Ricardo; Valadas, Emilia; Doroana, Manuela; Lucas, Margarida; Antunes, Francisco; Victorino, Rui M. M.; Sousa, Ana E.

2011-01-01

159

An observational, prospective study of monthly adalimumab therapy for disease maintenance in psoriasis patients: a possible new therapeutic option for good responders to the initial induction treatment.  

PubMed

Background? While adalimumab is a mainstay of treatment for moderate to severe chronic plaque psoriasis, the data regarding optimal treatment intervals for therapeutic maintenance are limited. Objective? We compared the clinical efficacy of biweekly maintenance administration of adalimumab with that of monthly treatment. Methods? 17 psoriasis patients treated with adalimumab 40?mg every other week with initial loading dose of 80?mg until week 24 were assigned to the maintenance therapy with adalimumab 40?mg either every other week (n?=?7), or every month (n?=?10). The treatment efficacy was evaluated by the proportion of patients who achieved PASI 75 from the baseline at weeks 36, 48 and 60. There was no selection bias between the two groups. Results? At week 24, all the patients except for one in each group achieved PASI 75. In both groups, all the patients who achieved PASI 75 at week 24 maintained PASI 75 responses at week 60. Regarding two patients who did not achieve PASI 75 at week 24, one biweekly treated patient experienced a gradual increase in therapeutic response while one monthly treated patient showed exacerbation after week 24. Conclusion? Monthly adalimumab treatment seems to be a reasonable treatment option for patients who responded well to initial standard adalimumab treatment for 24?weeks. Since there are several limitations in this study, including the number of patients, observation period, and patients' characteristics, large randomized controlled trials are needed to confirm these results. PMID:22702802

Taniguchi, T; Noda, S; Takahashi, N; Yoshimura, H; Mizuno, K; Adachi, M

2012-06-15

160

Neurophysiological study on possible protective and therapeutic effects of Sidr (Zizyphus spina-christi L.) leaf extract in male albino rats treated with pentylenetetrazol  

PubMed Central

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.

Waggas, Abeer M.; Al-Hasani, Reem H.

2010-01-01

161

Prophylaxis and follow-up after possible exposure to HIV, hepatitis B virus, and hepatitis C virus outside hospital: evaluation of policy 2000-3  

PubMed Central

Problem Prophylactic treatment and follow-up after exposure to HIV, hepatitis B, and hepatitis C outside hospital needs to be improved. Background and setting Until January 2000, people in Amsterdam could report exposure outside hospital to either a hospital or the municipal health service. If they reported to the municipal health service, they were then referred to hospitals for HIV prophylaxis, whereas the municipal health service handled treatment and follow-up related to hepatitis B and hepatitis C and traced sources. For cases reported to a hospital, hospital staff often did not trace HIV sources or follow up patients for hepatitis B and hepatitis C. Key measures for improvement Providing adequate treatment for HIV, hepatitis B and hepatitis C after exposure for all reported exposures outside hospital. Strategies for change On 1 January 2000, a new protocol was introduced in which three Amsterdam hospitals and the municipal health service collaborated in the treatment and follow-up of exposures outside hospital. Both municipal health service and hospitals can decide whether HIV prophylaxis is necessary and prescribe accordingly. All people exposed in the community who report to hospitals are subsequently referred to the municipal health service for further treatment and follow-up. Effects of change The protocol is effective in that most people comply with treatment and follow-up. When indicated, HIV prophylaxis is started soon after exposure. In nearly two thirds of cases the municipal health service traced and tested the source. Lessons learnt Provision of treatment and follow-up in one place enables treatment, tracing and testing sources, and follow-up, including counselling and registration of all reported exposures in Amsterdam, which allows for swift identification of emerging epidemiological trends. Since May 2004 all Amsterdam hospitals have participated in the protocol.

Sonder, Gerard J B; Regez, Rosa M; Brinkman, Kees; Prins, Jan M; Mulder, Jan-Willem; Spaargaren, Joke; Coutinho, Roel A; van den Hoek, Anneke

2005-01-01

162

Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring.  

PubMed

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users. PMID:17898644

Slish, Judianne; Ma, Qing; Zingman, Barry S; Reichman, Richard C; Fischl, Margaret A; Gripshover, Barbara; Forrest, Alan; Brazeau, Dan; Boston, Naomi S; Catanzaro, Linda; DiFrancesco, Robin; Morse, Gene D

2007-10-01

163

The Design and Implementation of A5146, a Prospective Trial Assessing the Utility of Therapeutic Drug Monitoring Using an Inhibitory Quotient in Antiretroviral-Experienced HIV-Infected Patients  

PubMed Central

The AIDS Clinical Trials Group designed and implemented a prospective, randomized, strategy trial in antiretroviral-experienced, HIV-infected patients, to evaluate the virologic impact of protease inhibitor dose escalation in response to therapeutic drug monitoring (TDM) with an inhibitory quotient, which integrates both drug exposure and viral drug resistance. In the process of developing this clinical trial several unique challenges were identified that required innovative solutions. The major challenge was the need to integrate resistance testing, pharmacokinetic data, medication adherence, toxicity data, clinical assessments, randomization assignment, and protocol-specified clinical management in a way that could be utilized in real-time by the protocol team, communicated promptly to the clinical sites, and transmitted accurately to the study database. In addition, the protocol team had to address the relative lack of commercially available therapeutic drug monitoring laboratories in the US that were experienced in antiretroviral drug assays, and a lack of familiarity with the principles of pharmacokinetic monitoring at participating clinical sites. This manuscript outlines the rationale for the design of this strategy trial, specific barriers to implementation that were identified, and solutions that were developed, with the hope that these experiences will facilitate the design and conduct of future trials of TDM.

Demeter, Lisa M.; Mukherjee, A. Lisa; DiFrancesco, Robin; Jiang, Hongyu; DiCenzo, Robert; Bastow, Barbara; Rinehart, Alex R.; Morse, Gene D.; Albrecht, Mary

2010-01-01

164

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

ERIC Educational Resources Information Center

|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…

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

2008-01-01

165

A hunter virus that targets both infected cells and HIV free virions: Implications for therapy  

PubMed Central

The design of ‘hunter’ viruses aimed at destroying human immunodeficiency virus (HIV) infected cells is an active area of research that has produced promising results in vitro. Hunters are designed to target exposed viral envelope proteins in the membranes of infected cells, but there is evidence that the hunter may also target envelope proteins of free HIV, inducing virus-virus fusion. In order to predict the effects of this fusion on therapy outcomes and determine whether fusion ability is advantageous for hunter virus design, we have constructed a model to account for the possibility of hunter-HIV fusion. The study was based on a target cell-limited model of HIV infection and it examined the hunter therapeutic effect on recovering the HIV main target cells, the activated CD4+ T lymphocytes. These cells assist in setting up an immune response to opportunistic infections. The study analyzed the hunter dual mechanisms to control infection and because of diverse estimates for viral production and clearance of HIV, simulations were examined at rates spanning an order of magnitude. Results indicate that without hunter-HIV fusion ability, hunters that kill HIV-infected cells lead to a substantial recovery of healthy cell population at both low and high HIV turnover rates. When hunter-HIV fusion is included, cell recovery was particularly enhanced at lower HIV turnover rates. This study shows that the fusion ability, in addition to hunter infection ability, could be a favorable attribute for improving the efficacy of hunter-viral therapy. These results provide support for the potential use of engineered viruses to control HIV and other viral infections.

2012-01-01

166

Gene Therapeutic Approaches for Immune Modulation in AIDS  

Microsoft Academic Search

Antiviral drug therapy can effectively suppress HIV replication, but emerging viral resistance and drug toxicity limit long-term therapeutic efficacy. In addition, regeneration of the T helper cell repertoire is often incomplete. The cur- rent major challenges in the treatment of HIV infection are therefore the reconstitution of cellular immunity, and espe- cially of the HIV-specific immune response, and the suppression

Dorothee von Laer; Christopher Baum; Axel Schambach; Klaus Kuhlcke; Roland Zahn; Sebastian Newrzela; Jan van Lunzen; R. Paul Johnson; Jorn E. Schmitz

2007-01-01

167

Genomics meets HIV1  

Microsoft Academic Search

Genomics is now a core element in the effort to develop a vaccine against HIV-1. Thanks to unprecedented progress in high-throughput genotyping and sequencing, in knowledge about genetic variation in humans, and in evolutionary genomics, it is finally possible to systematically search the genome for common genetic variants that influence the human response to HIV-1. The identification of such variants

David B. Goldstein; Amalio Telenti

2006-01-01

168

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

Microsoft Academic Search

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 = 314) found significantly better six-month post-prison outcomes for the

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

2008-01-01

169

Retinal pigment epithelial cells secrete neurotrophic factors and synthesize dopamine: possible contribution to therapeutic effects of RPE cell transplantation in Parkinson's disease  

PubMed Central

Background New strategies for the treatment of Parkinson's disease (PD) are shifted from dopamine (DA) replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE) cells as substitution for degenerated dopaminergic (DAergic) neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA. Methods We evaluated the protective effects of conditioned medium (CM) from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA)- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR). Results We report here: (1) CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2) cultured RPE cells express L-dopa decarboxylase (DDC) and synthesize DA; (3) RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4) GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues. Conclusion These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.

Ming, Ming; Li, Xuping; Fan, Xiaolan; Yang, Dehua; Li, Liang; Chen, Sheng; Gu, Qing; Le, Weidong

2009-01-01

170

Possible Increase in HIV and Syphilis Prevalence Among Men Who Have Sex with Men in Guangzhou, China: Results from a Respondent-Driven Sampling Survey  

Microsoft Academic Search

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

2011-01-01

171

Galectin-1-Specific Inhibitors as a New Class of Compounds To Treat HIV-1 Infection  

PubMed Central

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

2012-01-01

172

Hit-and-run stimulation: a novel concept to reactivate latent HIV-1 infection without cytokine gene induction.  

PubMed

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

2010-06-10

173

Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) - possible lessons from a systematic review of SARS-CoV therapy.  

PubMed

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been detected in a number of countries in the Middle East and Europe with an apparently high mortality rate. It is phylogenetically related to the SARS coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. Current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the SARS epidemic of 2003. It is possible that these might be active against the related MERS coronavirus. We have reviewed the literature on the safety and efficacy of therapies used in patients with SARS with a view to their potential use in patients with MERS-CoV infections. PMID:23993766

Momattin, Hisham; Mohammed, Khurram; Zumla, Alimuddin; Memish, Ziad A; Al-Tawfiq, Jaffar A

2013-08-29

174

Potential Anti-HIV Agents from Marine Resources: An Overview  

PubMed Central

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

2010-01-01

175

Therapeutic Touch  

MedlinePLUS

... Ashford RL. Therapeutic touch for healing acute wounds. Cochrane Database Syst Rev. 2003;(4):CD002766. Robinson J, ... FC, Dolk H. Therapeutic touch for anxiety disorders. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD006240. ...

176

Multivalent agents: a novel concept and preliminary practice in Anti-HIV drug discovery.  

PubMed

The term multivalency (polyvalency) in the biological science is defined as the simultaneous binding of multiple ligands to one receptor (or multiple receptors to one ligand). The possibility of gaining potency and selectivity was significantly increased through the use of multivalent ligand as a homo- or hetero-dimer, thus multivalent ligands provided a more attractive strategy to design novel anti-HIV agents with therapeutic applications. Moreover, similar to phenomenon of multivalency, an alternative strategy is called the "mixed sites inhibitor", viz. a single molecule that possesses enough chemical space to maximize interactions with its complementary binding pocket, or to bind simultaneously in more than one regions in a target. Actually, the addition of a third heterocyclic nucleus to the parent compound resulted in "mixed sites" anti-HIV agents with broad spectrum of activities against the mutant HIV-1 strains. Based on current representative examples, the present article provided a brief review on the rationale for the design of different classes of multivalency anti-HIV agents and also discussed the advantages over their monomeric counterparts, providing a novel paradigm to facilitate the development of anti-HIV/AIDS therapeutic agents in treatment of HIV infected community. PMID:23116144

Song, Yu'ning; Zhan, Peng; Li, Xiao; Rai, Diwakar; De Clercq, Erik; Liu, Xinyong

2013-02-01

177

Panic attack and SIDS: possible therapeutic conclusion  

Microsoft Academic Search

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.

I. Sos

2001-01-01

178

HIV-1 Inhibits Autophagy in Bystander Macrophage/Monocytic Cells through Src-Akt and STAT3  

PubMed Central

Autophagy is a homeostatic mechanism of lysosomal degradation. Defective autophagy has been linked to various disorders such as impaired control of pathogens and neurodegeneration. Autophagy is regulated by a complex array of signaling pathways that act upstream of autophagy proteins. Little is known about the role of altered regulatory signaling in disorders associated with defective autophagy. In particular, it is not known if pathogens inhibit autophagy by modulation of upstream regulatory pathways. Cells infected with HIV-1 blocked rapamycin-induced autophagy and CD40-induced autophagic killing of Toxoplasma gondii in bystander (non-HIV-1 infected) macrophage/monocytic cells. Blockade of autophagy was dependent on Src-Akt and STAT3 triggered by HIV-1 Tat and IL-10. Neutralization of the upstream receptors VEGFR, ?-integrin or CXCR4, as well as of HIV-1 Tat or IL-10 restored autophagy in macrophage/monocytic cells exposed to HIV-1-infected cells. Defective autophagic killing of T. gondii was detected in monocyte-derived macrophages from a subset of HIV-1+ patients. This defect was also reverted by neutralization of Tat or IL-10. These studies revealed that a pathogen can impair autophagy in non-infected cells by activating counter-regulatory pathways. The fact that pharmacologic manipulation of cell signaling restored autophagy in cells exposed to HIV-1-infected cells raises the possibility of therapeutic manipulation of cell signaling to restore autophagy in HIV-1 infection.

Van Grol, Jennifer; Subauste, Cecilia; Andrade, Rosa M.; Fujinaga, Koh; Nelson, Julie; Subauste, Carlos S.

2010-01-01

179

BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism.  

PubMed

The therapeutic potential of pharmacologic inhibition of bromodomain and extraterminal (BET) proteins has recently emerged in hematological malignancies and chronic inflammation. We find that BET inhibitor compounds (JQ1, I-Bet, I-Bet151 and MS417) reactivate HIV from latency. This is evident in polyclonal Jurkat cell populations containing latent infectious HIV, as well as in a primary T-cell model of HIV latency. Importantly, we show that this activation is dependent on the positive transcription elongation factor p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action. Instead, we find that the related BET protein, BRD2, enforces HIV latency in the absence of Tat, pointing to a new target for BET inhibitor treatment in HIV infection. In shRNA-mediated knockdown experiments, knockdown of BRD2 activates HIV transcription to the same extent as JQ1 treatment, while a lesser effect is observed with BRD4. In single-cell time-lapse fluorescence microscopy, quantitative analyses across ~2,000 viral integration sites confirm the Tat-independent effect of JQ1 and point to positive effects of JQ1 on transcription elongation, while delaying re-initiation of the polymerase complex at the viral promoter. Collectively, our results identify BRD2 as a new Tat-independent suppressor of HIV transcription in latently infected cells and underscore the therapeutic potential of BET inhibitors in the reversal of HIV latency. PMID:23255218

Boehm, Daniela; Calvanese, Vincenzo; Dar, Roy D; Xing, Sifei; Schroeder, Sebastian; Martins, Laura; Aull, Katherine; Li, Pao-Chen; Planelles, Vicente; Bradner, James E; Zhou, Ming-Ming; Siliciano, Robert F; Weinberger, Leor; Verdin, Eric; Ott, Melanie

2012-02-01

180

Controlling neuropathic pain in HIV  

Microsoft Academic Search

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

2004-01-01

181

HIV infection and advanced age  

Microsoft Academic Search

While the mean age of HIV\\/AIDS patients at first diagnosis is progressively rising, no updated epidemiological estimates, controlled clinical data, and randomized therapeutic trials, are available regarding clinical and laboratory response to antiretroviral therapy, safety of anti-HIV compounds and their associations, potential drug–drug interactions, short- and long-term toxicity, consequences on underlying disorders, or interactions with concomitant pharmacological regimens, in the

Roberto Manfredi

2004-01-01

182

HIV latency: present knowledge, future directions  

PubMed Central

Summary Current therapies do not eradicate HIV from infected patients. Indeed, HIV hides in a latent form insensitive to these therapies. Thus, one priority is to purge these latent reservoirs. But what mechanisms are responsible for latency and what are the reservoirs of latently infected cells? The present knowledge in terms of HIV latency is still incomplete and current therapeutic strategies fail to eradicate completely latently infected cells. What could the future bring?

Contreras, Xavier; Lenasi, Tina; Peterlin, B. Matija

2009-01-01

183

Naturally derived anti-HIV agents  

Microsoft Academic Search

The urgent need for new anti-HIV\\/AIDS drugs is a global concern. In addition to obvious economical and commercial hurdles, HIV\\/AIDS patients are faced with multifarious difficulties associated with the currently approved anti-HIV drugs. Adverse effects, the emergence of drug resistance and the narrow spectrum of activity have limited the therapeutic usefulness of the various reverse transcriptase and protease inhibitors that

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

2005-01-01

184

Addressing Cost Barriers for HIV Care  

MedlinePLUS

... Size Print E-mail Addressing the Cost of Care Paying for HIV Care HIV care and treatment involves a commitment to ... Johnson (Janssen Therapeutics), Merck and ViiV Healthcare. Find Care & Treatment You & Your Provider Discrimination By Providers Locating ...

185

HIV/AIDS - Sharing Your HIV Status  

MedlinePLUS Videos and Cool Tools

... the Mouse and Choose "Save link as...." Audio Mobile Video Handout Audio Terms of Use Close Window This information made possible with support from The Division of Specialized Information Services of the National Library of Medicine For more information on HIV/AIDS ...

186

Therapeutic Community.  

National Technical Information Service (NTIS)

Therapeutic community programs were the subject of a 1976 conference which was intended to establish a working environment in which representatives of such programs could work towards conceptualizing the status of the field and formulating suitable respon...

G. deLeon G. M. Beschner

1977-01-01

187

HIV/AIDS and Pregnancy  

MedlinePLUS

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

188

HIV and preconceptional counselling.  

PubMed

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

Steele, S J

1991-01-01

189

Ontogeny of anti-human immunodeficiency virus (HIV) antibody production in HIV-1-infected infants.  

PubMed Central

The early serologic response of infants to infection with human immunodeficiency virus type 1 (HIV-1) is normally obscured by the presence of transplacentally acquired maternal HIV antibody. By measuring HIV antibody produced in vitro by lymphocytes isolated from peripheral blood of infants and children of HIV-1-infected mothers, we have been able to study the natural acquisition of humoral immunity to perinatal HIV-1 infection. One hundred ninety-seven infants of HIV-1-infected women were studied prospectively and longitudinally from birth. In the neonatal period, infected infants produced only small amounts of HIV-specific IgG antibodies to a restricted number of antigens. The amount of immunoglobulin to HIV-1 and the number of HIV-1 antigens recognized increased with age. After 6 months of life 85% of infected infants made detectable antibody to two or more viral proteins. Antibody to gp160 appeared first and was the most frequently found at all ages, followed by antibody to the envelope proteins gp120 and gp41. The amount of HIV antibody produced correlated positively with the percentage of CD4+ T lymphocytes in peripheral blood. This assay provides a method of studying the immunogenicity of vaccines against HIV-1 in HIV-1-infected infants and of assessing the effect of early therapeutic interventions on the humoral response to HIV-1.

Pollack, H; Zhan, M X; Ilmet-Moore, T; Ajuang-Simbiri, K; Krasinski, K; Borkowsky, W

1993-01-01

190

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

PubMed Central

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

2013-01-01

191

HIV chemotherapy  

Microsoft Academic Search

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.

Douglas D. Richman

2001-01-01

192

HIV infection and the gastrointestinal immune system  

PubMed Central

There has recently been a resurgence of interest in the gastrointestinal pathology observed in patients infected with HIV. The gastrointestinal tract is a major site of HIV replication, which results in massive depletion of lamina propria CD4 T cells during acute infection. Highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of gastrointestinal CD4 T cells. The gastrointestinal pathology associated with HIV infection comprises significant enteropathy with increased levels of inflammation and decreased levels of mucosal repair and regeneration. Assessment of gut mucosal immune system has provided novel directions for therapeutic interventions that modify the consequences of acute HIV infection.

Brenchley, JM; Douek, DC

2009-01-01

193

A macaque model of HIV-1 infection.  

PubMed

The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st)HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (Macaca nemestrina) lymphocytes. Importantly, infection of pig-tailed macaques with stHIV-1 results in acute viremia, approaching the levels observed in HIV-1-infected humans, and an ensuing persistent infection for several months. stHIV-1 replication was controlled thereafter, at least in part, by CD8+ T cells. We demonstrate the potential utility of this HIV-1-based animal model in a chemoprophylaxis experiment, by showing that a commonly used HIV-1 therapeutic regimen can provide apparently sterilizing protection from infection following a rigorous high-dose stHIV-1 challenge. PMID:19255423

Hatziioannou, Theodora; Ambrose, Zandrea; Chung, Nancy P Y; Piatak, Michael; Yuan, Fang; Trubey, Charles M; Coalter, Vicky; Kiser, Rebecca; Schneider, Doug; Smedley, Jeremy; Pung, Rhonda; Gathuka, Mercy; Estes, Jacob D; Veazey, Ronald S; KewalRamani, Vineet N; Lifson, Jeffrey D; Bieniasz, Paul D

2009-03-02

194

Therapeutic Nanodevices  

NASA Astrophysics Data System (ADS)

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

195

Therapeutic Nanodevices  

NASA Astrophysics Data System (ADS)

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

196

HIV Protease Inhibitors Modulate Ca2+ Homeostasis and Potentiate Alcoholic Stress and Injury in Mice and Primary Mouse and Human Hepatocytes  

PubMed Central

A portion of HIV-infected patients under therapy with protease inhibitors (HIV PIs) concomitantly consume or abuse alcohol leading to hepatic injury. The underling mechanisms are not known. We hypothesize that HIV PI aggravates alcohol-induced liver injury through an endoplasmic reticulum (ER) stress mechanism. To address this, we treated mice and primary mouse and human hepatocytes (PMH and PHH respectively) with alcohol and the two HIV PIs: ritonavir and lopinavir. In mice, ritonavir and lopinavir (15 mg/kg body weight each) induced mild ER stress and inhibition of Sarco/ER Calcium-ATPase (SERCA) without significant increase in serum ALT levels. However, a single dose of alcohol by gavage (5g/kg body weight) plus the two HIV PIs caused a greater than 5-fold increase in serum ALT, a synergistic increase in alcohol-induced liver lipid accumulation and ER stress response, and a decrease of SERCA. Mice treated with chronic HIV PIs and alcohol developed moderate liver fibrosis. In PMH, the HIV drugs plus alcohol also inhibited SERCA expression and increased expression of GRP78, CHOP, SREBP1c and phosphorylated JNK2, which were accompanied by a synergistic increase in cell death compared to alcohol or the HIV drugs alone. In PHH, ritonavir and lopinavir or alcohol alone treatment increased mRNA of spliced Xbp1 and decreased SERCA, which were accompanied by reduced levels of intracellular calcium. Alcohol combined with the HIV drugs significantly reduced intracellular calcium levels and potentiated cell death, which was comparable to the cell death caused by the SERCA inhibitor-thapsigargin. Our findings suggest the possibility that HIV PIs potentiate alcohol-induced ER stress and injury through modulation of SERCA and maintaining calcium homeostasis should be a therapeutic aim for a better care of HIV patients.

Kao, Eddy; Shinohara, Masao; Feng, Min; Lau, Mo Yin; Ji, Cheng

2012-01-01

197

'And what are you reading, Miss? Oh, it is only a website': The New Media and the Pedagogical Possibilities of Digital Culture as a South African 'Teen Guide' to HIV\\/AIDS and STDs  

Microsoft Academic Search

This article comes out of a recognition that access to information on sexuality and HIV and AIDS is all part of a survival strategy for young people. This is particularly an issue in South Africa where in some parts of the country the HIV infection rate for girls and young women is between 20 and 30 per cent, and where

Claudia Mitchell; Jacqueline Reid-Walsh; Kathleen Pithouse

2004-01-01

198

Therapeutic proteins.  

PubMed

Protein-based therapeutics are highly successful in clinic and currently enjoy unprecedented recognition of their potential. More than 100 genuine and similar number of modified therapeutic proteins are approved for clinical use in the European Union and the USA with 2010 sales of US$108 bln; monoclonal antibodies (mAbs) accounted for almost half (48%) of the sales. Based on their pharmacological activity, they can be divided into five groups: (a) replacing a protein that is deficient or abnormal; (b) augmenting an existing pathway; (c) providing a novel function or activity; (d) interfering with a molecule or organism; and (e) delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins. Therapeutic proteins can also be grouped based on their molecular types that include antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, and thrombolytics. They can also be classified based on their molecular mechanism of activity as (a) binding non-covalently to target, e.g., mAbs; (b) affecting covalent bonds, e.g., enzymes; and (c) exerting activity without specific interactions, e.g., serum albumin. Most protein therapeutics currently on the market are recombinant and hundreds of them are in clinical trials for therapy of cancers, immune disorders, infections, and other diseases. New engineered proteins, including bispecific mAbs and multispecific fusion proteins, mAbs conjugated with small molecule drugs, and proteins with optimized pharmacokinetics, are currently under development. However, in the last several decades, there are no conceptually new methodological developments comparable, e.g., to genetic engineering leading to the development of recombinant therapeutic proteins. It appears that a paradigm change in methodologies and understanding of mechanisms is needed to overcome major challenges, including resistance to therapy, access to targets, complexity of biological systems, and individual variations. PMID:22735943

Dimitrov, Dimiter S

2012-01-01

199

New Tools for Quantifying HIV-1 Reservoirs: Plasma RNA Single Copy Assays and Beyond  

PubMed Central

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.

2013-01-01

200

Bone Disease and HIV Infection  

Microsoft Academic Search

The high prevalence of bone demineralization among human immunodeficiency virus (HIV)-infected patients in the current therapeutic era has been described in multiple studies, sounding the alarm that we may expect an epidemic of fragility fractures in the future. However, despite noting high overall prevalences of osteopenia and osteoporosis, recent longitudinal studies that we review here have generally not observed accelerated

Valerianna Amorosa; Pablo Tebas

201

Multispot HIV-1/HIV-2 Rapid Test  

Center for Biologics Evaluation and Research (CBER)

... Multispot HIV-1/HIV-2 Rapid Test. ... Approval Date: 11/12/2004. -. Product Information. Label - Multispot HIV-1/HIV-2 Rapid Test (PDF - 491KB ... More results from www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts

202

HIV1 Langerhans' Cell Tropism Associated with Heterosexual Transmission of HIV  

Microsoft Academic Search

Heterosexual transmission by vaginal intercourse accounts for most transmission of human immunodeficiency virus-type 1 (HIV-1) in Africa and Asia but is less important in the HIV-1 epidemics of the United States and Western Europe. Epithelial Langerhans' cells (LCs) represent a possible source of initial cell contact for vaginal infection. Fifteen primary isolates of HIV-1 from U.S. homosexuals and 18 HIV-1

Luis E. Soto-Ramirez; Boris Renjifo; Mary F. McLane; Richard Marlink; Carl O'Hara; Ruengpung Sutthent; Chantapong Wasi; Prakong Vithayasai; Vicharn Vithayasai; Chatchawann Apichartpiyakul; Prasert Auewarakul; Victor Pena Cruz; Dao-Shan Chui; Rapin Osathanondh; Kenneth Mayer; Tun-Hou Lee; Max Essex

1996-01-01

203

Revisiting HIV-1 uncoating.  

PubMed

HIV uncoating is defined as the loss of viral capsid that occurs within the cytoplasm of infected cells before entry of the viral genome into the nucleus. It is an obligatory step of HIV-1 early infection and accompanies the transition between reverse transcription complexes (RTCs), in which reverse transcription occurs, and pre-integration complexes (PICs), which are competent to integrate into the host genome. The study of the nature and timing of HIV-1 uncoating has been paved with difficulties, particularly as a result of the vulnerability of the capsid assembly to experimental manipulation. Nevertheless, recent studies of capsid structure, retroviral restriction and mechanisms of nuclear import, as well as the recent expansion of technical advances in genome-wide studies and cell imagery approaches, have substantially changed our understanding of HIV uncoating. Although early work suggested that uncoating occurs immediately following viral entry in the cell, thus attributing a trivial role for the capsid in infected cells, recent data suggest that uncoating occurs several hours later and that capsid has an all-important role in the cell that it infects: for transport towards the nucleus, reverse transcription and nuclear import. Knowing that uncoating occurs at a later stage suggests that the viral capsid interacts extensively with the cytoskeleton and other cytoplasmic components during its transport to the nucleus, which leads to a considerable reassessment of our efforts to identify potential therapeutic targets for HIV therapy. This review discusses our current understanding of HIV uncoating, the functional interplay between infectivity and timely uncoating, as well as exposing the appropriate methods to study uncoating and addressing the many questions that remain unanswered. PMID:21083892

Arhel, Nathalie

2010-11-17

204

HIV Transmission Networks  

PubMed Central

Purpose of Review Over the past several years, one segment of the complex field of HIV transmission dynamics —heterosexual networks—has dominated theoretical and empirical investigation. This review provides an overview of recent work on HIV risks and networks, with a focus on recent findings in heterosexual network dynamics. Recent findings Qualitative (ethnographic) assessments have demonstrated the heterogeneity and complexity of heterosexual connections, particular in Africa where tradition, official polygamy, and unofficial multi-person arrangements lead to concurrency of sexual partnerships. A large, quantitative study on Likoma Island, Malawi, demonstrated the considerable, interlocking sexual connections that arise from a high-concurrency sexual setting, even with a low average number of partnerships (low-degree) of long duration. Such settings, as suggested by ethnographic studies, may be common in Africa and, coupled with newer information about transmissibility during acute and early infection, may provide a plausible explanation for endemic transmission and possibly for rapid HIV propagation. Summary Recognition of high- concurrency, low-degree networks is an important development for understanding HIV transmission dynamics. Their relevance to heterosexual transmission, and possible extension to other epidemiologic settings, reinforces the heterogeneity and complexity of HIV transmission dynamics.

Rothenberg, Richard

2010-01-01

205

Women and HIV. Microbicides for HIV prevention.  

PubMed

We all know about the "feminization" of AIDS. Approximately 8000 women and girls are infected with HIV daily, the vast majority by their husbands or boyfriends. In Africa, women make up 60% of all people living with HIV/AIDS, and girls make up 6% of HIV positive African youth. While fewer than half of all new HIV infections in the United States occur among women, the transmission pattern is similar. Heterosexual contact is the source of at least 78% of all new infections among U.S. women. Biologically, a woman is at least twice as likely as a man to contract HIV from a single act of unprotected vaginal intercourse. Even with the "female condom," a woman cannot protect herself during heterosexual sex without the cooperation of her partner. The "ABCs" (abstain, be faithful, use condoms) fail millions of women who lack the social and economic power to negotiate when and how sex occurs and whether protection is used. Microbicides could change this picture with just a simple cream, foam, or gel that can be inserted vaginally to protect women condom use isn't possible. Five candidate microbicides are now in large-scale efficacy trials and dozens more are in the preclinical and clinical trial pipeline. Research to develop rectal microbicides is also finally underway. We now have the scientific means and the public health motivation to put the first totally new HIV prevention technology into the hands of receptive sex partners--male and female--in the very near future. PMID:17019789

Forbes, Anna

2006-01-01

206

HIV Medicine  

NSDL National Science Digital Library

From Flying Publisher, _HIV Medicine 2005_ is a free, online "medical textbook that provides a comprehensive and up-to-date overview of the treatment of HIV Infection." This edition is an update of the 2003 version of the textbook (reported on in the June 13, 2003 NSDL Scout Report for Life Sciences). Chapter titles in the textbook include HIV Testing, HIV and Pulmonary Diseases, Mitochondrial Toxicity, HIV and HBV Coinfections, and Traveling with HIV, to name a few. The textbook is available in both German and English. Please note that while certain sections of the 2005 edition are currently available, many sections are still in the process of being published on the site. Sections from the 2003 edition are standing in for some of the forthcoming 2005 sections. The entire 352-page 2003 edition is available for download at this site as well.

207

Sulfamates and their therapeutic potential.  

PubMed

Starting from the very simple molecule sulfamic acid, O-substituted-, N-substituted-, or di-/tri-substituted sulfamates may be obtained, which show specific biological activities which were or started to be exploited for the design of many types of therapeutic agents. Among them, sulfamate inhibitors of aminoacyl-tRNA synthetases (aaRSs) were recently reported, constituting completely new classes of antibiotics, useful in the fight of drug-resistant infections. Anti-viral agents incorporating sulfamate moieties have also been obtained, with at least two types of such derivatives investigated: the nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, and the HIV protease inhibitors (PIs). In the increasing armamentarium of anti-cancer drugs, the sulfamates occupy a special position, with at least two important targets evidenced so far: the steroid sulfatases (STSs) and the carbonic anhydrases (CAs). An impressing number of inhibitors of STSs of the sulfamate type have been reported in the last years, with several compounds, such as 667COUMATE among others, progressing to clinical trials for the treatment of hormone-dependent tumors (breast and prostate cancers). This field is rapidly evolving, with many types of new inhibitors being constantly reported and designed in such a way as to increase their anti-tumor properties, and decrease undesired features (for example, estrogenicity, a problem encountered with the first generation such inhibitors, such as EMATE). Among the many isozymes of CAs, at least two, CA IX and CA XII, are highly overexpressed in tumors, being generally absent in the normal tissues. Inhibition of tumor-associated CAs was hypothesized to lead to novel therapeutic approaches for the treatment of cancer. Many sulfamates act as very potent (low nanomolar) CA inhibitors. The X-ray crystal structure of the best-studied isozyme, CA II, with three sulfamates (sulfamic acid, topiramate, and EMATE) has recently been reported, which allowed for a rationale drug design of new inhibitors. Indeed, low nanomolar CA IX inhibitors of the sulfamate type have been reported, although such compounds also act as efficient inhibitors of isozymes CA I and II, which are not associated with tumors. A large number of anti-convulsant sulfamates have been described, with one such compound, topiramate, being widely used clinically as anti-epileptic drug. By taking into consideration a side effect of topiramate, an anti-epileptic drug leading to weight loss in some patients, it has recently been proposed to use this drug and related sulfamates for the treatment of obesity. The rationale of this use is based on the inhibition of the mitochondrial CA isozyme, CA V, involved in lipogenesis. Some sulfamates were also shown to possess potent inhibitory activity against acyl coenzyme A:cholesterol acyltransferase, an enzyme involved in cholesterol metabolism. One such agent, avasimibe, is in advanced clinical trials for the treatment of hyperlipidemia and atherosclerosis. Thus, the sulfamate moiety offers very attractive possibilities for the drug design of various pharmacological agents, which are on one hand due to the relative ease with which such compounds are synthesized, and on the other one, due to the fact that biological activity of most of them is impressive. PMID:15478125

Winum, Jean-Yves; Scozzafava, Andrea; Montero, Jean-Louis; Supuran, Claudiu T

2005-03-01

208

Application of Shiga toxin and Herpes simplex virus virion host shut-off genes to HIV inhibition: Implications for HIV gene therapy  

Microsoft Academic Search

A wide variety of therapeutic approaches to HIV infection have been vigorously pursued since the isolation of the virus in 1983. Traditional drug therapies have met with little success, primarily due to the rapid generation of drug-resistant virus mutants and the high toxicity of currently available anti-HIV drugs. Clearly, a more efficacious treatment for HIV infection is required. One such

Roderick A Mcphee

1997-01-01

209

Dendritic cell dysregulation during HIV-1 infection.  

PubMed

Dendritic cells (DCs) are a diverse subset of innate immune cells that are key regulators of the host response to human immunodeficiency virus-1 (HIV-1) infection. HIV-1 directly and indirectly modulates DC function to hinder the formation of effective antiviral immunity and fuel immune activation. This review focuses upon the differential dysregulation of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) at various stages of HIV-1 infection providing insights into pathogenesis. HIV-1 evades innate immune sensing by mDCs resulting in suboptimal maturation, lending to poor generation of antiviral adaptive responses and contributing to T-regulatory cell (Treg) development. Dependent upon the stage of HIV-1 infection, mDC function is altered in response to Toll-like receptor ligands, which further hinders adaptive immunity and limits feasibility of therapeutic vaccine strategies. pDC interactions with HIV-1 are pleotropic, modulating immune responses on an axis between immunostimulatory and immunosuppressive. pDCs promote immune activation through an altered phenotype of persistent type I interferon secretion and weak antigen presentation capacity. Conversely, HIV-1 stimulates secretion of indolemine 2,3 dioxygenase (IDO) by pDCs resulting in Treg induction. An improved understanding of the roles and underlying mechanisms of DC dysfunction will be valuable to the development of therapeutics to enhance HIV-specific adaptive responses and to dampen immune activation. PMID:23772620

Miller, Elizabeth; Bhardwaj, Nina

2013-07-01

210

Expression of a modified form of CD4 results in the release of an anti-HIV factor derived from the Env sequence.  

PubMed

We have studied the inhibitory effect of a CD4 chimera (CD4epsilon15) on HIV replication. This chimera is retained in the endoplasmic reticulum and traps the HIV envelope precursor gp160, preventing its maturation. Retroviral expression of the chimera strongly inhibited HIV replication even when it is expressed by only a minority of the T cell population. This protective effect on bystander nontransduced cells is mediated by a soluble factor that we identified as a fragment of HIV gp120 envelope protein and accordingly, we named this factor Env-derived antiviral factor (EDAF). Biochemical and immunoreactivity data show that EDAF is comprised of the gp120 C3-C5 regions and indeed, a recombinant protein bearing this sequence reproduces the anti-HIV properties of EDAF. Surprisingly, three tryptic peptides derived from EDAF are homologous but not identical with the corresponding sequences of the HIV isolate used to generate EDAF. We propose that EDAF results from an alternative intracellular processing of the Env protein provoked by its association to CD4epsilon15 and the selection of the best fitted Env protein sequences contained within the HIV isolate. The presence of EDAF improves the therapeutic potential of the CD4epsilon15 gene and it opens new possibilities for antiviral treatment and vaccine development. PMID:19553524

Zaldívar, Irene; Muñoz-Fernández, María Angeles; Alarcón, Balbino; San José, Ester

2009-06-24

211

Focused assessment with sonography for HIV-associated tuberculosis (FASH): a short protocol and a pictorial review  

PubMed Central

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.

2012-01-01

212

The future of HIV treatment.  

PubMed

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

2012-08-01

213

Pharmacotherapy of Pediatric HIV Infection  

PubMed Central

SYNOPSIS With the ongoing epidemic of human immune deficiency virus (HIV) infections in the pediatric age group, the delivery of safe and effective antiretroviral therapy to children and adolescents is crucial to save the lives of millions of children worldwide. Antiretroviral drugs have been demonstrated to significantly decrease HIV-associated morbidity and mortality, assure normal growth and development, and improve survival and quality of life in children and adolescents. The immunologic response to HIV infection is closely related to the child’s development and creates age specific parameters for the evaluation of therapeutic response to antiretroviral therapy in pediatric HIV disease. In addition to the changes in immunological response to HIV infection, the development and maturation of organ systems involved in drug absorption, distribution, metabolism, and elimination determines significant changes in the pharmacokinetics of antiretroviral drugs throughout the childhood. Multiple factors including age-specific adherence barriers, changes in social and economical surroundings, and psychological and sexual maturation affect the choices and outcomes of the treatment of pediatric HIV disease. In this chapter we will review the evolution of antiretroviral treatment from early infancy through adolescence.

Rakhmanina, Natella; Phelps, Ryan

2012-01-01

214

HIV1, chemokines and neurogenesis  

Microsoft Academic Search

HIV-1 infection of the brain results in a large number of behavioural defecits accompanied by diverse neuropathological signs.\\u000a However,it is not clear how the virus produces these effects or exactly how the neuropathology and behavioural defecits are\\u000a related. In this article we discuss the possibility that HIV-1 infection may negatively impact the process of neurogenesis\\u000a in the adult brain and

Phuong B. Tran; Richard J. Miller

2005-01-01

215

The Argument for HIV-Antibody Testing in Chemical Dependence Treatment Programs  

Microsoft Academic Search

Controversy surrounds the issue of human immunodeficiency virus (HIV) antibody testing in chemically dependent patients. However, HIV testing can be clinically and therapeutically useful in chemical dependence treatment programs. Prerequisites for HIV testing include: staff education, high-quality pre- and posttest counseling for patients, assurance of confidentiality of results, and the use of accurate screening and confirmatory tests. Reasons to offer

Elizabeth F. Howell; Robert G. Niven

1989-01-01

216

A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics  

Microsoft Academic Search

Some anticancer drugs, but not all, inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. Such drugs, unlike the traditional HIV enzyme inhibitors, could suppress HIV strains that are resistant to inhibitors of viral enzymes, decrease proviral burden in vivo, or reduce reservoirs of infection via killing infected cells. Thus, they may be an effective adjunct

M. Reza Sadaie; Ronald Mayner; Jay Doniger

2004-01-01

217

Therapeutic hypothermia following cardiac arrest.  

PubMed

More than 10 years ago, the randomised studies of therapeutic hypothermia after cardiac arrest showed significant improvement of neurological outcome and survival. Since then, it has become clear that most of the possible adverse events of therapeutic hypothermia are mild and can easily be controlled by proper administration of intensive care. Although implementation of this effective therapy is quite successful, many questions of the exact treatment protocol still remain unanswered. Therapeutic hypothermia treatment therefore must be tailored to the specific patient's needs. Hence, the exact level of target temperature, duration of cooling, rewarming, timing of the therapy and concomitant medication to facilitate therapeutic hypothermia will be important in the future. Additionally, the use of a post-resuscitation treatment bundle (specialised cardiac-arrest centres including intensive post-resuscitation care, appropriate haemodynamic and respiratory management, therapeutic hypothermia and percutaneous coronary intervention) could further improve treatment of cardiac arrest. PMID:24054512

Holzer, Michael

2013-09-01

218

The Pharmacology of TUG-891, a Potent and Selective Agonist of the Free Fatty Acid Receptor 4 (FFA4/GPR120), Demonstrates Both Potential Opportunity and Possible Challenges to Therapeutic Agonism.  

PubMed

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 Ca(2+) 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 Ca(2+) signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4. PMID:23979972

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

2013-08-26

219

A universal real-time PCR assay for the quantification of group-M HIV1 proviral load  

Microsoft Academic Search

Quantification of human immunodeficiency virus type-1 (HIV-1) proviral DNA is increasingly used to measure the HIV-1 cellular reservoirs, a helpful marker to evaluate the efficacy of antiretroviral therapeutic regimens in HIV-1–infected individuals. Furthermore, the proviral DNA load represents a specific marker for the early diagnosis of perinatal HIV-1 infection and might be predictive of HIV-1 disease progression independently of plasma

Gabriella Scarlatti; Francesca Gatto; Francesca Salvatori; Giulia Cassina; Teresa Rutigliano; Rosy Volpi; Mauro S Malnati; Paolo Lusso

2008-01-01

220

Finding a cure for HIV: will it ever be achievable?  

Microsoft Academic Search

Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life-long treatment, there is now a real urgency to find a cure for HIV.

Sharon R Lewin; Vanessa A Evans; Julian H Elliott; Bruno Spire; Nicolas Chomont

2011-01-01

221

HIV Infection, Inflammation, Immunosenescence, and Aging  

PubMed Central

Although antiretroviral therapy for HIV infection prevents AIDS related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at higher than expect risk for a number of complications typically associated with aging, including cardiovascular disease, cancer, osteoporosis and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly exhibited by a number of immunologic abnormalities that persist despite effect suppression of HIV replication. These changes are consistent with some of the changes to the adaptive immune system that are seen in the very old (“immunosenescence”) and that are likely related in part to persistent inflammation. HIV-associated inflammation and immunosenescence have been implicated as causally related to the premature onset of other end organ diseases. Novel therapeutic strategies aimed at preventing or reversing these immunologic defects may be necessary if HIV infected patients are achieve normal life span.

Deeks, Steven G.

2013-01-01

222

HIV and Atherosclerosis  

MedlinePLUS

... and lower risks. Simple, low-cholesterol food choices, exercise and medications can all improve your cholesterol ratios, with or without HIV. HIV and Your Heart • Home • About HIVHIV and Cardiovascular Disease (Heart ...

223

Motivational Strategies Can Enhance HIV Risk Reduction Programs  

Microsoft Academic Search

This article advances the view that motivational strategies can augment the effectiveness of skills-based HIV risk reduction interventions. We articulate the empirical and theoretical rationale for a motivational approach and describe how we developed a motivationally based HIV risk reduction intervention. We also describe the strategic exercises and the therapeutic style that constitutes this approach, and then present detailed reviews

Michael P. Carey; Brian P. Lewis

1999-01-01

224

Feedback control of a biodynamical model of HIV1  

Microsoft Academic Search

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

2001-01-01

225

Stem cell-based anti-HIV gene therapy  

Microsoft Academic Search

Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self-renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately

Scott G. Kitchen; Saki Shimizu; Dong Sung An

2011-01-01

226

Living with HIV: Women's experience in Burkina Faso, West Africa  

Microsoft Academic Search

Our study aimed at studying HIV-infected women's experience with sharing serostatus with their partner and their group support. A survey was carried out among 79 seropositive women involved in a therapeutic trial in Bobo-Dioulasso, following freely consented prenatal HIV testing. The study revealed that women are reluctant to inform their partners and fear being stigmatized by relatives and friends. The

S. Issiaka; M. Cartoux; O. Ky-Zerbo; S. Tiendrebéogo; N. Meda; F. Dabis; P. Van de Perre

2001-01-01

227

Dock-and-lock (DNL) constructs for human immunodeficiency virus (HIV) therapy  

US Patent & Trademark Office Database

The present invention concerns methods and compositions for treatment of HIV infection in a subject, utilizing a DNL complex comprising at least one anti-HIV therapeutic agent, attached to an antibody, antibody fragment or PEG. In a preferred embodiment, the antibody or fragment binds to an antigen selected from gp120, gp41, CD4 and CCR5. In a more preferred embodiment the antibody is P4/D10 or 2G12, although other anti-HIV antibodies are known and may be utilized. In a most preferred embodiment, the anti-HIV therapeutic agent is a fusion inhibitor, such as T20, T61, T651, T1249, T2635, CP32M or T-1444, although other anti-HIV therapeutic agents are known and may be utilized. The DNL complex may be administered alone or may be co-administered with one or more additional anti-HIV therapeutic agents.

2013-07-09

228

HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury  

PubMed Central

The present paper describes possible connections between antiretroviral therapies (ARTs) used to treat human immunodeficiency virus (HIV) infection and adverse drug reactions (ADRs) encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART) has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search) and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication.

Neuman, Manuela G.; Schneider, Michelle; Nanau, Radu M.; Parry, Charles

2012-01-01

229

Umbilical cord blood mononuclear cell HIV1 LTR binding activities  

Microsoft Academic Search

Vertically transmitted HIV disease constitutes a significant problem in pediatrics. In order to characterize some of the possible host factors involved in HIV replication in fetuses and newborns, we surveyed the HIV-1 LTR binding factors present in nuclear extracts from cord blood mononuclear cells. A series of electrophoretic mobility shift assays (EMSAs) showed that protein extracts from cord blood interacted

Padmini S. Kedar; Katherine Arden; Marie Foyle; John H. Pope; Steven L. Zeichner

1997-01-01

230

Pattern of neuropsychological performance among HIV positive patients in Uganda  

Microsoft Academic Search

BACKGROUND: Few studies have examined cognitive functioning of HIV positive patients in sub-Saharan Africa. It cannot be assumed that HIV positive patients in Africa exhibit the same declines as patients in high-resource settings, since there are differences that may influence cognitive functioning including nutrition, history of concomitant disease, and varying HIV strains, among other possibilities. Part of the difficulty of

Kevin R Robertson; Noeline Nakasujja; Matthew Wong; Seggane Musisi; Elly Katabira; Thomas D Parsons; Allan Ronald; Ned Sacktor

2007-01-01

231

Polymorphisms of CUL5 Are Associated with CD4+ T Cell Loss in HIV-1 Infected Individuals  

PubMed Central

Human apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (Apobec3) antiretroviral factors cause hypermutation of proviral DNA leading to degradation or replication-incompetent HIV-1. However, HIV-1 viral infectivity factor (Vif) suppresses Apobec3 activity through the Cullin 5-Elongin B-Elongin C E3 ubiquitin ligase complex. We examined the effect of genetic polymorphisms in the CUL5 gene (encoding Cullin 5 protein) on AIDS disease progression in five HIV-1 longitudinal cohorts. A total of 12 single nucleotide polymorphisms (SNPs) spanning 93 kb in the CUL5 locus were genotyped and their haplotypes inferred. A phylogenetic network analysis revealed that CUL5 haplotypes were grouped into two clusters of evolutionarily related haplotypes. Cox survival analysis and mixed effects models were used to assess time to AIDS outcomes and CD4+ T cell trajectories, respectively. Relative to cluster I haplotypes, the collective cluster II haplotypes were associated with more rapid CD4+ T cell loss (relative hazards [RH] = 1.47 and p = 0.009), in a dose-dependent fashion. This effect was mainly attributable to a single cluster II haplotype (Hap10) (RH = 2.49 and p = 0.00001), possibly due to differential nuclear protein–binding efficiencies of a Hap10-specifying SNP as indicated by a gel shift assay. Consistent effects were observed for CD4+ T cell counts and HIV-1 viral load trajectories over time. The findings of both functional and genetic epidemiologic consequences of CUL5 polymorphism on CD4+ T cell and HIV-1 levels point to a role for Cullin 5 in HIV-1 pathogenesis and suggest interference with the Vif-Cullin 5 pathway as a possible anti-HIV-1 therapeutic strategy.

An, Ping; Duggal, Priya; Wang, Li Hua; O'Brien, Stephen J; Donfield, Sharyne; Goedert, James J; Phair, John; Buchbinder, Susan; Kirk, Gregory D; Winkler, Cheryl A

2007-01-01

232

Stem cell based anti-HIV Gene therapy  

PubMed Central

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

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

2011-01-01

233

HIV controllers: a multifactorial phenotype of spontaneous viral suppression  

PubMed Central

A small minority of HIV-infected individuals, known as HIV controllers, is able to exert long-term control over HIV replication in the absence of treatment. Increasing evidence suggests that the adaptive immune system plays a critical role in this control but also that a combination of several host and/or viral factors, rather than a single cause, leads to this rare phenotype. Here, we review recent advances in the study of these remarkable individuals. We summarize the epidemiology and clinical characteristics of HIV controllers, and subsequently describe contributing roles of host genetic factors, innate and adaptive immune responses, and viral factors to this phenotype. We emphasize distinctive characteristics of HIV-specific CD4 T cell responses and of CD4 T cell subpopulations that are frequently found in HIV controllers. We discuss major controversies in the field and the relevance of the study of HIV controllers for the development of novel therapeutic strategies and vaccines.

Theze, Jacques; Chakrabarti, Lisa A.; Vingert, Benoit; Porichis, Filippos; Kaufmann, Daniel E.

2011-01-01

234

Impact of Multi-Targeted Antiretroviral Treatment on Gut T Cell Depletion and HIV Reservoir Seeding during Acute HIV Infection  

Microsoft Academic Search

BackgroundLimited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy.Methods and FindingsWe prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II,

Jintanat Ananworanich; Alexandra Schuetz; Claire Vandergeeten; Irini Sereti; Mark de Souza; Rungsun Rerknimitr; Robin Dewar; Mary Marovich; Frits van Griensven; Rafick Sekaly; Suteeraporn Pinyakorn; Nittaya Phanuphak; Rapee Trichavaroj; Wiriya Rutvisuttinunt; Nitiya Chomchey; Robert Paris; Sheila Peel; Victor Valcour; Frank Maldarelli; Nicolas Chomont; Nelson Michael; Praphan Phanuphak; Jerome H. Kim

2012-01-01

235

HIV induces thymus depletion in vivo  

Microsoft Academic Search

HUMAN immunodeficiency virus (HIV) disease is typified by declining CD4+ T lymphocyte counts in the peripheral circulation, a loss which may be secondary to accelerated destruction, to suppressed differentiation, and\\/or to sequestration of circulating cells into tissue spaces. As it is hard to distinguish between these possibilities in human subjects, the pathogenic mechanisms associated with HIV infection are unclear. In

Mark L. Bonyhadi; Linda Rabin; Suzan Salimi; Daniel A. Brown; Jon Kosek; Joseph M. McCune; Hideto Kaneshima

1993-01-01

236

HIV in the accident and emergency department  

Microsoft Academic Search

This article is intended as an introduction to some of the issues which arise from the increasing incidence in the UK of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). It is not possible fully to address, nor offer answers to, all of these issues. HIV and AIDS present many challenges to nurses. It tests not only our

D. Sinclair

1995-01-01

237

Laser palliation of the HIV+ patient  

Microsoft Academic Search

Many oral manifestations of HIV infection can be used as markers for degree of immunosupression. These manifestations may be treated with antibiotics, analgesics, and antineoplastics, which may interact and interfere with antiviral agents used to treat the disease, and possibly exacerbate it. Dentists will see more HIV-infected patients as medical research transforms this disease into a chronic illness. Lasers have

Robert A. Convissar

2003-01-01

238

Four novel bis-(naphtho-?-pyrones) isolated from Fusarium species as inhibitors of HIV1 integrase  

Microsoft Academic Search

Integration of viral DNA into host cell DNA is an essential step in retroviral (HIV-1) replication and is catalyzed by HIV-1 integrase. HIV-1 integrase is a novel therapeutic target and is the focus of efforts to identify effective inhibitors that will prevent\\/or cure HIV infections. Four novel naphtho-?-pyrones, belonging to the chaetochromin and ustilaginoidin family, were discovered as inhibitors of

Sheo B. Singh; Deborah L. Zink; Gerald F. Bills; Ana Teran; Keith C. Silverman; Russell B. Lingham; Peter Felock; Daria J. Hazuda

2003-01-01

239

Severe hepatotoxicity after therapeutic doses of acetaminophen  

Microsoft Academic Search

Background: Acetaminophen overdose is a frequent cause of acute liver failure. Controversy exists over the rare association of severe hepatotoxicity or acute liver failure with therapeutic doses of acetaminophen.Case summary: A 45-year-old white man weighing 85 kg with asymptomatic HIV, hepatitis B virus, and hepatitis C virus (HCV) infection presented with signs of severe hepatotoxicity: aspartate aminotransferase (AST), 8581 IU\\/L;

Oswald Moling; Elena Cairon; Giovanni Rimenti; Francesco Rizza; Raffaele Pristerá; Peter Mian

2006-01-01

240

Role of endolysosomes in HIV-1 Tat-induced neurotoxicity  

PubMed Central

Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder). Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription) protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND.

Hui, Liang; Chen, Xuesong; Haughey, Norman J; Geiger, Jonathan D

2012-01-01

241

Family wellness, not HIV prevention.  

PubMed

HIV exceptionalism (and disease-specific programs generally) garner both unbalanced funding and the most talented personnel, distorting local health priorities. In support of HIV exceptionalism, the successful mobilization of significant global health sector resources was not possible prior to HIV. Both sides of the debate have merits; rather than perpetuating polarization, we suggest that sustained improvements in global health require creating a prevention infrastructure to meet multiple health challenges experienced by local communities. We propose four fundamental shifts in HIV and disease prevention: (1) horizontally integrating prevention at one site locally, with priorities tailored to local health challenges and managed by local community leaders; (2) using a family wellness metaphor for services, not disease prevention; (3) implementing evidence-based prevention programs (EBPP) based on common principles, factors, and processes, rather than replication of specific programs; and (4) utilizing the expertise of private enterprise to re-design EBPP into highly attractive, engaging, and accessible experiences. PMID:19148744

Rotheram-Borus, Mary Jane; Swendeman, Dallas; Flannery, Diane

2009-01-16

242

Antioxidant therapeutics for schizophrenia.  

PubMed

Pharmaceutical treatment for millions worldwide who have schizophrenia is limited to a handful of antipsychotics. Despite the proven efficacy of these drugs, the overall outcome for schizophrenia remains suboptimal. Thus, alternative treatment options are urgently needed. One possible approach may be antioxidant therapy. The extant evidence for the role of oxidative stress in the pathophysiology of schizophrenia offers a hypothesis-derived therapeutic approach in the form of antioxidants. Vitamins C and E, for example, are suitable for human clinical trials because they are readily available, inexpensive, and relatively safe. Research into the therapeutic use of antioxidants in schizophrenia can be grouped into two main clusters: for psychopathology and for side effects. Of these studies, some have been carefully conducted, but majority are open label. Use of antioxidants for treatment-related side effects has been more extensively investigated. The totality of the evidence to date suggests that specific antioxidants, such as N-acetyl cysteine, may offer tangible benefits for the clinical syndrome of schizophrenia, and vitamin E may offer salutary effects on glycemic effects of antipsychotics. However, a great deal of fundamental clinical research remains to be done before antioxidants can be routinely used therapeutically for schizophrenia and treatment-related complications. PMID:20977337

Reddy, Ravinder; Reddy, Rajiv

2011-04-20

243

[Fertility and HIV: equal opportunity for everyone].  

PubMed

Highly active antiretroviral treatment (HAART), the increase in life expectancy and improved HIV viral detection methods, have all led to a change in attitude towards fertility in people living with HIV. There is now acknowledgment of the fundamental rights of HIV patients to parenthood and growing implementation of assisted fertility in this group. The aims of fertility treatment are prevention of infection in HIV-discordant couples, and treatment for fertility problems, identical to the general population. We review the influence of HIV on the reproduction systems of males and females, conditions requiring fertility intervention, various methods that are possible and describe the optional treatment existing in Israel for patients with viral infection, and specifically HIV. PMID:23844527

Kedem, Eynat; Shahar, Eduardo; Hassoun, Gammal; Pollack, Shimon

2013-04-01

244

The Therapeutic School.  

ERIC Educational Resources Information Center

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

Rice, John Steadman

2002-01-01

245

Assessing pharmacists' perspectives of HIV and the care of HIV-infected patients in Alabama  

PubMed Central

Objective The purpose was to assess factors potentially affecting care pharmacists provide to HIV/AIDS patients including comfort level, confidence, education, experience, professional competence, continuity of care and patient-provider relationship between pharmacists and HIV-infected patients. Methods A 24-item questionnaire assessed the constructs of this study. Surveys were distributed from October 2009 to April 2010 to pharmacists in Alabama with varying levels of experience treating HIV-infected patients. Chi-square tests determined whether relationships existed between responses, consisting of how often respondents reported treating HIV-infected patients, amount of HIV education respondents had, participants’ confidence with HIV/AIDS knowledge and comfort level counseling HIV-infected patients about their medications. Results Thirty-three percent of the pharmacists cared for HIV-infected patients on a monthly basis, yet 86% do not feel very confident with their HIV/AIDS knowledge. Forty-four percent were not comfortable counseling patients on antiretroviral medications, and 77% would feel more comfortable with more education. Significant, positive relationships were revealed concerning how often respondents treat HIV-infected patients and their comfort level counseling them (r=0.208, p<0.05). Similar relationships pertaining to the amount of education respondents had regarding HIV, how confident they are in their HIV/AIDS knowledge (r=0.205, p< 0.05), and their comfort level counseling HIV-infected patients on their medications (r=0.312, p<0.01) were found. The time spent treating HIV-infected patients and the education respondents had pertaining to HIV/AIDS related to increased comfort levels concerning counseling patients on their medications. Conclusions This research uncovered areas where pharmacists can improve care and treatment for HIV-infected patients. Increasing education on HIV/AIDS and treatment options may lead to increased comfort and confidence in therapeutic management. Through changes in pharmacists’ perspectives and abilities to care for their patients, the patient-provider relationship could strengthen, potentially leading to improved medication compliance, enhanced overall health, and a better quality of life for HIV-infected patients.

Davis Pate, Margaret; Shell, Ami T.; King, Sean R.

246

Alcohol Consumption, Progression of Disease and Other Comorbidities, and Responses to Antiretroviral Medication in People Living with HIV  

PubMed Central

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

2012-01-01

247

Alcohol Consumption, Progression of Disease and Other Comorbidities, and Responses to Antiretroviral Medication in People Living with HIV.  

PubMed

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. PMID:22496971

Neuman, Manuela G; Schneider, Michelle; Nanau, Radu M; Parry, Charles

2012-03-11

248

Update on Human Immunodeficiency Virus (HIV)-2 Infection  

PubMed Central

Infection with human immunodeficiency virus type 2 (HIV-2) occurs mainly in West Africa, but an increasing number of cases have been recognized in Europe, India, and the United States. In this era of global integration, clinicians must be aware of when to consider the diagnosis of HIV-2 infection and how to test for this virus. Although there is debate regarding when therapy should be initiated and which regimen should be chosen, recent trials have provided important information on treatment options for HIV-2 infection. In this review, we present information on recent clinical advances in our understanding of HIV-2 infection and highlight remaining diagnostic and therapeutic challenges.

Campbell-Yesufu, Omobolaji T.

2011-01-01

249

HIV latency.  

PubMed

HIV-1 can establish a state of latent infection at the level of individual T cells. Latently infected cells are rare in vivo and appear to arise when activated CD4(+) T cells, the major targets cells for HIV-1, become infected and survive long enough to revert back to a resting memory state, which is nonpermissive for viral gene expression. Because latent virus resides in memory T cells, it persists indefinitely even in patients on potent antiretroviral therapy. This latent reservoir is recognized as a major barrier to curing HIV-1 infection. The molecular mechanisms of latency are complex and include the absence in resting CD4(+) T cells of nuclear forms of key host transcription factors (e.g., NF?B and NFAT), the absence of Tat and associated host factors that promote efficient transcriptional elongation, epigenetic changes inhibiting HIV-1 gene expression, and transcriptional interference. The presence of a latent reservoir for HIV-1 helps explain the presence of very low levels of viremia in patients on antiretroviral therapy. These viruses are released from latently infected cells that have become activated and perhaps from other stable reservoirs but are blocked from additional rounds of replication by the drugs. Several approaches are under exploration for reactivating latent virus with the hope that this will allow elimination of the latent reservoir. PMID:22229121

Siliciano, Robert F; Greene, Warner C

2011-09-01

250

Therapeutic Response to Peg IFN-alpha-2b and Ribavirin in HIV/HCV Co-infected African American and Caucasian Patients as a function of HCV Viral Kinetics and Interferon Pharmacodynamics  

PubMed Central

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.

2010-01-01

251

Expression and purification of retroviral HIV-1 reverse transcriptase.  

PubMed

Modern molecular biology techniques have provided valuable tools which allow for the expression of large amounts of enzyme in E. coli. For potential therapeutic targets such as HIV-1 reverse transcriptase, it is desirable that the enzyme studied is pure and correlates to the active form of the enzyme found in vivo. This poses a particular challenge for those researchers studying HIV-RT since a significant degree of heterogeneity is introduced by nonspecific proteolytic cleavage of the p66 subunit by E. coli proteases. The advantage of the purification protocol presented here is that the association of monomers is facilitated by mixing an excess of p51 subunit, which is truncated at a site that is N-terminal to known bacterial cleavage sites, with p66 protein. This avoids enzymatic processing of the larger subunit since the formation of heterodimeric RT is rapid and the dimer is stable against proteolytic cleavage. Therefore, it is possible to isolate a pure homogeneous p66/p51 heterodimer. An enzyme prepared in this manner yields crystals that defract to a 3.2-A resolution. It has also been used to study both sensitivity of HIV-1 RT mutants to azidothymidine triphosphate and the kinetics of a potent nonnucleoside RT inhibitor (L-743,726). Finally, it is interesting to note the similarity of HIV-1 RT with reverse transcriptases from other lentiviruses (FIV and EIAV RT). Both of these enzymes consist of heterodimers of p66 and p51 subunits and share other biophysical characteristics. Purification of these reverse transcriptases can, in all likelihood, be optimized by using methods similar to those described in this chapter. PMID:9026635

Stahlhut, M W; Olsen, D B

1996-01-01

252

Broad-Spectrum Anti-Human Immunodeficiency Virus (HIV) Potential of a Peptide HIV Type 1 Entry Inhibitor?  

PubMed Central

The AIDS epidemic continues to spread at an alarming rate worldwide, especially in developing countries. One approach to solving this problem is the generation of anti-human immunodeficiency virus (HIV) compounds with inhibition spectra broad enough to include globally prevailing forms of the virus. We have examined the HIV type 1 (HIV-1) envelope specificity of a recently identified entry inhibitor candidate, HNG-105, using surface plasmon resonance spectroscopy and pseudovirus inhibition assays. The combined results suggest that the HNG-105 molecule may be effective across the HIV-1 subtypes, and they highlight its potential as a lead for developing therapeutic and microbicidal agents to help combat the spread of AIDS.

Cocklin, Simon; Gopi, Hosahudya; Querido, Bianca; Nimmagadda, Manideepthi; Kuriakose, Syna; Cicala, Claudia; Ajith, Sandya; Baxter, Sabine; Arthos, James; Martin-Garcia, Julio; Chaiken, Irwin M.

2007-01-01

253

Financing of U.S. Biomedical Research and New Drug Approvals across Therapeutic Areas  

Microsoft Academic Search

BackgroundWe estimated U.S. biomedical research funding across therapeutic areas, determined the association with disease burden, and evaluated new drug approvals that resulted from this investment.Methodology\\/Principal FindingsWe calculated funding from 1995 to 2005 and totaled Food and Drug Administration approvals in eight therapeutic areas (cardiovascular, endocrine, gastrointestinal, genitourinary, HIV\\/AIDS, infectious disease excluding HIV, oncology, and respiratory) primarily using public data. We

E. Ray Dorsey; Joel P. Thompson; Melisa Carrasco; Jason de Roulet; Philip Vitticore; Sean Nicholson; S. Claiborne Johnston; Robert G. Holloway; Hamilton Moses; Pedro R. Lowenstein

2009-01-01

254

Important Customer Notification - Vironostika HIV-1 ...  

Center for Biologics Evaluation and Research (CBER)

... Use of cloudy EnzAbody could possibly increase your risk of inaccurate HIV test results in ... Division of Communication and Consumer Affairs. ... More results from www.fda.gov/biologicsbloodvaccines/safetyavailability/recalls

255

Dual role of autophagy in HIV-1 replication and pathogenesis  

PubMed Central

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.

2012-01-01

256

[HIV, AIDS and ethics].  

PubMed

The epidemic spread of HIV infections and the AIDS disease in the last two decades of the 20th century has quite unexpectedly confronted European civilization, including North America, with a great number of ethical problems. Today, two decades after the first signs of AIDS' possibly epidemic threat not only to individual regions but to the entire population of the world, we can already answer the questions whether Western society has learned from the past and whether the concern for the rights of the individual and of groups previously discriminated in one way or another (a concern increasing since the 1950 s initially in the USA and then in Europe) has led to a more sensitive stance in dealing with victims of the HIV and AIDS epidemic. In Europe and North America, after initial unrest and occasionally exaggerated reactions, the confrontation with HIV infection and AIDS has mostly shown a marked improvement over the way epidemics and their victims were dealt with in earlier centuries. A substantial difference from earlier epidemics is that the understandable temptation to identify the disease with a specific group of persons has meanwhile been overcome; instead of collectively discriminating against people whose style of life substantially contributes to the spread of the disease, the focus of investigation is on behaviors; increasingly, the actors are not mentioned. There is probably no other disease that touches upon a comparably broad spectrum of ethical principles. HIV infection and the AIDS disease provide models for evaluating almost all basic ethical principles that can find application in a medical context. From the identification of those infected, the search for an effective therapy, the treatment of the diseased, to the compassion with the dying and in many other respects a historically unprecedented degree of taking into regard the interests of groups at risk and of those affected have been taken into account. It is in view of the global dimension of the HIV/AIDS epidemic that a second challenge confronts European civilisation. Here the formulation of relevant politics has not been (and is unlikely to be) influenced by emotions or an abstract morale. Rather, it has been a recognition of a self-interest of Western nations vis-a-vis a possible scenario of a breakdown of public order and democratic structures in some parts of the world that has brought about a reorientation. Increasingly, the resources of governments, of science, and of private enterprise of Western nations are brought together to match the needs of those non-Western countries where the HIV/AIDS epidemic has reached catastrophic dimensions. It may well be that these efforts will support the development of vaccines and therapies affordable in these countries. PMID:11151813

Unschuld, P U

2000-11-01

257

Anti-HIV designer T cells progressively eradicate a latently infected cell line by sequentially inducing HIV reactivation then killing the newly gp120-positive cells.  

PubMed

The current antiretroviral therapy (ART) can effectively reduce plasma HIV loads to undetectable levels, but cannot eliminate latently infected resting memory CD4 T cells that persist for the lifetime of infected patients. Therefore, designing new therapeutic approaches to eliminate these latently infected cells or the cells that produce HIV upon reactivation from latency is a priority in the ART era in order to progress to a cure of HIV. Here, we show that "designer" T cells expressing chimeric antigen receptor (CAR), CD4-CD28-CD3?, can target and kill HIV Env-expressing cells. Further, they secrete effector cytokines upon contact with HIV Env+ target cells that can reactivate latent HIV in a cell line model, thereby exposing those cells to recognition and killing by anti-HIV CAR+ T cells. Taken to the limit, this process could form the basis for an eventual functional or sterilizing cure for HIV in patients. PMID:24074590

Sahu, Gautam K; Sango, Kaori; Selliah, Nithianandan; Ma, Qiangzhong; Skowron, Gail; Junghans, Richard P

2013-09-06

258

Mannose-binding lectin in HIV infection  

PubMed Central

Infection with HIV represents a significant global health problem, with high infection rates and high mortality worldwide. Treatment with antiretroviral therapy is inaccessible to many patients and efficacy is limited by development of resistance and side effects. The interactions of HIV with the human immune system, both innate and humoral, are complex and complicated by the profound ability of the virus to disable the host immune response. Mannose-binding lectin, a component of the innate immune system, has been demonstrated to play a role in host-virus interactions. This protein may have a key role in determining host susceptibility to infection, pathogenesis and progression of disease, and may contribute to the extensive variability of host response to infection. Further understanding and manipulation of the mannose-binding lectin response may represent a target for immunomodulation in HIV infection, which may, in conjunction with highly active antiretroviral therapy, allow development of a novel therapeutic approach to HIV infection.

Eisen, Sarah; Dzwonek, Agnieszka; Klein, Nigel J

2010-01-01

259

African herbal medicines in the treatment of HIV: Hypoxis and Sutherlandia. An overview of evidence and pharmacology.  

PubMed

In Africa, herbal medicines are often used as primary treatment for HIV/AIDS and for HIV-related problems. In general, traditional medicines are not well researched, and are poorly regulated. We review the evidence and safety concerns related to the use of two specific African herbals, which are currently recommended by the Ministry of Health in South Africa and member states for use in HIV: African Potato and Sutherlandia. We review the pharmacology, toxicology and pharmacokinetics of these herbal medicines. Despite the popularity of their use and the support of Ministries of Health and NGOs in some African countries, no clinical trials of efficacy exist, and low-level evidence of harm identifies the potential for drug interactions with antiretroviral drugs. Efforts should be made by mainstream health professionals to provide validated information to traditional healers and patients on the judicious use of herbal remedies. This may reduce harm through failed expectations, pharmacologic adverse events including possible drug/herb interactions and unnecessary added therapeutic costs. Efforts should also be directed at evaluating the possible benefits of natural products in HIV/AIDS treatment. PMID:15927053

Mills, Edward; Cooper, Curtis; Seely, Dugald; Kanfer, Izzy

2005-05-31

260

African herbal medicines in the treatment of HIV: Hypoxis and Sutherlandia. An overview of evidence and pharmacology  

PubMed Central

In Africa, herbal medicines are often used as primary treatment for HIV/AIDS and for HIV-related problems. In general, traditional medicines are not well researched, and are poorly regulated. We review the evidence and safety concerns related to the use of two specific African herbals, which are currently recommended by the Ministry of Health in South Africa and member states for use in HIV: African Potato and Sutherlandia. We review the pharmacology, toxicology and pharmacokinetics of these herbal medicines. Despite the popularity of their use and the support of Ministries of Health and NGOs in some African countries, no clinical trials of efficacy exist, and low-level evidence of harm identifies the potential for drug interactions with antiretroviral drugs. Efforts should be made by mainstream health professionals to provide validated information to traditional healers and patients on the judicious use of herbal remedies. This may reduce harm through failed expectations, pharmacologic adverse events including possible drug/herb interactions and unnecessary added therapeutic costs. Efforts should also be directed at evaluating the possible benefits of natural products in HIV/AIDS treatment.

Mills, Edward; Cooper, Curtis; Seely, Dugald; Kanfer, Izzy

2005-01-01

261

Macrophage signaling in HIV-1 infection  

PubMed Central

The human immunodeficiency virus-1 (HIV-1) is a member of the lentivirus genus. The virus does not rely exclusively on the host cell machinery, but also on viral proteins that act as molecular switches during the viral life cycle which play significant functions in viral pathogenesis, notably by modulating cell signaling. The role of HIV-1 proteins (Nef, Tat, Vpr, and gp120) in modulating macrophage signaling has been recently unveiled. Accessory, regulatory, and structural HIV-1 proteins interact with signaling pathways in infected macrophages. In addition, exogenous Nef, Tat, Vpr, and gp120 proteins have been detected in the serum of HIV-1 infected patients. Possibly, these proteins are released by infected/apoptotic cells. Exogenous accessory regulatory HIV-1 proteins are able to enter macrophages and modulate cellular machineries including those that affect viral transcription. Furthermore HIV-1 proteins, e.g., gp120, may exert their effects by interacting with cell surface membrane receptors, especially chemokine co-receptors. By activating the signaling pathways such as NF-kappaB, MAP kinase (MAPK) and JAK/STAT, HIV-1 proteins promote viral replication by stimulating transcription from the long terminal repeat (LTR) in infected macrophages; they are also involved in macrophage-mediated bystander T cell apoptosis. The role of HIV-1 proteins in the modulation of macrophage signaling will be discussed in regard to the formation of viral reservoirs and macrophage-mediated T cell apoptosis during HIV-1 infection.

2010-01-01

262

Interaction of HIV Tat and matrix metalloproteinase in HIV neuropathogenesis: a new host defense mechanism  

Microsoft Academic Search

Tat, the HIV transactivating protein, and matrix metalloproteinases (MMPs), a family of extra- cellular matrix (ECM) endopeptidases, have been im- plicated in the pathogenesis of HIV-associated demen- tia. However, the possibility that MMPs interact with viral proteins has remained unexplored. We therefore treated mixed human fetal neuronal cultures with re- combinant Tat and select MMPs. Neurotoxicity was determined by measuring

J. Rumbaugh; J. Turchan-Cholewo; D. Galey; C. Anderson; K. Conant; A. Nath

2006-01-01

263

Inhibition of highly productive HIV1 infection in T cells, primary human macrophages, microglia, and astrocytes by Sargassum fusiforme  

Microsoft Academic Search

BACKGROUND: The high rate of HIV-1 mutation and increasing resistance to currently available antiretroviral (ART) therapies highlight the need for new antiviral agents. Products derived from natural sources have been shown to inhibit HIV-1 replication during various stages of the virus life cycle, and therefore represent a potential source of novel therapeutic agents. To expand our arsenal of therapeutics against

Elena E Paskaleva; Xudong Lin; Wen Li; Robin Cotter; Michael T Klein; Emily Roberge; Er K Yu; Bruce Clark; Jean-Claude Veille; Yanze Liu; David Y-W Lee; Mario Canki

2006-01-01

264

Pulmonary Hypertension Associated With HIV Infection  

PubMed Central

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.

2010-01-01

265

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

PubMed Central

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

2012-01-01

266

Human immunodeficiency virus (HIV) latency: the major hurdle in HIV eradication.  

PubMed

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

Tyagi, Mudit; Bukrinsky, Michael

2012-09-25

267

Life after HIV: examination of HIV serodiscordant couples' desire to conceive through assisted reproduction.  

PubMed

The current study addresses fertility desires and considerations among 143 HIV serodiscordant, opposite-sex couples (in which only the male partner is HIV positive) in the Northeastern U.S. Couples responded to questionnaires during their initial consultation for assisted reproduction, and data were collected over 7 years and analyzed retrospectively. Results indicated that a majority of the male participants had HIV when they met their partner, and a majority also disclosed their HIV status upon meeting. Most couples reported that they had previously discussed or considered a host of fertility-related issues, including the potential risk of HIV infection to the mother and the fetus during the process of fertility treatment. The majority of couples had also discussed the possibility that the male partner could die prematurely due to HIV/AIDS and had considered making arrangements for third-party parenting in the event of the male partner's death. If their fertility treatment were to be successful in the future, most couples desired additional children, and most believed that their future child should be told of the male partner's HIV status. Predictors of the desire for additional children after successful fertility treatment included: younger age, shorter relationship duration, being childless currently, and beginning their relationship after the male partner had already been diagnosed as HIV positive. Future research on fertility desires should include perspectives of HIV positive men on fatherhood, as well as concerns and issues specific to HIV serodiscordant couples. PMID:20960049

Gosselin, Jennifer T; Sauer, Mark V

2011-02-01

268

HIV/AIDS Basics - Treatment  

MedlinePLUS Videos and Cool Tools

... the Mouse and Choose "Save link as...." Audio Mobile Video Handout Audio Terms of Use Close Window This information made possible with support from The Division of Specialized Information Services of the National Library of Medicine For more information on HIV/AIDS ...

269

HIV/AIDS - Viral Load  

MedlinePLUS Videos and Cool Tools

... the Mouse and Choose "Save link as...." Audio Mobile Video Handout Audio Terms of Use Close Window This information made possible with support from The Division of Specialized Information Services of the National Library of Medicine For more information on HIV/AIDS ...

270

HIV Home Test Kits  

Center for Biologics Evaluation and Research (CBER)

... Testing for HIV. -. -. Related Information. HIV and AIDS Activities Consumer information for patients and patient advocates; ... More results from www.fda.gov/biologicsbloodvaccines/safetyavailability/hivhometestkits

271

Major Depletion of Plasmacytoid Dendritic Cells in HIV-2 Infection, an Attenuated Form of HIV Disease  

PubMed Central

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-? production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-? production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-? inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-? levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of “attenuated” HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-? production does occur.

Cavaleiro, Rita; Baptista, Antonio P.; Soares, Rui S.; Tendeiro, Rita; Foxall, Russell B.; Gomes, Perpetua; Victorino, Rui M. M.; Sousa, Ana E.

2009-01-01

272

Antiretroviral therapy for adults infected with HIV: Guidelines for health care professionals from the Quebec HIV care committee  

PubMed Central

The appropriate use of antiretrovirals reduces morbidity and mortality caused by HIV infection. The present article provides health care professionals with a practical guide for the use of antiretrovirals. Therapy should be initiated based predominantly on clinical presentation and CD4 count, and should consist of three active drugs or at least two active drugs when this is not possible, as in cases of some treatment-experienced patients. This is the most effective way to achieve long-term suppression of viral replication. Selection of individual drugs in the regimen should consider the weight of the evidence supporting these choices, as well as their tolerability profiles and ease of use, the patients’ comorbidities and treatment history. Treatment interruption is not recommended, either in aviremic patients or in those who have experienced virological failure. Instead, the therapeutic regimen should be adjusted to minimize side effects, promote adherence and suppress viral replication.

Rouleau, Danielle; Fortin, Claude; Trottier, Benoit; Lalonde, Richard; Lapointe, Normand; Cote, Pierre; Routy, Jean-Pierre; Matte, Marie-France; Tsarevsky, Irina; Baril, Jean-Guy

2011-01-01

273

Migration, Marital Change, and HIV Infection in Malawi  

PubMed Central

Research on the relationship between migration and HIV infection in sub-Saharan Africa often suggests that migrants are at higher risk of HIV infection because they are more likely to engage in risk behavior than non-migrants, and tend to move to areas with a relatively higher HIV prevalence. While migration may be a risk factor for HIV infection, I instead focus on the possibility that the HIV positive are more likely to migrate. Using a longitudinal dataset of permanent rural residents and migrants from Malawi, I find that migrants originating from rural areas are indeed more likely than non-migrants to be HIV positive and to have engaged in HIV risk behavior. The increased HIV risk among migrants may be due to the selection of HIV positive individuals into migration; I find that HIV positive individuals are more likely migrate than those who are HIV negative. The explanation for this phenomenon appears to be marital instability, which occurs more frequently among HIV positive individuals and leads to migration after marital change.

Anglewicz, Philip

2013-01-01

274

Role of cellular iron and oxygen in the regulation of HIV-1 infection  

PubMed Central

Despite efficient antiretroviral therapy, eradication of HIV-1 infection is challenging and requires novel biological insights and therapeutic strategies. Among other physiological and environmental factors, intracellular iron greatly affects HIV-1 replication. Higher iron stores were shown to be associated with faster progression of HIV-1 infection and to inversely correlate with the survival of HIV-1 infected patients. Iron is required for several steps in the HIV-1 life cycle, including reverse transcription, HIV-1 gene expression and capsid assembly. Here, the authors present a comprehensive review of the molecular mechanisms involved in iron- and oxygen-mediated regulation of HIV-1 replication. We also propose key intracellular pathways that may be involved in regulating HIV-1 replication, via protein kinase complexes, CDK9/cyclin T1 and CDK 2/cyclin E, protein phosphatase-1 and other host factors.

Nekhai, Sergei; Kumari, Namita; Dhawan, Subhash

2013-01-01

275

Role of cellular iron and oxygen in the regulation of HIV-1 infection.  

PubMed

Despite efficient antiretroviral therapy, eradication of HIV-1 infection is challenging and requires novel biological insights and therapeutic strategies. Among other physiological and environmental factors, intracellular iron greatly affects HIV-1 replication. Higher iron stores were shown to be associated with faster progression of HIV-1 infection and to inversely correlate with the survival of HIV-1 infected patients. Iron is required for several steps in the HIV-1 life cycle, including reverse transcription, HIV-1 gene expression and capsid assembly. Here, the authors present a comprehensive review of the molecular mechanisms involved in iron- and oxygen-mediated regulation of HIV-1 replication. We also propose key intracellular pathways that may be involved in regulating HIV-1 replication, via protein kinase complexes, CDK9/cyclin T1 and CDK 2/cyclin E, protein phosphatase-1 and other host factors. PMID:23678366

Nekhai, Sergei; Kumari, Namita; Dhawan, Subhash

2013-03-01

276

Quantification of Total HIV1-DNA in Peripheral Blood Mononuclear Cells.  

PubMed

HIV reservoir measurement in patients is one of the challenges at the time of testing new treatment approaches aiming at eradicating HIV infection. HIV reservoirs are complex and disseminated in a large number of organs and lymphoid tissues. We chose to quantify total cell-associated HIV-DNA in PBMC as a marker of HIV reservoirs and described the method we developed. The marker was used in large cohort studies at different stages of HIV disease and in therapeutical trials. Our results show how informative is this marker, as well as that plasma HIV-RNA and CD4 T cell count are representative of each patient when measured in blood. Such a series of results might help to adapt simplification or structured interruption strategies, design new clinical trials targeting HIV reservoirs, and select populations that could benefit of such new treatments. PMID:24158829

Rouzioux, Christine; Mélard, Adeline; Avéttand-Fénoël, Véronique

2014-01-01

277

[Therapeutic drug monitoring of levetiracetam].  

PubMed

Levetiracetam is an anticonvulsant drug used to treat partial seizures, myoclonic seizures of juvenile myoclonic epilepsy and primary generalized tonic-clonic seizures. A review of the literature with an evidence-based medicine method highlighted parameters (age, renal failure, pregnancy, combination with other anticonvulsant drugs) which affect levetiracetam pharmacokinetics but no significant relationship between plasma concentration of levetiracetam and efficacy or toxicity. Concentrations usually observed in therapeutics is from 6 to 18 mg/L. However, the determination of an individual therapeutic concentration, associated with an effective and well tolerated therapy, could be recommended particularly before pregnancy. Consequently, therapeutic drug monitoring of levetiracetam which is not currently recommended could be possibly useful in specific clinical situations. PMID:20205999

Dailly, Eric; Bouquié, Régis; Bentué-Ferrer, Danièle

2010-03-08

278

Oligonucleotide conjugates for therapeutic applications  

PubMed Central

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.

Winkler, Johannes

2013-01-01

279

HIV Infection in Women conference.  

PubMed

A national conference was held in the US in February 1995 on the issue of human immunodeficiency virus (HIV) infection in women. The conference took place after the Centers for Disease Control (CDC) revised the definition of acquired immunodeficiency syndrome (AIDS) to include invasive cervical cancer. This fact, then, acknowledged that HIV infection in women is not the same as in men. This fact also allowed researchers to focus on women and possibly develop gender-specific prevention and control measures. The conference was the forum to initiate women-specific research efforts. Collaboration in the biological, political, and socioeconomic arenas was strongly promoted. Topics addressed included scientific advancements, program development models, policy and advocacy issues, epidemiological studies, perinatal transmission, counseling, women-controlled prevention methods, and the relationship between violence against women and HIV. The conference was well attended. An address for program and abstract requests is provided. PMID:12346007

280

HIV/AIDS and HIV nephropathy.  

PubMed

HIV is a profound disease. The impact of HIV on the renal system is also profound, requiring nephrology nurses to have an increased awareness and understanding of the challenges and issues facing HIV-infected patients. Comorbid conditions, such as anemia, HIVAN, and even stress can further impair an already compromised patient. The nephrology nurse can provide meaningful and efficacious care through an enhanced knowledge of drug and treatment interventions known to improve outcomes in HIV. PMID:12674952

Burns, Jerry; Longton, Sharon; Robinson, F Patrick; Wolfe, Gary

2003-02-01

281

HIV Treatment as Prevention: Optimising the Impact of Expanded HIV Treatment Programmes  

Microsoft Academic Search

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

2012-01-01

282

Structural Analysis of the Epitope of the Anti-HIV Antibody 2F5 Sheds Light into Its Mechanism of Neutralization and HIV Fusion  

Microsoft Academic Search

Inhibition of human immunodeficiency virus (HIV) fusion with the host cell has emerged as a viable therapeutic strategy, and rational design of inhibitors and vaccines, interfering with this process, is a prime target for antiviral research. To advance our knowledge of the structural biology of HIV fusion, we have studied the membrane-proximal region of the fusogenic envelope subunit gp41, which

Gaetano Barbato; Elisabetta Bianchi; Paolo Ingallinella; William H. Hurni; Michael D. Miller; Gennaro Ciliberto; Riccardo Cortese; Renzo Bazzo; John W. Shiver; Antonello Pessi

2003-01-01

283

A parallel genome-wide mRNA and microRNA profiling of the frontal cortex of HIV patients with and without HIV-associated dementia shows the role of axon guidance and downstream pathways in HIV-mediated neurodegeneration  

PubMed Central

Background HIV-associated dementia (HAD) is the most common dementia type in young adults less than 40 years of age. Although the neurotoxins, oxidative/metabolic stress and impaired activity of neurotrophic factors are believed to be underlying reasons for the development of HAD, the genomic basis, which ultimately defines the virus-host interaction and leads to neurologic manifestation of HIV disease is lacking. Therefore, identifying HIV fingerprints on the host gene machinery and its regulation by microRNA holds a great promise and potential for improving our understanding of HAD pathogenesis, its diagnosis and therapy. Results A parallel profiling of mRNA and miRNA of the frontal cortex autopsies from HIV positive patients with and without dementia was performed using Illumina Human-6 BeadChip and Affymetrix version 1.0 miRNA array, respectively. The gene ontology and pathway analysis of the two data sets showed high concordance between miRNA and mRNAs, revealing significant interference with the host axon guidance and its downstream signalling pathways in HAD brains. Moreover, the differentially expressed (DE) miRNAs identified in this study, in particular miR-137, 153 and 218, based on which most correlations were built cumulatively targeted neurodegeneration related pathways, implying their future potential in diagnosis, prognosis and possible therapies for HIV-mediated and possibly other neurodegenerative diseases. Furthermore, this relationship between DE miRNAs and DE mRNAs was also reflected in correlation analysis using Bayesian networks by splitting-averaging strategy (SA-BNs), which revealed 195 statistically significant correlated miRNA-mRNA pairs according to Pearson’s correlation test (P<0.05). Conclusions Our study provides the first evidence on unambiguous support for intrinsic functional relationship between mRNA and miRNA in the context of HIV-mediated neurodegeneration, which shows that neurologic manifestation in HIV patients possibly occurs through the interference with the host axon guidance and its downstream signalling pathways. These data provide an excellent avenue for the development of new generation of diagnostic/prognostic biomarkers and therapeutic intervention strategies for HIV-associated neurodegeneration.

2012-01-01

284

HIV-associated pulmonary tuberculosis.  

PubMed

The problems of diagnosis, treatment and management of tuberculosis associated with HIV infection in Africa are placed in perspective by the former director of the Kenya Medical Research Institute. Tuberculosis (TB) has increased as much as 3-fold in many African countries due to heightened susceptibility of HIV patients. HIV infection may both re-activate latent TB, which virtually all Africans harbor, or increase the likelihood of exogenous infection or re-infection by TB. In most of Africa diagnosis by stained sputum smear is standard: in late AIDS, this method may yield false negatives due to non-pulmonary TB, or pulmonary TB with a negative smear. Chest x-rays are also atypical, since cavitation of the upper zones is not as common, but lobar consolidation and lower zone involvement, and various unusual findings are likely. There is no evidence that mycobacterium avium intracellular has occurred in Africa. Treatment in Africa often centers on long-term thiazina (thiacetazone and isoniazid combined). HIV+ patients are more prone to skin rashes or even lethal epidermal neurolysis as a complication of treatment. Treated patients should be monitored for other symptoms such as diarrhea, recurrent fevers, other chest infections, cerebral space occupying lesions, urinary infections. Many can be treated with broad spectrum antibiotics such as chloramphenicol. Nursing HIV-infected young adults is an expensive and burdensome prospect for overworked and underpaid staff, but curing TB in AIDS patients is possible and worthwhile because of the public health advantages. PMID:12343452

Nunn, P

1991-11-01

285

Therapeutic Area Standards Table  

Center for Drug Evaluation (CDER)

Text Version... Group5 51 Diabetic Nephropathy 13 Tier 2 ... therapeutic The term “therapeutic area” also includes diagnostic and preventive areas. Some ... More results from www.fda.gov/downloads/drugs/developmentapprovalprocess

286

T-Cell Signaling in HIV-1 Infection.  

PubMed

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

Abbas, Wasim; Herbein, Georges

2013-07-26

287

HIV-Associated Cardiomyopathy  

Microsoft Academic Search

Human immunodeficiency virus (HIV) disease is recognized as an important cause of dilated cardiomyopathy. Myocarditis and myocardial infection with HIV-1 are the best-studied causes of cardiomyopathy in HIV disease. HIV-1 virions appear to infect myocardial cells in a patchy distribution with no direct association between the presence of the virus and myocyte dysfunction. Myocardial dendritic cells seem to play a

Giuseppe Barbaro

2005-01-01

288

HIV infection and surgeons  

Microsoft Academic Search

The human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome, which remains uniformly fatal in affected individuals. A common route of HIV transmission is via inoculation of contaminated blood, which may occur during surgical procedures. Surgeons may estimate their risk of HIV infection over a 30-year surgical career based on HIV prevalence among surgical patients, percutaneous injury rate per operation, and

Eric Y. Lin; F. Charles Brunicardi

1994-01-01

289

HIV Testing and Pregnancy  

MedlinePLUS

... my state? ?e U.S. Department of Health and Human Services (HHS) o?ers information on HIV testing for each state. Contact HHS at 1–877– ... infections) produces HIV antibodies. HIV and Pregnancy – HIV Testing and ... of Health and Human Services’ Recommendations for Use of Antiretroviral Drugs in ...

290

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

PubMed

Potent anti-retroviral therapy 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 that 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 long terminal repeat-activated transcription. Using biological assays followed by similar in silico analysis to find second-generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the second-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. PMID:23247501

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

2012-12-13

291

Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis.  

PubMed

HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy. PMID:23444290

Nyamweya, Samuel; Hegedus, Andrea; Jaye, Assan; Rowland-Jones, Sarah; Flanagan, Katie L; Macallan, Derek C

2013-02-26

292

Slow Human Immunodeficiency Virus (HIV) Infectivity Correlated with Low HIV Coreceptor Levels  

PubMed Central

The absolute number of CD4+ lymphocytes in blood is prognostic for disease progression, yet the cell surface density of CD4 receptors or chemokine receptors on a single cell has not previously been found to be predictive of human immunodeficiency virus (HIV) infectivity outcome. It has recently been shown that human leukocyte elastase (HLE) and its ligand ?1 proteinase inhibitor (?1PI; ?1 antitrypsin) act as HIV fusion cofactors. The present study shows that decreased HIV infectivity is significantly correlated with decreased cell surface density of HLE but not with decreased CD4 nor chemokine receptors. In vitro HIV infectivity outcome in this study was predicted by the surface density of HLE on mononuclear phagocytes but not on lymphocytes. The set point HLE surface density was in part determined by ?1PI. Decreased circulating ?1PI was correlated with increased cell surface HLE and with increased HIV infectivity. The correlation of HIV infectivity outcome with surface HLE and circulating ?1PI supports the utility of these HIV cofactors in diagnostic analysis and therapeutic intervention.

Bristow, Cynthia L.

2001-01-01

293

Reducing the cost of HIV antibody testing.  

PubMed

Available tests to detect antibody to human immunodeficiency virus (HIV) have a range of applications, and injudicious selection and inappropriate use can add a significant financial burden to budgets for AIDS programmes in developing countries. There are several ways by which the cost of HIV antibody testing can be reduced; they include use of tests appropriate for existing laboratory capabilities; adoption of cost-effective testing strategies; pooling of serum samples before testing; and ensuring best possible purchase prices. Each approach can significantly reduce the cost of HIV antibody testing alone or in combination, which increases the potential sustainability of antibody testing programmes, even in settings of limited resources. PMID:8100916

Tamashiro, H; Maskill, W; Emmanuel, J; Fauquex, A; Sato, P; Heymann, D

1993-07-10

294

[Aspects of rehabilitation in HIV and AIDS].  

PubMed

Medical treatment of HIV infection has changed dramatically since 1997. The uncontrollable threat became a chronic disease. On the other hand, many HIV-infected people suffer from high psychological distress and multiple physical complaints. Interaction in HIV prevention could transform into psychological counseling. Counselors should initiate rehabilitation measures and occupational reintegration by utilizing all legal possibilities for handicapped people. Patients and physicians, psychologists and social workers as well as self-help groups should initiate successful reintegration into the workforce and daily life; this could positively influence compliance behavior. PMID:15912397

Franke, G H; Hackbarth, K P; Potthoff, A; Brockmeyer, N

2005-07-01

295

Neuromodulatory activities of CD4+CD25+ regulatory T cells in a murine model of HIV-1 associated neurodegeneration1  

PubMed Central

HIV-1 associated neurocognitive impairments are intrinsically linked to microglial immune activation, persistent viral infection, and inflammation. In the era of antiretroviral therapy more subtle cognitive impairments occur without adaptive immune compromise. We posit that adaptive immunity is neuroprotective serving both in eliminating infected cells through CD8+ cytotoxic T cell activities and by regulating the neuroinflammatory responses of activated microglia. For the latter, little is known. Thus, we studied the neuromodulatory effects of CD4+ regulatory T cells (CD4+CD25+, Treg) or effector T cells (Teff) in HIV-1 associated neurodegeneration. A newly developed HIV-1 encephalitis mouse model system was employed wherein murine bone marrow-derived macrophages are infected with a full length HIV-1YU2/vesicular stomatitis viral pseudotype and injected into basal ganglia of syngeneic immunocompetent mice. Adoptive transfer of CD3-activated Treg attenuated astrogliosis and microglia inflammation with concomitant neuroprotection. Moreover, Treg-mediated anti-inflammatory activities and neuroprotection were associated with upregulation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor expression and downregulation of pro-inflammatory cytokines, oxidative stress, and viral replication. Teff showed contrary effects. These results, taken together, demonstrate the importance of Treg in disease control and raise the possibility of their utility for therapeutic strategies.

Liu, Jianuo; Gong, Nan; Huang, Xiuyan; Reynolds, Ashley D.; Mosley, R. Lee; Gendelman, Howard E.

2009-01-01

296

Feedback Control of a Biodynamical Model of HIV1  

Microsoft Academic Search

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

2001-01-01

297

Penicillinosis in a HIV-positive individual  

PubMed Central

Penicillium marneffei is a dimorphic fungus, which can cause fatal infection in HIV-infected patients. The aim of this article is to report a rare case of penicillinosis in an HIV-positive patient from a nonendemic area such as Paonta Sahib, Himachal Pradesh. The patient presented with nonhealing painful ulcer on tongue, chest pain, cough, and chronic diarrhea. Diagnosis was made possible through blood investigations and culture reports of saliva and blood samples.

Dahiya, Parveen; Kamal, Reet; Puri, Abhiney; Saini, Gaurav; Arora, Anupama

2012-01-01

298

RNA-based Therapeutics- Current Progress and Future Prospects  

PubMed Central

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.

2012-01-01

299

Possible people.  

PubMed

Where we have a choice between bringing someone into existence and not doing so, the interests of the possible person must be considered. The implications of this view for population policy are explored, concluding with a version of utilitarianism that proposes increasing the population of a society while increasing the total utility, without altering its proportionate distribution, until the lowest segment of the population comes below the break-even point at which life is just worth living. Questions of whether poverty is the chief cause of misery and how great an obligation is owed to reducing social and economic inequalities are examined. PMID:11651921

Hare, R M

1988-10-01

300

Stimulation of HIV-specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV infection  

Microsoft Academic Search

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral

Annette Oxenius; David A. Price; Huldrych F. Günthard; Sara J. Dawson; Catherine Fagard; Luc Perrin; Marek Fischer; Rainer Weber; Montserrat Plana; Felipe García; Bernard Hirschel; Angela McLean; Rodney E. Phillips

2002-01-01

301

Polymorphisms of HIV2 integrase and selection of resistance to raltegravir  

Microsoft Academic Search

BACKGROUND: Human Immunodeficiency Virus type 2 is naturally resistant to some antiretroviral drugs, restricting therapeutic options for patients infected with HIV-2. Regimens including integrase inhibitors (INI) seem to be effective, but little data on HIV-2 integrase (IN) polymorphisms and resistance pathways are available. MATERIALS AND METHODS: The integrase coding sequence from 45 HIV-2-infected, INI-naïve, patients was sequenced and aligned against

Danielle Perez Bercoff; Perrine Triqueneaux; Christine Lambert; Aboubacar Alassane Oumar; Anne-Marie Ternes; Sounkalo Dao; Patrick Goubau; Jean-Claude Schmit; Jean Ruelle

2010-01-01

302

Structural basis for HIV1 neutralization by a gp41 fusion intermediate–directed antibody  

Microsoft Academic Search

Elicitation of potent and broadly neutralizing antibodies is an important goal in designing an effective human immunodeficiency virus-1 (HIV-1) vaccine. The HIV-1 gp41 inner-core trimer represents a functionally and structurally conserved target for therapeutics. Here we report the 2.0-Å-resolution crystal structure of the complex between the antigen-binding fragment of D5, an HIV-1 cross-neutralizing antibody, and 5-helix, a gp41 inner-core mimetic.

Micah A Luftig; Marco Mattu; Paolo Di Giovine; Romas Geleziunas; Renee Hrin; Gaetano Barbato; Elisabetta Bianchi; Michael D Miller; Antonello Pessi; Andrea Carfí

2006-01-01

303

In vivo emergence of HIV1 variants resistant to multiple protease inhibitors  

Microsoft Academic Search

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

1995-01-01

304

Designed oligomers of cyanovirin-N show enhanced HIV neutralization.  

PubMed

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN(2)) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN(2) variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants. PMID:21799112

Keeffe, Jennifer R; Gnanapragasam, Priyanthi N P; Gillespie, Sarah K; Yong, John; Bjorkman, Pamela J; Mayo, Stephen L

2011-07-28

305

Impact of Tat Genetic Variation on HIV-1 Disease  

PubMed Central

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

2012-01-01

306

Designed oligomers of cyanovirin-N show enhanced HIV neutralization  

PubMed Central

Cyanovirin-N (CV-N) is a small, cyanobacterial lectin that neutralizes many enveloped viruses, including human immunodeficiency virus type I (HIV-1). This antiviral activity is attributed to two homologous carbohydrate binding sites that specifically bind high mannose glycosylation present on envelope glycoproteins such as HIV-1 gp120. We created obligate CV-N oligomers to determine whether increasing the number of binding sites has an effect on viral neutralization. A tandem repeat of two CV-N molecules (CVN2) increased HIV-1 neutralization activity by up to 18-fold compared to wild-type CV-N. In addition, the CVN2 variants showed extensive cross-clade reactivity and were often more potent than broadly neutralizing anti-HIV antibodies. The improvement in activity and broad cross-strain HIV neutralization exhibited by these molecules holds promise for the future therapeutic utility of these and other engineered CV-N variants.

Keeffe, Jennifer R.; Gnanapragasam, Priyanthi N. P.; Gillespie, Sarah K.; Yong, John; Bjorkman, Pamela J.; Mayo, Stephen L.

2011-01-01

307

HIV\\/AIDS in Ethiopia: where is the epidemic heading?  

Microsoft Academic Search

Objectives: A possible decline in prevalence of HIV in some sub-Saharan African countries has been reported recently. The present study aimed to evaluate the prevalence and incidence of HIV and behavioural data to investigate trends in HIV\\/AIDS in Ethiopia.Methods: A review was conducted of published reports and literature, raw and modelled (using Epidemic Projection Package and Spectrum software) surveillance data

W Hladik; I Shabbir; A Jelaludin; A Woldu; M Tsehaynesh; W Tadesse

2006-01-01

308

Emerging trends in plasma-free manufacturing of recombinant protein therapeutics expressed in mammalian cells  

PubMed Central

Mammalian cells are the expression system of choice for therapeutic proteins, especially those requiring complex post-translational modifications. Traditionally, these cells are grown in medium supplemented with serum and other animal-or human-derived components to support viability and productivity. Such proteins are also typically added as excipients and stabilizers in the final drug formulation. However, the transmission of hepatitis B in the 1970s and of hepatitis C and HIV in the 1980s through plasma-derived factor VIII concentrates had catastrophic consequences for hemophilia patients. Thus, due to regulatory concerns about the inherent potential for transmission of infectious agents as well as the heterogeneity and lack of reliability of the serum supply, a trend has emerged to eliminate the use of plasma-derived additives in the production and formulation of recombinant protein therapeutics. This practice began with products used in the treatment of hemophilia and is progressively expanding throughout the entire industry. The plasma-free method of producing recombinant therapeutics is accomplished by the use of both cell culture media and final product formulations that do not contain animal-or human-derived additives. A number of recombinant therapeutic proteins for the treatment of several different diseases have been produced by plasma-free processes, with the objective of improving safety by eliminating blood-borne pathogens or by reducing immunogenicity. This review describes the factors that drove the development of plasma-free protein therapeutics and provides examples of advances in manufacturing that have made possible the removal of human and animal-derived products from all steps of recombinant protein production.

Grillberger, Leopold; Kreil, Thomas R; Nasr, Sonia; Reiter, Manfred

2009-01-01

309

Therapeutic Actions of Melatonin in Cancer: Possible Mechanisms  

Microsoft Academic Search

Melatonin is a phylogenetically well-preserved molecule with diverse physiological functions. In addition to its well-known regulatory control of the sleep\\/wake cycle, as well as circadian rhythms generally, melatonin is involved in immunomodulation, hematopoiesis, and antioxidative processes. Recent human and animal studies have now shown that melatonin also has important oncostatic properties. Both at physiological and pharmacological doses melatonin exerts growth

Venkataramanujan Srinivasan; D Warren Spence; Seithikurippu R. Pandi-Perumal; Ilya Trakht; Daniel P. Cardinali

2008-01-01

310

Analysis Using TCGA Data Identifies New Therapeutic Possibility  

Cancer.gov

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.

311

Human endogenous retroviruses and cancer: Causality and therapeutic possibilities  

PubMed Central

A substantial part of the human genome is derived from transposable elements; remnants of ancient retroviral infections. Conservative estimates set the percentage of human endogenous retroviruses (HERVs) in the genome at 8%. For the most part, the interplay between mutations, epigenetic mechanisms and posttranscriptional regulations silence HERVs in somatic cells. We first highlight mechanisms by which activation of members of several HERV families may be associated with tumor development before discussing the arising chances for both diagnosis and therapy. It has been shown that at least in some cases, tumor cells expressing HERV open reading frames (ORFs) thus gain tumor-promoting functions. However, since these proteins are not expressed in healthy tissues, they become prime target structures. Of potential pharmacological interest are the prevention of HERV transposition, the inhibition of HERV-encoded protein expression and the interference with these proteins’ activities. Evidence from recent studies unequivocally proves that HERV ORFs represent a very interesting source of novel tumor-specific antigens with even the potential to surpass entity boundaries. The development of new tumor (immune-) therapies is a very active field and true tumor-specific targets are of outstanding interest since they minimize the risk of autoimmunity and could reduce side effects. Finally, we postulate on main future research streams in order to stimulate discussion on this hot topic.

Mullins, Christina S; Linnebacher, Michael

2012-01-01

312

The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth  

PubMed Central

Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF), endothelin-1 (ET-1), angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-?, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth.

Alitheen, Noorjahan Banu

2013-01-01

313

Insulin Resistance in Brain and Possible Therapeutic Approaches.  

PubMed

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 Yildirim; Ertek, Sibel

2013-04-25

314

HIV-1 Subtypes and Recombinants in Northern Tanzania: Distribution of Viral Quasispecies  

PubMed Central

This study analyzed the distribution and prevalence of HIV-1 subtypes, multiplicity of HIV-1 infection, and frequency of inter-subtype recombination among HIV-1-infected female bar and hotel workers in Moshi, Kilimanjaro Region, Tanzania, from 2004 to 2007. The HIV-1 viral sequences spanning the V1-C5 region of HIV-1 env gp120 were analyzed from 50 subjects by single genome amplification and sequencing (SGA/S) technique. A total of 1740 sequences were amplified and sequenced from the HIV-1 proviral DNA template. The median env sequences analyzed per subject per two time points was 38 (IQR 28–50) over one year of HIV infection. In a subset of 14 subjects, a total of 239 sequences were obtained from HIV-1 RNA template at the baseline visit. The most prevalent HIV-1 subtypes were A1 (56%) and C (30%), while HIV-1 subtype D and inter-subtype recombinant viruses were found in 6% and 8% of subjects respectively. Transmission of multiple HIV-1 variants was evident in 27% of the subjects infected with pure HIV-1 subtypes A1, C, or D. The HIV-1 inter-subtype recombinants were found in 8% including HIV-1 C/A, D/A, and complex mosaic recombinants. Multiple viral variants were found in two subjects infected with inter-subtype recombinants. One subject harbored quasispecies of both pure HIV-1 A1 and C/A recombinant. The other subject was infected with two complex mosaic inter-subtype recombinant variants belonging to subtype D. HIV-1 multiple infections and ongoing recombination contribute significantly to the genetic diversity of circulating HIV-1 in Tanzania and have important implications for vaccine design and the development of therapeutic strategies.

Kiwelu, Ireen E.; Novitsky, Vladimir; Margolin, Lauren; Baca, Jeannie; Manongi, Rachel; Sam, Noel; Shao, John; McLane, Mary F.; Kapiga, Saidi H.; Essex, M.

2012-01-01

315

Drug transporters relevant to HIV therapy.  

PubMed

Membrane transporters play a key role in the intestinal absorption, tissue distribution, cellular accumulation and renal excretion of anti-HIV drugs. A clear understanding of the individual roles of these transporters is, therefore, essential if we are to attempt to design new drugs and use drug combinations that are more clinically effective. This review attempts to provide an overview of those membrane transporters considered to be relevant to the disposition and effectiveness of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). However, we are still at an early stage in our understanding of these drug transporters and their interactions with anti-HIV drugs. Rapid progress in this area is essential if the therapeutic potential of anti-HIV drugs is to be fully exploited. PMID:15731741

Thomas, Sarah A

2004-11-01

316

Pregnancy loss and role of infant HIV status on perinatal mortality among HIV-infected women  

PubMed Central

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.

2012-01-01

317

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.  

PubMed

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations. PMID:22371894

Arab-Alameddine, Mona; Fayet-Mello, Aurélie; Lubomirov, Rubin; Neely, Michael; di Iulio, Julia; Owen, Andrew; Boffito, Marta; Cavassini, Matthias; Günthard, Huldrych F; Rentsch, Katharina; Buclin, Thierry; Aouri, Manel; Telenti, Amalio; Decosterd, Laurent Arthur; Rotger, Margalida; Csajka, Chantal

2012-02-27

318

Antiretroviral Drug Resistance Mutations Sustain or Enhance CTL Recognition of Common HIV1 Pol Epitopes  

Microsoft Academic Search

Antiretroviral drug resistance and escape from CTL are major obstacles to effective control of HIV replication. To investigate the possibility of combining drug and immune-based selective pressures against HIV, we studied the effects of antiretroviral drug resistance mutations on CTL recognition of five HIV-1 Pol epitopes presented by common HLA molecules. We found that these common drug resistance mutations sustain

Rosemarie D. Mason; M. Ian Bowmer; Constance M. Howley; Maureen Gallant; Jennifer C. E. Myers; Michael D. Grant

319

A Low cost VR group support system for people living with HIV  

Microsoft Academic Search

Abstract: Social support has been shown to improve the quality of life of HIV\\/AIDS patients, and HIV\\/AIDS counseling and support groups have traditionally been used as a means of providing social support to patients. Given the high HIV infection rate, South Africa faces a shortage of counseling resources. This study investigated the possibility of using virtual reality technologyto provide emotional

Sabeeha Hamza; Mignon Coetzee; Edwin Blake; David Nunez

320

Pseudomonas DING proteins as human transcriptional regulators and HIV-1 antagonists  

PubMed Central

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.

2013-01-01

321

Allosteric Inhibitor Development Targeting HIV-1 Integrase  

PubMed Central

HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand transfer specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US FDA approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been US FDA approved for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached Phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the development of HIV-1 IN strand transfer specific drug resistant viral strains upon clinical use of the compounds is expected in the patient. Furthermore the problem of strand transfer specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand transfer drug resistant viral strains, and would likely show synergy with all available FDA approved antiretroviral HIV-1 therapeutics, including the IN strand transfer specific compounds. Here we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active site regions to inhibit IN function.

Al-Mawsawi, Laith Q.; Neamati, Nouri

2011-01-01

322

Experimental Therapeutics for Dystonia  

PubMed Central

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.

2008-01-01

323

Therapeutic devices for epilepsy.  

PubMed

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 (VNS), which continues to develop new technology, is approved for use in the United States. Deep brain stimulation of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to 1 or 2 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 are split on efficacy, which 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 electroencephalography (EEG) is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures, and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience. PMID:22367987

Fisher, Robert S

2012-02-01

324

Therapeutic Devices for Epilepsy  

PubMed Central

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.

2011-01-01

325

Therapeutic use exemption  

PubMed Central

Football players who have either physical symptoms or disease after injury may need to be treated with specific medicines that are on the list of prohibited substances. Therapeutic use exemption may be granted to such players, in accordance with strictly defined criteria—these are presented in this article. Procedures of how to request for an abbreviated or a standard therapeutic use exemption are explained, and data on therapeutic use exemptions (UEFA and FIFA, 2004 and 2005) are also presented.

Dvorak, J; Kirkendall, D; Vouillamoz, M

2006-01-01

326

[Major therapeutic advances and new perspectives in onco-hematology].  

PubMed

Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed. PMID:23735575

Bay, Jacques-Olivier; Guièze, Romain; Ravinet, Aurélie; Lemal, Richard; Xhaard, Aliénor; Bailly, Sébastien; Moluçon-Chabrot, Cécile; Hermet, Eric; Biau, Julian; Verrelle, Pierre; Peffault de Latour, Régis; Tournilhac, Olivier

2013-06-01

327

Changes in parietal cell structure and function in HIV disease  

Microsoft Academic Search

The mechanisms underlying acid secretory failure in patients with HIV disease are unknown. We evaluated, in a series of preliminary studies, changes associated with parietal cell structure and function in early and late HIV disease, in an attempt to elucidate possible underlying mechanisms. Gastric acid and intrinsic factor secretion, vitamin B12 absorption, and light and electron microscopic evaluation of gastric

Gerond Lake-Bakaar; Magdy Elsakr; Nabil Hagag; Sergey Lyubsky; Jagbir Ahuja; Barbara Craddock; ROY T. STEIGBIGEL

1996-01-01

328

Food Insecurity is Associated with Poor Virologic Response among HIV-Infected Patients Receiving Antiretroviral Medications  

Microsoft Academic Search

BACKGROUND AND OBJECTIVE  Food insecurity negatively impacts HIV disease outcomes in international settings. No large scale U.S. studies have investigated\\u000a the association between food insecurity and severity of HIV disease or the mechanism of this possible association. The objective\\u000a of this study was to examine the impact of food insecurity on HIV disease outcomes in a large cohort of HIV-infected patients

Emily A. Wang; Kathleen A. McGinnis; David A. Fiellin; Joseph L. Goulet; Kendall Bryant; Cynthia L. Gibert; David A. Leaf; Kristin Mattocks; Lynn E. Sullivan; Nicholas Vogenthaler; Amy C. Justice

329

HIV-1 Prevention for HIV-1 Serodiscordant Couples  

PubMed Central

A substantial proportion of HIV-1-infected individuals in sub-Saharan Africa are in stable relationships with HIV-1-uninfected partners, and HIV-1 serodiscordant couples thus represent an important target population for HIV-1 prevention. Couple-based HIV-1 testing and counseling facilitates identification of HIV-1 serodiscordant couples, counseling about risk reduction, and referrals to HIV-1 treatment, reproductive health services, and support services. Maximizing HIV-1 prevention for HIV-1 serodiscordant couples requires a combination of strategies, including counseling about condoms, sexual risk, fertility, contraception, and the clinical and prevention benefits of antiretroviral therapy (ART) for the HIV-1-infected partner; provision of clinical care and ART for the HIV-1-infected partner; antenatal care and services to prevent mother to child transmission for HIV-1- infected pregnant women; male circumcision for HIV-1-uninfected men; and, pending guidelines and demonstration projects, oral pre-exposure prophylaxis (PrEP) for HIV-1-uninfected partners.

Curran, Kathryn; Baeten, Jared M.; Coates, Thomas J.; Kurth, Ann; Mugo, Nelly R.

2013-01-01

330

Inhaled corticosteroids in persons with HIV infection: not that harmless.  

PubMed

There is a growing group of HIV-seropositive patients at risk for chronic lung disease due to their life style and age. The interaction between certain antiretroviral drugs and corticosteroid inhalation therapy is potentially dangerous but often unrecognised. We present three cases from our HIV-clinic of whom two developed full blown Cushing's syndrome over a short period of time and one presented with asymptomatic hypocortisolaemia due to serious drug interactions between HIV-drugs and inhaled corticosteroids. General practitioners, HIV and chest physicians should all be aware of this potentially life-threatening interaction and the combination of those products should be avoided where possible. PMID:22712167

Spruyt, S; Vlieghe, E; Bomans, P; Moerman, F; Colebunders, R; Van den Ende, J

331

Non-Invasive Coronary Imaging for Atherosclerosis in HIV Infection  

PubMed Central

Coronary artery disease (CAD) is increasingly recognized as an important contributor to morbidity and mortality among persons living with HIV infection. Traditional cardiovascular disease risk factors as well as aspects of HIV infection and its therapy contribute to the increased CAD observed in HIV. Advances in non-invasive imaging methodologies in both computed tomography and magnetic resonance imaging provide opportunities to evaluate coronary artery atherosclerosis in ways not possible by conventional invasive x-ray angiography. Application of these techniques may prove very useful in the study of atherosclerosis in many diseases such as HIV.

Gharib, Ahmed M.; Abd-Elmoniem, Khaled Z.; Pettigrew, Roderic I.; Hadigan, Colleen

2011-01-01

332

Nutritional and metabolic abnormalities in pre-AIDS HIV infection.  

PubMed

Since the earliest reports of human immunodeficiency virus (HIV) disease, undernutrition has been associated with HIV infection, typically with the late stages of the disease (namely acquired immunodeficiency syndrome), and may advance to severe wasting and cachexia. Specific micronutrient deficiencies are also recognized to occur with HIV infection, but their actual effect on the clinical course of the disease is hard to assess. The studies reviewed provide more insight into the complex interface between undernutrition and, in some cases, obesity and HIV/acquired immunodeficiency syndrome and highlight the possibility of alleviating or curing undernutrition by means of simple and comparatively inexpensive dietary adjustments. PMID:16704957

Faintuch, Joel; Soeters, Peter B; Osmo, Helio G

2006-06-01

333

Successful aging and the epidemiology of HIV  

PubMed Central

By 2015, it is estimated that nearly half of those living with HIV in the US will be 50 years of age and older. This dramatic change in the demographics of this clinical population represents unique challenges for patients, health care providers, and society-at-large. Fortunately, because of highly active antiretroviral therapy (HAART) and healthy lifestyle choices, it is now possible for many infected with HIV to age successfully with this disease; however, this depends upon one’s definition of successful aging. It is proposed that successful aging is composed of eight factors: length of life, biological health, cognitive efficiency, mental health, social competence, productivity, personal control, and life satisfaction. Unfortunately, HIV and medication side effects can compromise these factors, thus diminishing one’s capacity to age successfully with this disease. This article explores how HIV, medication side effects from HAART, and lifestyle choices can compromise the factors necessary to age successfully. Implications for practice and research are posited.

Vance, David E; McGuinness, Teena; Musgrove, Karen; Orel, Nancy Ann; Fazeli, Pariya L

2011-01-01

334

Molecular Understanding of HIV-1 Latency  

PubMed Central

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.

2012-01-01

335

Drug Resistance in HIV-1  

PubMed Central

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.

2011-01-01

336

Iron chelators ICL670 and 311 inhibit HIV-1 transcription  

SciTech Connect

HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics.

Debebe, Zufan; Ammosova, Tatyana [Center for Sickle Cell Disease, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States); Jerebtsova, Marina [Children's National Medical Center, CRI Center for Cancer and Immunology, 111 Michigan Ave., N.W., Washington, DC 20060 (United States); Kurantsin-Mills, Joseph [Department of Biophysics and Physiology, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States); Niu, Xiaomei; Charles, Sharroya [Center for Sickle Cell Disease, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States); Richardson, Des R. [Iron Metabolism and Chelation Program, Department of Pathology, Blackburn Building (D06), University of Sydney, Sydney, New South Wales, 2006 Australia (Australia); Ray, Patricio E. [Children's National Medical Center, CRI Center for Cancer and Immunology, 111 Michigan Ave., N.W., Washington, DC 20060 (United States); Gordeuk, Victor R. [Center for Sickle Cell Disease, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States); Nekhai, Sergei [Center for Sickle Cell Disease, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States); Department of Biochemistry and Molecular Biology, Howard University College of Medicine, 520 W. St., N.W., Washington, DC 20060 (United States)], E-mail: snekhai@howard.edu

2007-10-25

337

HIV infection and HERV expression: a review.  

PubMed

The human genome contains multiple copies of retrovirus genomes known as endogenous retroviruses (ERVs) that have entered the germ-line at some point in evolution. Several of these proviruses have retained (partial) coding capacity, so that a number of viral proteins or even virus particles are expressed under various conditions. Human ERVs (HERVs) belong to the beta-, gamma-, or spuma- retrovirus groups. Endogenous delta- and lenti- viruses are notably absent in humans, although endogenous lentivirus genomes have been found in lower primates. Exogenous retroviruses that currently form a health threat to humans intriguingly belong to those absent groups. The best studied of the two infectious human retroviruses is the lentivirus human immunodeficiency virus (HIV) which has an overwhelming influence on its host by infecting cells of the immune system. One HIV-induced change is the induction of HERV transcription, often leading to induced HERV protein expression. This review will discuss the potential HIV-HERV interactions.Several studies have suggested that HERV proteins are unlikely to complement defective HIV virions, nor is HIV able to package HERV transcripts, probably due to low levels of sequence similarity. It is unclear whether the expression of HERVs has a negative, neutral, or positive influence on HIV-AIDS disease progression. A positive effect was recently reported by the specific expression of HERVs in chronically HIV-infected patients, which results in the presentation of HERV-derived peptides to CD8+ T-cells. These cytotoxic T-cells were not tolerant to HERV peptides, as would be expected for self-antigens, and consequently lysed the HIV-infected, HERV-presenting cells. This novel mechanism could control HIV replication and result in a low plasma viral load. The possibility of developing a vaccination strategy based on these HERV peptides will be discussed. PMID:22248111

van der Kuyl, Antoinette C

2012-01-16

338

HIV/AIDS  

MedlinePLUS

... a man’s risk of acquiring HIV through heterosexual contact–and perhaps could lead to fewer infections in women. Despite this progress, HIV/AIDS has become a global epidemic. According to the Joint United Nations Program ...

339

HIV and AIDS  

MedlinePLUS

... a serious infection. Continue How Many People Have HIV/AIDS? Since the discovery of the virus almost 30 ... million. Back Continue What Are the Symptoms of HIV/AIDS? It's important to know that you can't ...

340

Living with HIV  

MedlinePLUS

... Comprehensive Prevention Programs for Health Departments Supported Activities Technical Assistance Prevention With Persons With HIV The Context ... Grantees Correspondence Web Conferences Capacity Building Assistance and Technical Assistance National HIV Prevention Monitoring & Evaluation (NHM&E) ...

341

HIV among Women  

MedlinePLUS

... Comprehensive Prevention Programs for Health Departments Supported Activities Technical Assistance Prevention With Persons With HIV The Context ... Grantees Correspondence Web Conferences Capacity Building Assistance and Technical Assistance National HIV Prevention Monitoring & Evaluation (NHM&E) ...

342

Chicanoizing the Therapeutic Community  

ERIC Educational Resources Information Center

|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.…

Aron, William S.; And Others

1974-01-01

343

Therapeutic applications of microbubbles  

Microsoft Academic Search

Microbubbles, currently used as contrast agents have potential therapeutic applications. Microbubbles, upon insonation of sufficiently intense ultrasound will cavitate. Cavitation with microbubbles can be used to dissolve blood clots or deliver drugs. Targeting ligands and drugs can be incorporated into microbubbles to make highly specific diagnostic and therapeutic agents for activation with ultrasound. In this paper I will review some

Evan C. Unger; Terry Onichi Matsunaga; Thomas McCreery; Patricia Schumann; Robert Sweitzer; Rachel Quigley

2002-01-01

344

A clinical review of micronutrients in HIV infection.  

PubMed

This article reviews current literature on the role of micronutrients in human immunodeficiency virus (HIV) infection. Deficiencies of micronutrients are common in HIV-infected persons. They occur due to malabsorption, altered metabolism, gut infection, and altered gut barrier function. There is a compelling association of deficiencies of micronutrients in HIV-infection with immune deficiency, rapid disease progression, and mortality. Also, there is increased risk of vertical HIV transmission from mother to child with deficiency of vitamin A, and of neurological impairment with vitamin B12. The last five years have been exciting in micronutrient research, and there is promise that some micronutrients may be key factors in maintaining health in HIV immunodeficiency, and in reducing mortality. Selenium appears important in reducing virulence of HIV and slowing disease progression. Vitamin A supplementation in pregnant women with HIV may reduce maternal mortality and improve birth outcomes. Supplementation in children with HIV may accelerate growth. Carotenoid supplementation is being evaluated. Vitamin B12 may slow HIV immune deficiency disease progression, and reverse neurological compromise. Clinical benefit of supplementation with some micronutrients may be measurable in the presence of pre-existing deficiency. Apart from improved general nutrition, the impact of micronutrient supplements on health and their optimal use in HIV infection is controversial because there are so few controlled clinical trials. Further research is needed to elucidate the role of micronutrient deficiencies on the course of HIV infection, and the preventive and therapeutic role of supplementation in its clinical management. Nevertheless, current knowledge supports the use of routine multivitamin and trace element supplementation as adjuvant to conventional antiretroviral drug treatment as a relatively low-cost intervention. PMID:12942678

Singhal, Neera; Austin, James

2002-01-01

345

Primary HIV infection  

Microsoft Academic Search

Primary HIV infection refers to the events surrounding acquisition of HIV infection. It is associated with a nonspecific clinical\\u000a syndrome that occurs 2 to 4 weeks after exposure in 40% to 90% of individuals acquiring HIV. Patients identified before seroconversion\\u000a often have very high plasma HIV RNA titers that, without treatment, gradually decrease to reach a set point. Treatment of

Joanne Stekler; Ann C. Collier

2004-01-01

346

HIV protease inhibitors  

US Patent & Trademark Office Database

HIV protease inhibitors, obtainable by chemical synthesis, inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds, as well as pharmaceutical compositions that contain these compounds and optionally other anti-viral agents as active ingredients, are suitable for treating patients or hosts infected with the HIV virus, which is known to cause AIDS.

Albizati; Kim F. (San Diego, CA); Reichi; Siegfried H. (Solana Beach, CA); Varney; Michael D. (Solana Beach, CA); Zhang; Kanyin E. (Cardiff by the

1999-12-14

347

HIV1 superinfection  

Microsoft Academic Search

During the past year, a number of reports have described HIV-1 superinfection in human subjects, defined as the reinfection of an individual with a second heterologous strain of HIV-1. These reports have challenged the assumption that HIV-1–specific immune responses generated during primary infection are protective against subsequent infection and have raised concern, not only with respect to HIV-1–positive individuals engaging

Todd M Allen; Marcus Altfeld

2003-01-01

348

Therapeutic Drug Monitoring in Human Immunodeficiency Virus\\/Acquired Immunodeficiency Syndrome  

Microsoft Academic Search

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), and it is estimated that 42 million people\\u000a are infected with HIV. Four classes of drugs are used today to treat people with AIDS; nucleoside reverse transcriptase (NRTIs),\\u000a non-NRTIs (NNRTIs), protease inhibitors (PIs), and entry blockers (EIs). Evidence is accumulating that both PIs and NNRTIs\\u000a are good candidates for therapeutic drug

Steven J. Soldin

349

Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles  

SciTech Connect

We recently showed that both replicating and resting cells cultivated with ganciclovir (GCV) were killed when challenged with vesicular stomatitis virus G glycoprotein pseudotyped HIV-1-based virus-like particles (VLPs) carrying the Nef7 (i.e., an HIV-1 Nef mutant incorporating in virions at high levels)/herpes simplex virus-1 thymidine kinase (HSV-TK) fusion product. On this basis, a novel anti-HIV therapeutic approach based on Nef7/TK VLPs expressing X4 or R5 HIV cell receptor complexes has been attempted. We here report that (CD4-CXCR4) and (CD4-CCR5) Nef7-based VLPs efficiently enter cells infected by X4- or R5-tropic HIV-1 strains, respectively. Importantly, the delivery of the VLP-associated Nef7/TK led to cell death upon GCV treatment. Of interest, VLPs were effective also against non-replicating, HIV-1-infected primary human monocyte-derived macrophages. HIV-targeted VLPs represent a promising candidate for the treatment of persistently HIV-1-infected cells that are part of virus reservoirs resistant to HAART therapies.

Peretti, Silvia [AIDS Center, Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161, Rome (Italy); Schiavoni, Ilaria [AIDS Center, Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161, Rome (Italy); Pugliese, Katherina [AIDS Center, Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161, Rome (Italy); Federico, Maurizio [AIDS Center, Istituto Superiore di Sanita, Viale Regina Elena, 299, 00161, Rome (Italy)]. E-mail: federico@iss.it

2006-02-05

350

Immunogenetics of HIV and HIV associated tuberculosis.  

PubMed

Tuberculosis (TB) is the frequent major opportunistic infection in HIV-infected patients, and is the leading cause of mortality among HIV-infected patients. Genetic susceptibility to TB in HIV negative subjects is well documented. Since coinfections can influence the way in which immune system respond to different pathogens, genetic susceptibility to TB in HIV patients might also change. Studies from India and other parts of the world have shown that genetic susceptibility to TB is influenced by HIV infection. In the present review, we emphasize the role of genetic factors in determining susceptibility to HIV infection, disease progression and development of TB in HIV-infected patients. Polymorphisms in human leukocyte antigen (HLA), MBL2, CD209, vitamin D receptor, cytokine, chemokine and chemokine receptor genes have been shown to be associated with development of TB in HIV patients. However, the results are inconclusive and larger well-defined studies with precise clinical data are required to validate these associations. Apart from candidate gene approach, genome-wide association studies are also needed to unravel the unknown or to establish the previously reported genetic associations with HIV associated TB. Despite the preliminary status of the reported associations, it is becoming clear that susceptibility to development of TB in HIV patients is influenced by both environmental and genetic components. Understanding the genetic and immunologic factors that influence susceptibility to TB in HIV patients could lead to novel insights for vaccine development as well as diagnostic advances to target treatment to those who are at risk for developing active disease. PMID:21943869

Raghavan, S; Alagarasu, K; Selvaraj, P

2011-09-22

351

Minors' Rights and HIV  

Microsoft Academic Search

This article will examine the concept of minors' legal rights and their relationship to HIV prevention, HIV counseling and testing, and the treatment of HIV infection. The legal concept of minors' rights being equal to adults' legal rights has emerged in the last three decades. Parallel to this emergence is the changing nature of child\\/adolescent morbidity and mortality. Significant increases

Thera M. Meehan; Kevin Cranston

1999-01-01

352

Children and HIV  

MedlinePLUS

... healthy lives. Can HIV affect my child’s performance in school? Children living with HIV can face developmental challenges related to the disease. With advice and treatment from trained professionals, these challenges ... - HIV Infection in Infants and Children NIH - Guidelines for the Use ...

353

Treatment of HIV Infection  

MedlinePLUS

... JavaScript on. Read more information on enabling JavaScript. HIV/AIDS Skip Content Marketing Share this: Treatment of HIV ... drugs in order to maintain their health quality. HIV/AIDS Treatment Research NIAID is focused on finding new ...

354

HIV/AIDS Basics  

MedlinePLUS

Home HIV/AIDS Basics Before we can stop any epidemic, we first have to recognize the magnitude of the disease. ... the facts: HIV/AIDS 101 Video What is HIV/AIDS? You need javascript enabled to view this content ...

355

HIV and adolescents  

Microsoft Academic Search

Seroprevalence studies and documented sex and drug use risk behaviors indicate the importance of primary prevention programs for HIV among adolescents. Females and minority adolescents are at particular risk. Prevention workers must decide which strategies to advocate: abstinence, monogamy, HIV testing, screening partners, or explicit instruction of safer acts. Youths must be helped to personalize knowledge of HIV, acquire coping

Mary Jane Rotheram-Borus; Cheryl Koopman

1991-01-01

356

HIV infection and immune defense of the penis.  

PubMed

Recent evidence that circumcision decreases HIV infection in heterosexual men by 50-60% has focused research on the foreskin as a target of HIV infection. In this review article, we discuss potential mechanisms underlying the circumcision effect and re-examine the assumption that the foreskin is the principle penile HIV infection site. HIV target cells are present in the foreskin epithelium, but are also found in the epithelia of the penile shaft, glans/corona, meatus and urethral introitus. Sexually transmitted infections (STIs) can affect any of these sites and increase susceptibility to HIV acquisition by eroding the protective epithelial layer and by attracting and activating HIV target cells in the epithelium. The moist subpreputial cavity, which encompasses the entire penile tip in most uncircumcised men including the glans, meatus and urethral introitus, plays an important role in STI acquisition. Circumcised men have a lower rate of STIs that infect not only the foreskin but also other distal penile sites, especially the urethra. Likewise, the foreskin may trap HIV and HIV-infected cells after intercourse thereby increasing the risk of HIV acquisition not only through the inner foreskin but also other sites covered by the foreskin. The subpreputial cavity also hosts a unique microbiome that may also play a role in HIV infection. We hypothesize that the penile urethra may be the primary HIV acquisition site in circumcised men and possibly also in non-circumcised men because of the presence of superficial HIV target cells and a high incidence of STIs at this site. Both innate and adaptive immune defense mechanisms are operative in the lower male genital region. The penile urethral mucosa contains accumulations of IgA(+) plasma cells and T lymphocytes and may provide a responsive target for future mucosal vaccines to prevent HIV sexual transmission. PMID:21214659

Anderson, Deborah; Politch, Joseph A; Pudney, Jeffrey

2011-01-09

357

Multi-Scale Modeling of HIV Infection in vitro and APOBEC3G-Based Anti-Retroviral Therapy  

PubMed Central

The human APOBEC3G is an innate restriction factor that, in the absence of Vif, restricts HIV-1 replication by inducing excessive deamination of cytidine residues in nascent reverse transcripts and inhibiting reverse transcription and integration. To shed light on impact of A3G-Vif interactions on HIV replication, we developed a multi-scale computational system consisting of intracellular (single-cell), cellular and extracellular (multicellular) events by using ordinary differential equations. The single-cell model describes molecular-level events within individual cells (such as production and degradation of host and viral proteins, and assembly and release of new virions), whereas the multicellular model describes the viral dynamics and multiple cycles of infection within a population of cells. We estimated the model parameters either directly from previously published experimental data or by running simulations to find the optimum values. We validated our integrated model by reproducing the results of in vitro T cell culture experiments. Crucially, both downstream effects of A3G (hypermutation and reduction of viral burst size) were necessary to replicate the experimental results in silico. We also used the model to study anti-HIV capability of several possible therapeutic strategies including: an antibody to Vif; upregulation of A3G; and mutated forms of A3G. According to our simulations, A3G with a mutated Vif binding site is predicted to be significantly more effective than other molecules at the same dose. Ultimately, we performed sensitivity analysis to identify important model parameters. The results showed that the timing of particle formation and virus release had the highest impacts on HIV replication. The model also predicted that the degradation of A3G by Vif is not a crucial step in HIV pathogenesis.

Hosseini, Iraj; Mac Gabhann, Feilim

2012-01-01

358

HIV disclosure among adults living with HIV  

Microsoft Academic Search

Research on disclosure among heterosexual adult person(s) living with HIV (PLH) was reviewed, omitting disclosure of parental HIV to children. Disclosure has been studied within five additional relational contexts: with partners, family members, friends, healthcare professionals and in work settings. Disclosure is higher among women than men, among Latino and white compared to African-American families, and among younger compared to

E. Mayfield Arnold; E. Rice; D. Flannery; M. J. Rotheram-Borus

2008-01-01

359

Therapeutic effects of organic germanium.  

PubMed

Germanium is present in all living plant and animal matter in micro-trace quantities. Its therapeutic attributes include immuno-enhancement, oxygen enrichment, free radical scavenging, analgesia and heavy metal detoxification. Toxicological studies document Germanium's rapid absorption and elimination from the body, and its safety. Clinical trials and use in private practices for more than a decade have demonstrated Germanium's efficacy in treating a wide range of serious afflictions, including cancer, arthritis and senile osteoporosis. Germanium's anti-viral and immunological properties, including the induction of interferon, macrophages, T-suppressor cells and augmentation of natural killer cell activity, suggest its possible efficacy in treating and/or preventing AIDS. PMID:3043151

Goodman, S

1988-07-01

360

Molecular basis for interactions of HIV and drugs of abuse.  

PubMed

In certain populations around the world, the HIV pandemic is being driven by drug-abusing populations. Mounting evidence suggests that these patient populations have accelerated and more severe neurocognitive dysfunction compared with non-drug-abusing HIV-infected populations. Because most drugs of abuse are central nervous system stimulants, it stands to reason that these drugs may synergize with neurotoxic substances released during the course of HIV infection. Clinical and laboratory evidence suggests that the dopaminergic systems are most vulnerable to such combined neurotoxicity. Identifying common mechanisms of neuronal injury is critical to developing therapeutic strategies for drug-abusing HIV-infected populations. This article reviews 1) the current evidence for neurodegeneration in the setting of combined HIV infection and use of methamphetamine, cocaine, heroin or alcohol; 2) the proposed underlying mechanisms involved in this combined neurotoxicity; and 3) future directions for research. This article also suggests therapeutic approaches based on our current understanding of the neuropathogenesis of dementia due to HIV infection and drugs of abuse. PMID:12394784

Nath, Avi; Hauser, Kurt F; Wojna, Valerie; Booze, Rosemarie M; Maragos, William; Prendergast, Mark; Cass, Wayne; Turchan, Jadwiga T

2002-10-01

361

The changing distribution of HIV infection: HIV surveillance in Lazio, Italy, 1985 through 1994. Lazio HIV Surveillance Collaborative Group.  

PubMed Central

OBJECTIVES: This study sought to describe the human immunodeficiency virus (HIV) surveillance system in Lazio, Italy, and to analyze exposure patterns and time trends of HIV serodiagnoses from January 1985 to December 1994. METHODS: A linkage procedure made it possible to identify newly diagnosed HIV cases. Anonymous information was collected on demographic and exposure factors for each individual. RESULTS: Of 35,425 reports, 13,660 were newly diagnosed HIV cases, 70.9% of them in men. The proportion of women increased at the beginning of the study period (the male:female ratio declined from 3.5 in 1985 to 2.6 in 1986) and then remained stable. The proportion of subjects reporting heterosexual exposure, in men and women, respectively, increased from 1.5% and 2.0% in 1985 to 21.2% and 60.8% in 1994. Starting in 1992, heterosexual contact has become the main transmission route for women. CONCLUSIONS: A changing pattern in the HIV epidemic is emerging, with a shift in the incidence of HIV diagnosis from "core" high-risk groups (drug injectors) to the large low-risk population (the general population) exposed through heterosexual transmission. This is probably occurring in other areas (e.g., large urban centers in the United States) with a similar epidemiological situation.

Brancato, G; Perucci, C A; Abeni, D D; Sangalli, M; Ippolito, G; Arca, M

1997-01-01

362

High-efficiency Transduction of Rhesus Hematopoietic Repopulating Cells by a Modified HIV1-based Lentiviral Vector  

PubMed Central

Human immunodeficiency virus type 1 (HIV1) vectors poorly transduce rhesus hematopoietic cells due to species-specific restriction factors, including the tripartite motif-containing 5 isoform? (TRIM5?) which targets the HIV1 capsid. We previously developed a chimeric HIV1 (?HIV) vector system wherein the vector genome is packaged with the simian immunodeficiency virus (SIV) capsid for efficient transduction of both rhesus and human CD34+ cells. To evaluate whether ?HIV vectors could efficiently transduce rhesus hematopoietic repopulating cells, we performed a competitive repopulation assay in rhesus macaques, in which half of the CD34+ cells were transduced with standard SIV vectors and the other half with ?HIV vectors. As compared with SIV vectors, ?HIV vectors achieved higher vector integration, and the transgene expression rates were two- to threefold higher in granulocytes and red blood cells and equivalent in lymphocytes and platelets for 2 years. A recipient of ?HIV vector-only transduced cells reached up to 40% of transgene expression rates in granulocytes and lymphocytes and 20% in red blood cells. Similar to HIV1 and SIV vectors, ?HIV vector frequently integrated into gene regions, especially into introns. In summary, our ?HIV vector demonstrated efficient transduction for rhesus long-term repopulating cells, comparable with SIV vectors. This ?HIV vector should allow preclinical testing of HIV1-based therapeutic vectors in large animal models.

Uchida, Naoya; Hargrove, Phillip W.; Lap, Coen J.; Evans, Molly E.; Phang, Oswald; Bonifacino, Aylin C.; Krouse, Allen E.; Metzger, Mark E.; Nguyen, Anh-Dao; Hsieh, Matthew M.; Wolfsberg, Tyra G.; Donahue, Robert E.; Persons, Derek A.; Tisdale, John F.

2012-01-01

363

Neuromuscular complications in HIV.  

PubMed

HIV affects many organs of the body, including the nervous system. As a result, a series of neurologic complications have created challenges for scientists and clinicians alike. Among these, HIV-associated neuropathy and myopathy may occur at all stages of the disease process. Of the neuropathies, distal symmetrical polyneuropathy is the most common form. The pathogenesis of primary HIV neuropathy is unknown. Other types of neuropathy seen in HIV-infected subjects include toxic neuropathy, inflammatory demyelinating polyneuropathy, progressive polyradiculopathy, and mononeuritis multiplex. In this review, we present the clinical manifestations, pathogenesis, diagnosis, and management of different types of neuropathy in HIV infection. Myopathy, another complication of HIV, is not associated with any particular stage of immunosuppression. Symptoms include symmetrical weakness of the proximal muscles in the extremities. Serum creatine kinase levels are often moderately elevated. Electromyography and muscle biopsy are helpful tests for diagnosis. Treatment of HIV myopathy includes corticosteroids, nonsteroidal anti-inflammatory agents, and intravenous immunoglobulin. PMID:14683631

Verma, Susama; Micsa, Elena; Estanislao, Lydia; Simpson, David

2004-01-01

364

Recent Advances in Humanized Mice: Accelerating the Development of an HIV Vaccine.  

PubMed

Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency virus (HIV) infection and to aid in the design of an effective HIV vaccine. This supplement of the Journal of Infectious Diseases summarizes work in the humanized mouse model presented at an HIV Humanized Mouse workshop in Boston, Massachusetts, in November 2012, including recent advances in the development of humanized mice, the trafficking of human immune cells following mucosal HIV transmission, the role of immune activation and Toll-like receptor agonists in the control of HIV, the induction and efficacy of HIV-specific cellular and humoral immune responses, and the preclinical modeling of novel anti-HIV therapeutics. Many gaps remain in our understanding of how to design an effective HIV vaccine and novel therapeutics to eliminate the viral reservoir. Promising early results from studies in humanized mice suggest great potential and enthusiasm for this model to accelerate these critical areas of HIV research. PMID:24151317

Tager, Andrew M; Pensiero, Michael; Allen, Todd M

2013-11-01

365

Women and HIV/AIDS  

MedlinePLUS

Home > HIV/AIDS HIV/AIDS This information in Spanish ( en español ) The human immunodeficiency (IH-myoo-noh-di-FISH-uhn-see) virus, or HIV, ... HIV/AIDS email updates. Enter email address Submit HIV/AIDS news September 23, 2013 - Nail Fungus Drug Might ...

366

Towards Therapeutic Arteriogenesis  

Cancer.gov

Arteriogenesis or the formation of arterial conduits is a promising therapeutic approach to the treatment of a number of ischemic vascular diseases. However, the molecular basis of this process remains poorly understood.

367

Therapeutic Biological Products Approvals  

Center for Drug Evaluation (CDER)

... Therapeutic Biological Products Approvals. We are no longer updating this page. The last update of this page occurred on December 12, 2003. ... More results from www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved

368

987. Foamy Virus Vectors That Block HIV Infection  

Microsoft Academic Search

Foamy virus (FV) vectors have been demonstrated to transduce human hematopoietic stem cells with a high frequency. We have developed FV vectors that can block HIV infection with the intention of developing a therapeutic vector. Additional features of FV vectors that support their use in clinical gene therapy include: a) no evidence of disease from the prototypic FV in infected

Jason Taylor; Ingrid Bahner; Lucia Vojtech; Erik Olson; James Allen; Dorothee von Laer; Donald B. Kohn; David W. Russell; Robert E. Richard

2005-01-01

369

Technologies of the HIV/AIDS corpse.  

PubMed

In the early 1980s, unprecedented numbers of gay men and intravenous drug users began dying of what would later become known as HIV/AIDS. What the HIV/AIDS corpse posed was a direct challenge to the institutional controls developed by funeral directors to normalize and transform the dead body. How the funeral service industry reacted and changed in response to the emergence of the HIV/AIDS corpse offers an opportunity to re-examine the productive potential of the dead human body. My article examines the epidemic's production of what I call the HIV/AIDS corpse, and the institutional affects those corpses had on the US funeral service industry. The theoretical concept I use to analyze the productive qualities of the HIV/AIDS corpse is the technologies of the corpse. These technologies are the machines, laws, and institutions that control the corpse by classifying, organizing, and physically transforming it. What emerges from the institutional challenges posed by the HIV/AIDS corpse is a specific kind of dead body that offers political possibilities for both the concept of a queer body and the broader subject of human death. PMID:20455141

Troyer, John Erik

2010-04-01

370

Antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected and passively immunized chimpanzees.  

PubMed Central

Based on recent reports of antibody-dependent enhancement of human immunodeficiency virus type 1 (HIV-1) infection in vitro by serum from HIV-1-infected humans, sera from HIV-1 antibody-positive chimpanzees (Pan troglodytes) was evaluated for enhancing activity in an in vitro infection assay that uses MT-2 cells (a human lymphoblastoid cell line). Although fresh chimpanzee serum was found to have pronounced infection-enhancing properties in the absence of antibody to HIV-1, this effect was abolished by heat inactivation (57 degrees C, 1 hr) or treatment with cobra venom anticomplementary protein. Heat-inactivated, HIV-1 antibody-positive chimpanzee serum could enhance HIV-1 infection of MT-2 cells in vitro when combined with fresh, normal human serum. By serial serum samples from three HIV-1-infected chimpanzees, HIV-1 antibody-positive chimpanzees are shown to develop enhancing antibodies early in infection (2 mo postchallenge), whereas neutralizing antibodies develop later. Over the course of HIV-1 infection, this enhancing activity decreases while neutralizing activity increases, suggesting a possible role for enhancing and neutralizing activities in HIV-1 pathogenesis. The enhancing activity of an IgG fraction used to passively immunize chimpanzees against HIV-1 infection is shown to be present at dilutions as high as 1:65,000, offering an interesting possible reason for the failure of passive immunization to protect chimpanzees from HIV infection. These results suggest that serum from HIV-1-immunized chimpanzees might be tested to determine whether current HIV-1 candidate vaccines induce production of antibodies that mediate antibody-dependent enhancement of HIV-1 infection in this in vitro assay. Images

Robinson, W E; Montefiori, D C; Mitchell, W M; Prince, A M; Alter, H J; Dreesman, G R; Eichberg, J W

1989-01-01

371

Towards Combination HIV Prevention for Injection Drug Users: Addressing Addictophobia, Apathy and Inattention  

PubMed Central

Purpose of the review Recent breakthroughs in HIV-prevention science led us to evaluate the current state of combination HIV-prevention for injection drug users (IDUs). We review the recent literature focusing on possible reasons why coverage of prevention interventions for HIV, HCV and tuberculosis among IDUs remains dismal. We make recommendations for future HIV research and policy. Recent findings IDUs disproportionately under-utilize VCT, primary care and ART, especially in countries that have the largest burden of HIV among IDUs. IDUs present later in the course of HIV infection and experience greater morbidity and mortality. Why are IDUs under-represented in HIV-prevention research, access to treatment for both HIV and addiction, and access to HIV combination prevention? Possible explanations include addictophobia, apathy, and inattention, which we describe in the context of recent literature and events. Summary This commentary discusses the current state of HIV-prevention interventions for IDUs including, VCT, NSP, OST, ART and PrEP, and discusses ways to work towards true combination HIV-prevention for IDU populations. Communities need to overcome tacit assumptions that IDUs can navigate through systems that are maintained as separate silos, and take a rights-based approach to HIV-prevention to ensure that IDUs have equitable access to life-saving prevention and treatments.

Strathdee, Steffanie A.; Shoptaw, Steven; Dyer, Typhanye Penniman; Quan, Vu Minh; Aramrattana, Apinun

2013-01-01

372

Are therapeutic communities therapeutic for women?  

PubMed Central

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

2006-01-01

373

Sustained Attention Deficits Among HIV-Positive Individuals With Comorbid Bipolar Disorder  

PubMed Central

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

2013-01-01

374

Multilevel Stigma as a Barrier to HIV Testing in Central Asia: A Context Quantified.  

PubMed

Central Asia is experiencing one of the fastest growing HIV epidemics in the world, with some areas' infection rates doubling yearly since 2000. This study examines the impact of multilevel stigma (individual, family, and community) on uptake of HIV testing and receipt of HIV testing results among women in Central Asia. The sample consists of 38,884 ever-married, Central Asian women between the ages of 15 and 49. Using multilevel modeling (MLM), HIV stigma variables at the individual, family, and community levels were used to assess the significance of differences in HIV testing and receipt of HIV test results among participants while adjusting for possible confounding factors, such as age, wealth, and education. MLM results indicate that HIV stigma is significantly associated with decreased HIV testing uptake at the individual, family, and community levels and with a decrease in receipt at the community level. A one standard deviation increase in individual, family, and community level composite stigma score was associated with a respective 49 %, 59 %, and 94 % (p < 0.001) decrease in the odds of having been tested for HIV. A one standard deviation increase in community composite stigma score was associated with a 99 % (p < 0.001) decrease in the odds of test receipt. HIV stigma operates on the individual, family, and community levels to hinder HIV testing uptake and at the community level to hinder receipt. These findings have important interventions implications to improve uptake of HIV testing and receipt of HIV test results. PMID:23904147

Smolak, Alex; El-Bassel, Nabila

2013-10-01

375

Sociocultural and epidemiological aspects of HIV/AIDS in Mozambique  

PubMed Central

Background A legacy of colonial rule coupled with a devastating 16-year civil war through 1992 left Mozambique economically impoverished just as the human immunodeficiency virus (HIV) epidemic swept over southern Africa in the late 1980s. The crumbling Mozambican health care system was wholly inadequate to support the need for new chronic disease services for people with the acquired immunodeficiency syndrome (AIDS). Methods To review the unique challenges faced by Mozambique as they have attempted to stem the HIV epidemic, we undertook a systematic literature review through multiple search engines (PubMed, Google Scholar™, SSRN, AnthropologyPlus, AnthroSource) using Mozambique as a required keyword. We searched for any articles that included the required keyword as well as the terms 'HIV' and/or 'AIDS', 'prevalence', 'behaviors', 'knowledge', 'attitudes', 'perceptions', 'prevention', 'gender', drugs, alcohol, and/or 'health care infrastructure'. Results UNAIDS 2008 prevalence estimates ranked Mozambique as the 8th most HIV-afflicted nation globally. In 2007, measured HIV prevalence in 36 antenatal clinic sites ranged from 3% to 35%; the national estimate of was 16%. Evidence suggests that the Mozambican HIV epidemic is characterized by a preponderance of heterosexual infections, among the world's most severe health worker shortages, relatively poor knowledge of HIV/AIDS in the general population, and lagging access to HIV preventive and therapeutic services compared to counterpart nations in southern Africa. Poor education systems, high levels of poverty and gender inequality further exacerbate HIV incidence. Conclusions Recommendations to reduce HIV incidence and AIDS mortality rates in Mozambique include: health system strengthening, rural outreach to increase testing and linkage to care, education about risk reduction and drug adherence, and partnerships with traditional healers and midwives to effect a lessening of stigma.

2010-01-01

376

HIV1 interaction with human mannose receptor (hMR) induces production of matrix metalloproteinase 2 (MMP-2) through hMR-mediated intracellular signaling in astrocytes  

Microsoft Academic Search

Astrocytes are susceptible to HIV-1 infection. We have recently demonstrated that human mannose receptor (hMR) is directly involved in CD4-independent HIV-1 infection of astrocytes. The apparent paradox between the vivid binding affinity of HIV-1 gp120 protein to hMR and the low efficiency of hMR-mediated HIV-1 infection raises the possibility that HIV-1 binding to hMR alone may negatively affect astrocyte function.

Albeiro López-Herrera; Ying Liu; Maria T. Rugeles; Johnny J. He

2005-01-01

377

HIV/AIDS and the Flu  

MedlinePLUS

... to... Añadir en... Favorites Delicious Digg Google Bookmarks HIV/AIDS and the Flu Questions & Answers HIV (human immunodeficiency ... to people with HIV/AIDS. Should people with HIV/AIDS receive the inactivated influenza vaccine? People with HIV/ ...

378

Novel piperidinylpyrimidine derivatives as inhibitors of HIV-1 LTR activation.  

PubMed

Piperidinylpyrimidine derivatives, previously prepared as inhibitors of TNF-alpha production, were evaluated for their inhibitory activity against HIV-1 LTR activation. Some of these derivatives inhibited activation of HIV-1 LTR-directed CAT gene expression induced by PMA in Jurkat cells. In this report, we describe SAR in this series of compounds and show that the 3,4-methylenedioxybenzoyl (piperonyloyl) group on the nitrogen of piperidine and lipophilic substitution at the C(6)-position of pyrimidine are important for this inhibitory activity. Some of the synthesized compounds also inhibited HIV-1 LTR transactivation induced by viral protein Tat. These results suggest that piperidinylpyrimidines are useful as potent AIDS therapeutics that directly inhibit HIV-1 LTR activation and indirectly suppress TNF-alpha production. PMID:18926711

Fujiwara, Norio; Nakajima, Takashi; Ueda, Yutaka; Fujita, Hitoshi; Kawakami, Hajime

2008-09-30

379

Antiretroviral therapy for prevention of HIV and tuberculosis: a promising intervention but not a panacea.  

PubMed

The demonstration of the efficacy of antiretroviral therapy (ART) for HIV prevention in heterosexual HIV serodiscordant couples has resulted in the call for widespread implementation of "Treatment as Prevention" (TasP) to confront the challenge of continued transmission of HIV. In addition, evidence of the possible effect of use of ART on decreasing the incidence of tuberculosis (TB) in persons living with HIV has also contributed further enthusiasm. Mathematical modeling studies evaluating the potential impact of TasP on the trajectory of the HIV and TB epidemics have inspired discussions about a possible future without AIDS. We present the evidence regarding the effect of ART on the incidence of HIV and TB, benefits and risks associated with embracing TasP, and the need for multicomponent prevention strategies and for further research to generate empiric data on the effect of TasP on HIV and TB at a population level. PMID:23764636

McNairy, Margaret L; Howard, Andrea A; El-Sadr, Wafaa M

2013-07-01

380

HIV/AIDS, conflict and security in Africa: rethinking relationships  

PubMed Central

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.

2008-01-01

381

Major depletion of plasmacytoid dendritic cells in HIV-2 infection, an attenuated form of HIV disease.  

PubMed

Plasmacytoid dendritic cells (pDC) provide an important link between innate and acquired immunity, mediating their action mainly through IFN-alpha production. pDC suppress HIV-1 replication, but there is increasing evidence suggesting they may also contribute to the increased levels of cell apoptosis and pan-immune activation associated with disease progression. Although having the same clinical spectrum, HIV-2 infection is characterized by a strikingly lower viremia and a much slower rate of CD4 decline and AIDS progression than HIV-1, irrespective of disease stage. We report here a similar marked reduction in circulating pDC levels in untreated HIV-1 and HIV-2 infections in association with CD4 depletion and T cell activation, in spite of the undetectable viremia found in the majority of HIV-2 patients. Moreover, the same overexpression of CD86 and PD-L1 on circulating pDC was found in both infections irrespective of disease stage or viremia status. Our observation that pDC depletion occurs in HIV-2 infected patients with undetectable viremia indicates that mechanisms other than direct viral infection determine the pDC depletion during persistent infections. However, viremia was associated with an impairment of IFN-alpha production on a per pDC basis upon TLR9 stimulation. These data support the possibility that diminished function in vitro may relate to prior activation by HIV virions in vivo, in agreement with our finding of higher expression levels of the IFN-alpha inducible gene, MxA, in HIV-1 than in HIV-2 individuals. Importantly, serum IFN-alpha levels were not elevated in HIV-2 infected individuals. In conclusion, our data in this unique natural model of "attenuated" HIV immunodeficiency contribute to the understanding of pDC biology in HIV/AIDS pathogenesis, showing that in the absence of detectable viremia a major depletion of circulating pDC in association with a relatively preserved IFN-alpha production does occur. PMID:19936055

Cavaleiro, Rita; Baptista, António P; Soares, Rui S; Tendeiro, Rita; Foxall, Russell B; Gomes, Perpétua; Victorino, Rui M M; Sousa, Ana E

2009-11-20

382

Inhibition of immunodeficiency type-1 virus (HIV1) life cycle by medicinal plant extracts and plant-derived compounds  

Microsoft Academic Search

Identification of molecules inhibiting the different steps of the life cycle of the human immunodeficiency virus type 1 (HIV-1) is central for the development of an efficient therapeutic treatment of AIDS. In this respect, this research takes great advantage from the fact that the molecular biology of the HIV-1 life cycle is well known. The present review summarizes and discusses

Roberto Gambari; Ilaria Lampronti

2006-01-01

383

HIV and Chronic Methamphetamine Dependence Affect Cerebral Blood Flow  

PubMed Central

Human immunodeficiency virus (HIV) and methamphetamine (METH) dependence are independently associated with neuronal dysfunction. The coupling between cerebral blood flow (CBF) and neuronal activity is the basis of many task-based functional neuroimaging techniques. We examined the interaction between HIV infection and a previous history of METH dependence on CBF within the lenticular nuclei (LN). Twenty-four HIV?/METH?, eight HIV?/METH+, 24 HIV+/METH?, and 15 HIV+/METH+ participants performed a finger tapping paradigm. A multiple regression analysis of covariance assessed associations and two-way interactions between CBF and HIV serostatus and/or previous history of METH dependence. HIV+ individuals had a trend towards a lower baseline CBF (?10%, p=0.07) and greater CBF changes for the functional task (+32%, p=0.01) than HIV? subjects. Individuals with a previous history of METH dependence had a lower baseline CBF (–16%, p= 0.007) and greater CBF changes for a functional task (+33%, p=0.02). However, no interaction existed between HIV serostatus and previous history of METH dependence for either baseline CBF (p=0.53) or CBF changes for a functional task (p=0.10). In addition, CBF and volume in the LN were not correlated. A possible additive relationship could exist between HIV infection and a history of METH dependence on CBF with a previous history of METH dependence having a larger contribution. Abnormalities in CBF could serve as a surrogate measure for assessing the chronic effects of HIV and previous METH dependence on brain function.

Vaida, Florin; Cherner, Mariana; Yeh, Melinda J.; Liang, Christine L.; Gardner, Carly; Grant, Igor; Ellis, Ronald J.; Buxton, Richard B.

2011-01-01

384

MicroRNAs and their potential involvement in HIV infection  

PubMed Central

Treatment and cure of human immunodeficiency virus-1(HIV-1) infection remains one of the greatest therapeutic challenges due to its persistent infection, which often leads to acquired immunodeficiency syndrome (AIDS). Although it has been 28 years since the discovery of the virus, the development of an effective vaccine is still years away. Relatively newly discovered microRNAs (miRNA) are a family of small non-coding RNAs that can regulate gene expression primarily by binding to the 3? untranslated region (UTR) of targeted transcripts. Understanding how HIV-1 infection affects the host miRNA pathway could generate new insights into the basic mechanisms underlying HIV-1-mediated pathologies and T-lymphocyte depletion. Here, we review literature related to the biogenesis of HIV-1 encoded miRNAs, cellular miRNAs that can directly target HIV-1 or essential cellular factors required for HIV-1 replication. We also discuss the feasibility of using miRNAs for HIV-1 therapy.

Sun, Guihua; Rossi, John J.

2011-01-01

385

Human HERC5 restricts an early stage of HIV-1 assembly by a mechanism correlating with the ISGylation of Gag  

PubMed Central

Background The identification and characterization of several interferon (IFN)-induced cellular HIV-1 restriction factors, defined as host cellular proteins or factors that restrict or inhibit the HIV-1 life cycle, have provided insight into the IFN response towards HIV-1 infection and identified new therapeutic targets for HIV-1 infection. To further characterize the mechanism underlying restriction of the late stages of HIV-1 replication, we assessed the ability of IFNbeta-induced genes to restrict HIV-1 Gag particle production and have identified a potentially novel host factor called HECT domain and RCC1-like domain-containing protein 5 (HERC5) that blocks a unique late stage of the HIV-1 life cycle. Results HERC5 inhibited the replication of HIV-1 over multiple rounds of infection and was found to target a late stage of HIV-1 particle production. The E3 ligase activity of HERC5 was required for blocking HIV-1 Gag particle production and correlated with the post-translational modification of Gag with ISG15. HERC5 interacted with HIV-1 Gag and did not alter trafficking of HIV-1 Gag to the plasma membrane. Electron microscopy revealed that the assembly of HIV-1 Gag particles was arrested at the plasma membrane, at an early stage of assembly. The mechanism of HERC5-induced restriction of HIV-1 particle production is distinct from the mechanism underlying HIV-1 restriction by the expression of ISG15 alone, which acts at a later step in particle release. Moreover, HERC5 restricted murine leukemia virus (MLV) Gag particle production, showing that HERC5 is effective in restricting Gag particle production of an evolutionarily divergent retrovirus. Conclusions HERC5 represents a potential new host factor that blocks an early stage of retroviral Gag particle assembly. With no apparent HIV-1 protein that directly counteracts it, HERC5 may represent a new candidate for HIV/AIDS therapy.

2011-01-01

386

[The endogenous cannabinoid system. Therapeutic implications for neurologic and psychiatric disorders].  

PubMed

For about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette's syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use. PMID:15776259

Schneider, U; Seifert, J; Karst, M; Schlimme, J; Cimander, K; Müller-Vahl, K R

2005-09-01

387

Detection of human immunodeficiency virus type 1 (HIV-1) RNA in pools of sera negative for antibodies to HIV-1 and HIV-2.  

PubMed

A total of 234 pools were prepared from 10,692 consecutive serum samples negative for antibodies to human immunodeficiency virus type 1 (HIV-1) and HIV-2 collected at five virological laboratories (average pool size, 45 serum samples). Pools were screened for the presence of HIV-1 RNA by a modified commercial assay (Amplicor HIV-1 Monitor test) which included an additional polyethylene glycol (PEG) precipitation step prior to purification of viral RNA (PEG Amplicor assay). The sensitivity of this assay for HIV-1 RNA detection in individual serum samples within pools matches that of standard commercial assays for individual serum samples, i.e., 500 HIV-1 RNA copies per ml. Five pools were identified as positive, and each one contained one antibody-negative, HIV-1 RNA-positive serum sample, corresponding to an average of 1 infected sample per 2,138 serum samples. Retrospective analysis revealed that the five HIV-1 RNA-positive specimens originated from individuals who had symptomatic primary HIV-1 infection at the time of sample collection and who were also positive for p24 antigenemia. We next assessed the possibility of performing the prepurification step by high-speed centrifugation (50,000 x g for 80 min) of 1.5-ml pools containing 25 microl of 60 individual serum samples, of which only 1 contained HIV-1 RNA (centrifugation Amplicor assay). The sensitivity of this assay also matches the sensitivities of standard commercial assays for HIV-1 RNA detection in individual serum samples. The results demonstrate that both assays with pooled sera can be applied to the screening of large numbers of serum samples in a time- and cost-efficient manner. PMID:9620372

Morandi, P A; Schockmel, G A; Yerly, S; Burgisser, P; Erb, P; Matter, L; Sitavanc, R; Perrin, L

1998-06-01

388

Depression and HIV/AIDS  

MedlinePLUS

... see the NIMH booklet on Depression . What is HIV/AIDS? Human immunodeficiency virus (HIV) is the virus that ... they can function normally. How are depression and HIV/AIDS linked? Studies show that people who are infected ...

389

HIV, AIDS, and the Future  

MedlinePLUS

Skip Navigation Bar Home Current Issue Past Issues HIV / AIDS HIV, AIDS, and the Future Past Issues / Summer 2009 Table ... to protect yourself and your loved ones from HIV/AIDS. The AIDS Memorial Quilt In 1987, a total ...

390

ABBOTT PRISM HIV O Plus  

Center for Biologics Evaluation and Research (CBER)

... Resources for You. HIV-1/2. -. ABBOTT PRISM HIV O Plus. ... Product Information. Package Insert - ABBOTT PRISM HIV O Plus (PDF - 563KB). -. -. ... More results from www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts

391

Pneumocystis Pneumonia (PCP) and HIV  

MedlinePLUS

... to Web version HIV and AIDS | Pneumocystis pneumonia (PCP) and HIV What is PCP? PCP is a kind of pneumonia caused by bacteria ... are weak because of HIV infection can get PCP. PCP is less common than it used to ...

392

Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses  

PubMed Central

Resistance to HIV infection in a small group of Kenyan sex workers is associated with CD8+-lymphocyte responses to HIV cytotoxic T-lymphocyte (CTL) epitopes. Eleven prostitutes meeting criteria for HIV resistance seroconverted between 1996 and 1999. The occurrence and specificity of preexisting HIV-1 epitope–specific responses were examined using the IFN-? enzyme–linked immunospot assay, and any epitopes recognized were cloned and sequenced from the infecting viral isolate. Immunologic and behavioral variables were compared between late seroconverters and persistently uninfected sex worker controls. HIV-1 CTL epitope responses were present in four of six cases, 5–18 months before seroconversion, and their presence was confirmed by bulk CTL culture. A possible viral escape mutation was found in one of six epitopes. The key epidemiologic correlate of late seroconversion was a reduction in sex work over the preceding year. In persistently uninfected controls, a break from sex work was associated with a loss of HIV-specific CD8+ responses. Late seroconversion may occur in HIV-1–resistant sex workers despite preceding HIV-specific CD8+ responses. Seroconversion generally occurs in the absence of detectable CTL escape mutations and may relate to the waning of HIV-specific CD8+ responses due to reduced antigenic exposure.

Kaul, Rupert; Rowland-Jones, Sarah L.; Kimani, Joshua; Dong, Tao; Yang, Hong-Bing; Kiama, Peter; Rostron, Timothy; Njagi, Ephantus; Bwayo, Job J.; MacDonald, Kelly S.; McMichael, Andrew J.; Plummer, Francis A.

2001-01-01

393

NYVAC immunization induces polyfunctional HIV-specific T-cell responses in chronically-infected, ART-treated HIV patients.  

PubMed

We report the results of the Theravac-01 phase I trial, which was conducted to evaluate the safety and immunogenicity of a poxvirus-based vector, NYVAC, expressing Gag, Pol, Nef, and Env from an HIV clade B isolate. NYVAC-B vaccine was injected intra-muscularly into ten HIV-infected patients successfully treated with antiretroviral therapy, twice on day 0 and again at week 4. Safety and immunogenicity were monitored for 48 weeks. HIV-specific T-cell responses following immunization were quantitatively analyzed using an IFN-? ELISPOT assay and qualitatively characterized for their functional profile (including multiple cytokines secretion plus cytotoxic and proliferation capacity) by polychromatic flow cytometry. Our results indicate that the NYVAC-B vaccine is safe and highly immunogenic, as indicated by increased HIV-specific T-cell responses in virtually all vaccinees. Interestingly, both an expansion of preexisting T-cell responses, and the appearance of newly detected HIV-specific CD4(+) and CD8(+) T-cell responses were observed. Furthermore, immunization mostly induced an increase in Gag-specific T-cell responses. In conclusion, NYVAC-B immunization induces broad, vigorous, and polyfunctional HIV-specific T-cell responses, suggesting that poxvirus-based vaccine regimens may be instrumental in the therapeutic HIV vaccine field. PMID:22930439

Harari, Alexandre; Rozot, Virginie; Cavassini, Matthias; Enders, Felicitas Bellutti; Vigano, Selena; Tapia, Gonzalo; Castro, Erika; Burnet, Séverine; Lange, Joep; Moog, Christiane; Garin, Daniel; Costagliola, Dominique; Autran, Brigitte; Pantaleo, Giuseppe; Bart, Pierre-Alexandre

2012-10-01

394

Modeling HIV-associated neurocognitive disorders in mice: new approaches in the changing face of HIV neuropathogenesis  

PubMed Central

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

2012-01-01

395

HIV/AIDS Basics - Signs & Symptoms  

MedlinePLUS Videos and Cool Tools

... the Mouse and Choose "Save link as...." Audio Mobile Video Handout Audio Terms of Use Close Window This information made possible with support from The Division of Specialized Information Services of the National Library of Medicine For more information on HIV/AIDS ...

396

HIV/AIDS - CD4 Count  

MedlinePLUS Videos and Cool Tools

... the Mouse and Choose "Save link as...." Audio Mobile Video Handout Audio Terms of Use Close Window This information made possible with support from The Division of Specialized Information Services of the National Library of Medicine For more information on HIV/AIDS ...

397

CD4 immunophenotyping in HIV infection  

Microsoft Academic Search

The ability to rapidly identify immune cell subsets such as CD4 cells, which became possible around the same time as the onset of the HIV\\/AIDS pandemic, was one of the greatest advances in clinical and diagnostic immunology. The evolution of this global pandemic and the subsequent development of treatment strategies to prolong the life of infected individuals mean that it

Brooke Walker; Alan Landay; Thomas N. Denny; David Barnett

2008-01-01

398

Genomic signal analysis of HIV variability  

Microsoft Academic Search

The conversion of genomic sequences into digital genomic signals offers the possibility to use powerful signal processing methods for the analysis of genomic information. The study of genomic signals reveals local and global features of chromosomes that would be difficult to identify by using only the symbolic representation used in genomic data bases. The paper presents a study of HIV

Paul D. Cristea; Dan Otelea; Rodica Aurora Tuduce

2005-01-01

399

Is there a therapeutic role for cranioplasty?  

PubMed

Cranioplasty is often undertaken as a joint neurosurgical and maxillofacial procedure. The principal aims remain to improve cosmesis and to protect the underlying brain. We report two cases of cranioplasty with subsequent improvement in neurological function and discuss the possible therapeutic role of cranioplasty. PMID:23415243

Alibhai, M K; Balasundaram, I; Bridle, C; Holmes, S B

2013-02-14

400

HIV-1 transcription and latency: an update  

PubMed Central

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.

2013-01-01