107 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

HIV

These pubmed results were generated on 2010/03/20

PubMed, a service of the National Library of Medicine, includes over 15 million citations for biomedical articles back to the 1950's. These citations are from MEDLINE and additional life science journals. PubMed includes links to many sites providing full text articles and other related resources.

HIV vaccine in healthy volunteers gets testing approval.

AIDS Patient Care STDS. 2010 Mar;24(3):198

Authors:

PMID: 20238443 [PubMed - in process]

Interaction of eight HIV protease inhibitors with the canalicular efflux transporter ABCC2 (MRP2) in sandwich-cultured rat and human hepatocytes.

Biopharm Drug Dispos. 2010 Mar 17;

Authors: Ye ZW, Camus S, Augustijns P, Annaert P

Hepatotoxicity has been reported as a side-effect in some patients on HIV protease inhibitors (PI). Since transporter interaction has been implicated as a mechanism underlying drug-mediated hepatotoxicity and drug-drug interactions, the interaction of PI with the hepatic canalicular efflux transporter ABCC2 (MRP2; multidrug resistance associated protein-2) was studied. Interaction with ABCC2/Abcc2 was evaluated in human and rat sandwich-cultured hepatocytes using 5(6)-carboxy-2',7'-dichlorofluorescein (CDF) as substrate. In rat hepatocytes, interaction with estradiol-17-beta-D-glucuronide (E17G) efflux was also studied. In human hepatocytes, saquinavir, ritonavir and atazanavir were the most efficient inhibitors of ABCC2-mediated biliary excretion of CDF, whereas in rat hepatocytes indinavir, lopinavir and nelfinavir were the most efficient. No species-similarity was found for ABCC2/Abcc2 inhibition. In rat hepatocytes, the effects on Abcc2 were substrate-dependent as inhibition of biliary excretion of E17G was most pronounced for saquinavir (completely blocked), amprenavir (82% inhibition) and indinavir (68% inhibition). In conclusion, several HIV PI showed substantial ABCC2 inhibition, which, combined with the effects of PI on other hepatobiliary disposition mechanisms, will determine the clinical relevance of these in vitro interaction data. Copyright (c) 2010 John Wiley & Sons, Ltd.

PMID: 20238377 [PubMed - as supplied by publisher]

Antiretroviral therapy (ART) for treating HIV infection in ART-eligible pregnant women.

Cochrane Database Syst Rev. 2010;3:CD008440

Authors: Sturt AS, Dokubo EK, Sint TT

BACKGROUND: This systematic review focuses on antiretroviral therapy (ART) for treating human immunodeficiency virus (HIV) infection in ART-eligible pregnant women. Mother-to-child transmission (MTCT) is the primary means by which children worldwide acquire HIV infection. MTCT occurs during three major timepoints during pregnancy and the postpartum period: in utero, intrapartum, and during breastfeeding. Strategies to reduce MTCT focus on these periods of exposure and include maternal and infant use of ART, caesarean section before onset of labour or rupture of membranes, and complete avoidance of breastfeeding. Where these combined interventions are available, the risk of MTCT is as low as 1-2%. Thus, ART used among mothers who require treatment of HIV for their own health also plays a significant role in decreasing MTCT.This review is one in a series of systematic reviews performed in preparation for the revision of the 2006 World Health Organization (WHO) Guidelines regarding "Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants" and "Antiretroviral therapy (ART) for HIV Infections in Adults and Adolescents." The findings from these reviews were discussed with experts, key stakeholders, and country representatives at the 2009 WHO guideline review meeting. The resulting WHO 2009 "rapid advice" preliminary guidance on adult and adolescent ART now recommends lifelong treatment for all adults with HIV infection and CD4 counts <350 cells/mm(3). These recommendations also apply to pregnant women who are HIV-infected and they place a high value on early ART to benefit the mother's own health (WHO 2009). The "rapid advice" preliminary guidance also aims to minimize side effects for mothers and their infants (WHO 2009). OBJECTIVES: Our objective was to assess the current literature regarding the treatment of HIV infection in pregnant women who are clinically or immunologically eligible for ART. This review includes an evaluation of the optimal time to start therapy in relation to the woman's laboratory parameters and/or gestational age. It also includes an analysis of which specific antiretroviral medications to start in women who are not yet on ART and which agents to continue in women who are already on ART. SEARCH STRATEGY: In June 2009, electronic searches were undertaken in these databases: Cochrane's "CENTRAL," EMBASE, PubMed, LILACS, and Web of Science/Web of Social Science. Hand searches were performed of the reference lists of all pertinent reviews and studies identified. Abstracts from relevant conferences were searched. Experts in the field were contacted to locate additional studies. The search strategy was iterative. SELECTION CRITERIA: We selected randomized controlled trials and observational studies that evaluated pregnant women with HIV infection who were eligible for ART according to criteria defined by the WHO guideline review committee. Studies were included in the systematic review when a comparison group was clearly defined and where the intervention comprised triple ART. For a study to be considered, each medication in the ART regimen needed to be clearly described. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the selected studies for relevance and inclusion. Relevant data was then extracted from included studies, and the risk of bias assessed. In each included study, the relative risk (RR) for the intervention versus the comparison group was calculated for each outcome, as appropriate, with 95% confidence intervals (CIs). MAIN RESULTS: To our knowledge, there are no randomized controlled trials or observational studies that address the optimal time to start antiretroviral drugs in ART-eligible pregnant women in relation to the woman's laboratory parameters and/or gestational age. The medications to continue in ART-eligible pregnant women who are already receiving ART also have not been evaluated systematically in the current literature. The long-term mortality of HIV-positive pregnant women on ART for their own health, and the long-term virologic or clinical efficacy of ART in treating them, has not been evaluated in randomized clinical trials. In this review, surrogate outcomes for long-term mortality and virologic and clinical efficacy (e.g. MTCT and infant HIV transmission or death) were evaluated to determine the efficacy of specific antiretroviral regimens to start in women who are not yet on ART.Three randomized controlled trials and six observational studies were selected. No studies addressed comparative maternal mortality, which regimens to continue in women already on ART, or the laboratory parameters and gestational age at which to start therapy. The use of zidovudine (AZT), lamivudine (3TC) and lopinavir/ritonavir (LPV-r) starting at 28-36 weeks gestation in a breastfeeding population reduced infant HIV-transmission or death at 12 months compared to a short-course regimen (RR 0.64, 95% CI: 0.44-0.92) (deVincenzi, 2009). Starting AZT, 3TC, and nevirapine (NVP) at 34 weeks in a mixed-feeding population reduced infant HIV-transmission or death at 7 months compared to a short-course regimen (RR 0.39, 95% CI: 0.12-0.85) (Bae, 2008).In the Mma Bana study (a randomized controlled trial in a breastfeeding population) there was no difference in MTCT at six months between the AZT/3TC/LPV-r and AZT, 3TC, and abacavir (ABC) arms (RR 0.17, 95% CI: 0.02-1.44) (Shapiro, 2009). Both regimens also showed 92-95% efficacy in virologic suppression at delivery and during the breastfeeding period. In the Kesho Bora study there was a significant difference in MTCT at 12 months between breastfeeding women who initiated AZT/3TC/LPV-r starting between 28 and 36 weeks and those receiving a short course regimen (RR 0.58, 95% CI: 0.34-0.97) (deVincenzi, 2009). MTCT also decreased significantly when AZT/3TC/NVP was compared with a short-course regimen at seven months in a feeding intervention study (RR 0.15, 95% CI: 0.04-0.62) (Bae, 2008) and 12 months in a population where either exclusive breastfeeding or replacement feeding was encouraged (RR 0.14, CI: 0.04-0.47) (Ekouevi, 2008).In the Mma Bana study, there was increased risk of prematurity among infants born to women receiving AZT/3TC/LPV-r (RR 1.52, CI: 1.07- 2.17) compared with AZT/3TC/ABC (Shapiro, 2009). Ekouevi 2008 showed higher rates of infant low birth weight on AZT/3TC/NVP started at 24 weeks compared to a short course regimen started between 32 and 36 weeks (RR 1.81, 95% CI: 1.09- 3.0). Tonwe-Gold 2007 showed an increase in maternal severe adverse events among the women receiving AZT/3TC/NVP compared with a short-course regimen (RR 25.33, CI 1.49- 340.51). AUTHORS' CONCLUSIONS: In ART-eligible pregnant women with HIV infection, ART is a safe and effective means of providing maternal virologic suppression, decreasing infant mortality, and reducing MTCT. Specifically, AZT/3TC/NVP, AZT/3TC/LPV-r, and AZT/3TC/ABC have been shown to decrease MTCT. More research is needed regarding the use of specific regimens and their maternal and infant side-effect profiles.

PMID: 20238370 [PubMed - in process]

Optimal time for initiation of antiretroviral therapy in asymptomatic, HIV-infected, treatment-naive adults.

Cochrane Database Syst Rev. 2010;3:CD008272

Authors: Siegfried N, Uthman OA, Rutherford GW

BACKGROUND: According to consensus, initiation of therapy is best based on CD4 cell count, a marker of immune status, rather than on viral load, a marker of virologic replication. For patients with advanced symptoms, treatment should be started regardless of CD4 count. However, the point during the course of HIV infection at which antiretroviral therapy (ART) is best initiated in asymptomatic patients remains unclear. Guidelines issued by various agencies provide different initiation recommendations according to resource availability. This can be confusing for clinicians and policy-makers when determining the best time to initiate therapy. Optimizing the initiation of ART is clearly complex and must, therefore, be balanced between individual and broader public health needs. OBJECTIVES: To assess the evidence for the optimal time to initiate ART in treatment-naive, asymptomatic, HIV-infected adults SEARCH STRATEGY: We formulated a comprehensive and exhaustive search strategy in an attempt to identify all relevant studies regardless of language or publication status (published, unpublished, in press, and in progress). In August 2009, we searched the following electronic journal and trial databases: MEDLINE, EMBASE, and CENTRAL. We also searched the electronic conference database of NLM Gateway, individual conference proceedings and prospective trials registers. We contacted researchers and relevant organizations and checked reference lists of all included studies. SELECTION CRITERIA: Randomized controlled trials that compared the effect of ART consisting of three drugs initiated early in the disease at high CD4 counts as defined by the trial. Early initiation could be at levels of 201-350, 351-500, or >500 cells/microL, with the comparison group initiating ART at CD4 counts below 200 x 10(6) cells/microL or as defined by the trial. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, and graded methodological quality. Data extraction and methodological quality were checked by a third author who resolved differences when these arose. Where clinically meaningful to do so, we meta-analysed dichotomous outcomes using the relative risk (RR) and report the 95% confidence intervals (95% CIs). MAIN RESULTS: One completed trial (N = 816) and one sub-group (N = 249) of a larger trial met inclusion criteria. We combined the mortality data for both trials comparing initiating ART at CD4 levels at 350 cells/microL or between 200 and 350 cells/microL with deferring initiation of ART to CD4 levels of 250 cells/microL or 200 cells/microL. There was a statistically significant reduction in death when starting ART at higher CD4 counts. Risk of death was reduced by 74% (RR = 0.26; 95% CI: 0.11, 0.62; P = 0.002). Risk of tuberculosis was reduced by 50% in the groups starting ART early; this was not statistically significant, with the reduction as much as 74% or an increased risk of up to 12% (RR = 0.54; 95% CI: 0.26, 1.12; P = 0.01). Starting ART at enrollment (when participants had CD4 counts of 350 cells/microL) rather than deferring to starting at a CD4 count of 250 cells/microL reduced the risk of disease progression by 70%; this was not statistically significant, with the reduction in risk as much as 97% or an increased risk of up to 185% (RR = 0.30; 95% CI: 0.03, 2.85; P = 0.29).One RCT found no statistically significant difference in the number of independent Grade 3 or 4 adverse events occurring in the early and standard ART groups when we conducted an intention-to-treat analysis (RR = 1.72; 95% CI: 0.98, 3.03; P = 0.06). However, when analyzing only participants who actually commenced ART in the deferred group (n = 160), the trial authors report a statistically significant increase in the incidence of zidovudine-related anaemia (8.1%) compared with those in the early initiation group (3.4%) (RR = 0.42; 95% CI: 0.20, 0.88; P = 0.02). AUTHORS' CONCLUSIONS: There is evidence of moderate quality that initiating ART at CD4 levels higher than 200 or 250 cells/microL reduces mortality rates in asymptomatic, ART-naive, HIV-infected people. Practitioners and policy-makers may consider initiating ART at levels </= 350 cells/microL for patients who present to health services and are diagnosed with HIV early in the infection.

PMID: 20238364 [PubMed - in process]

Differences in Patient-Provider Communication for Hispanic Compared to Non-Hispanic White Patients in HIV Care.

J Gen Intern Med. 2010 Mar 18;

Authors: Beach MC, Saha S, Korthuis PT, Sharp V, Cohn J, Wilson I, Eggly S, Cooper LA, Roter D, Sankar A, Moore R

BACKGROUND: Hispanic Americans with HIV/AIDS experience lower quality care and worse outcomes than non-Hispanic whites. While deficits in patient-provider communication may contribute to these disparities, no studies to date have used audio recordings to examine the communication patterns of Hispanic vs. non-Hispanic white patients with their health care providers. OBJECTIVE: To explore differences in patient-provider communication for English-speaking, HIV-infected Hispanic and non-Hispanic white patients. DESIGN: Cross-sectional analysis. SETTING: Two HIV care sites in the United States (New York and Portland) participating in the Enhancing Communication and HIV Outcomes (ECHO) study. SUBJECTS: Nineteen HIV providers and 113 of their patients. MEASUREMENTS: Patient interviews, provider questionnaires, and audio-recorded, routine, patient-provider encounters coded with the Roter Interaction Analysis System (RIAS). RESULTS: Providers were mostly non-Hispanic white (68%) and female (63%). Patients were Hispanic (51%), and non-Hispanic white (49%); 20% were female. Visits with Hispanic patients were less patient-centered (0.75 vs. 0.90, p = 0.009), with less psychosocial talk (80 vs. 118 statements, p < 0.001). This pattern was consistent among Hispanics who spoke English very well and those with less English proficiency. There was no association between patient race/ethnicity and visit length, patients' or providers' emotional tone, or the total number of patient or provider statements categorized as socioemotional, question-asking, information-giving, or patient activating. Hispanic patients gave higher ratings than whites (AOR 3.05 Hispanic vs. white highest rating of providers' interpersonal style, 95% CI 1.20-7.74). CONCLUSION: In this exploratory study, we found less psychosocial talk in patient-provider encounters with Hispanic compared to white patients. The fact that Hispanic patients rated their visits more positively than whites raises the possibility that these differences in patient-provider interactions may reflect differences in patient preferences and communication style rather than "deficits" in communication. If these findings are replicated in future studies, efforts should be undertaken to understand the reasons underlying them and their impact on the quality and equity of care.

PMID: 20238204 [PubMed - as supplied by publisher]

A Transitional Opioid Program to Engage Hospitalized Drug Users.

J Gen Intern Med. 2010 Mar 17;

Authors: Shanahan CW, Beers D, Alford DP, Brigandi E, Samet JH

BACKGROUND: Many opioid-dependent patients do not receive care for addiction issues when hospitalized for other medical problems. Based on 3 years of clinical practice, we report the Transitional Opioid Program (TOP) experience using hospitalization as a "reachable moment" to identify and link opioid-dependent persons to addiction treatment from medical care. METHODS: A program nurse identified, assessed, and enrolled hospitalized, out-of-treatment opioid-dependent drug users based on their receipt of methadone during hospitalization. At discharge, patients transitioned to an outpatient interim opioid agonist program providing 30-day stabilization followed by 60-day taper. The nurse provided case management emphasizing HIV risk reduction, health education, counseling, and medical follow-up. Treatment outcomes included opioid agonist stabilization then taper or transfer to long-term opioid agonist treatment. RESULTS: From January 2002 to January 2005, 362 unique hospitalized, opioid-dependent drug users were screened; 56% (n = 203) met eligibility criteria and enrolled into the program. Subsequently, 82% (167/203) presented to the program clinic post-hospital discharge; for 59% (119/203) treatment was provided, for 26% (52/203) treatment was not provided, and for 16% (32/203) treatment was not possible (pursuit of TOP objectives precluded by medical problems, psychiatric issues, or incarceration). Program patients adhered to a spectrum of medical recommendations (e.g., obtaining prescription medications, medical follow-up). CONCLUSIONS: The Transitional Opioid Program (TOP) identified at-risk hospitalized, out-of-treatment opioid-dependent drug users and, by offering a range of treatment intensity options, engaged a majority into addiction treatment. Hospitalization can be a "reachable moment" to engage and link drug users into addiction treatment.

PMID: 20237960 [PubMed - as supplied by publisher]

Erratum to: Abacavir/lamivudine fixed-dose combination antiretroviral therapy for the treatment of HIV.

Adv Ther. 2010 Mar 16;

Authors: Achenbach CJ, Scarsi KK, Murphy RL

PMID: 20237877 [PubMed - as supplied by publisher]

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

J Neuroimmune Pharmacol. 2010 Mar 17;

Authors: Nowacek AS, McMillan J, Miller R, Anderson A, Rabinow B, Gendelman HE

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

PMID: 20237859 [PubMed - as supplied by publisher]

[Gastric leishmaniasis : A rare type of gastritis.]

Pathologe. 2010 Mar 19;

Authors: Warich-Eitel S, Rauthe S, Eck M

Gastric leishmaniasis was diagnosed in a 43-year-old HIV infected patient by histopathology as an accidental diagnostic finding. Leishmania HIV co-infections have increasingly been reported recently as a result of intensive travelling and an increase in geographical extension. Nevertheless, Leishmania gastritis is a rare disease which can occur without clinical symptoms and in the absence of endoscopic abnormalities. In this case microscopic detection of the pathogen in macrophages of the gastric mucosa resulted in the correct diagnosis.

PMID: 20237783 [PubMed - as supplied by publisher]

[Timing of initiation of antiretroviral therapy in HIV-1-infected patients : Meta-analysis of the When To Start Consortium.]

Internist (Berl). 2010 Mar 18;

Authors: Goebel FD, Nitschmann S

PMID: 20237749 [PubMed - as supplied by publisher]

Feline leukemia virus integrase and capsid packaging functions do not change the insertion profile of standard Moloney retroviral vectors.

Gene Ther. 2010 Mar 18;

Authors: Métais JY, Topp S, Doty RT, Borate B, Nguyen AD, Wolfsberg TG, Abkowitz JL, Dunbar CE

Adverse events linked to perturbations of cellular genes by vector insertion reported in gene therapy trials and animal models have prompted attempts to better understand the mechanisms directing viral vector integration. The integration profiles of vectors based on MLV, ASLV, SIV and HIV have all been shown to be non-random, and novel vectors with a safer integration pattern have been sought. Recently, we developed a producer cell line called CatPac that packages standard MoMLV vectors with feline leukemia virus (FeLV) gag, pol and env gene products. We now report the integration profile of this vector, asking if the FeLV integrase and capsid proteins could modify the MoMLV integration profile, potentially resulting in a less genotoxic pattern. We transduced rhesus macaque CD34+ hematopoietic progenitor cells with CatPac or standard MoMLV vectors, and determined their integration profile by LAM-PCR. We obtained 184 and 175 unique integration sites (ISs) respectively for CatPac and standard MoMLV vectors, and these were compared with 10 000 in silico-generated random IS. The integration profile for CatPac vector was similar to MoMLV and equally non-random, with a propensity for integration near transcription start sites and in highly dense gene regions. We found an IS for CatPac vector localized 715 nucleotides upstream of LMO-2, the gene involved in the acute lymphoblastic leukemia developed by X-SCID patients treated by gene therapy using MoMLV vectors. In conclusion, we found that replacement of MoMLV env, gag and pol gene products with FeLV did not alter the basic integration profile. Thus, there appears to be no safety advantage for this packaging system. However, considering the stability and efficacy of CatPac vectors, further development is warranted, using potentially safer vector backbones, for instance those with a SIN configuration.Gene Therapy advance online publication 18 March 2010; doi:10.1038/gt.2010.24.

PMID: 20237508 [PubMed - as supplied by publisher]

Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort.

Neurology. 2010 Mar 17;

Authors: Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest DJ,

OBJECTIVE: Prior studies have shown improved neurocognition with initiation of antiretroviral treatment (ART) in HIV. We hypothesized that stopping ART would be associated with poorer neurocognitive function. METHODS: Neurocognitive function was assessed as part of ACTG 5170, a multicenter, prospective observational study of HIV-infected subjects who elected to discontinue ART. Eligible subjects had CD4 count >350 cells/mm(3), had HIV RNA viral load <55,000 cp/mL, and were on ART (>/=2 drugs) for >/=6 months. Subjects stopped ART at study entry and were followed for 96 weeks with a neurocognitive examination. RESULTS: A total of 167 subjects enrolled with a median nadir CD4 of 436 cells/mm(3) and 4.5 median years on ART. Significant improvements in mean neuropsychological scores of 0.22, 0.39, 0.53, and 0.74 were found at weeks 24, 48, 72, and 96 (all p < 0.001). In the 46 subjects who restarted ART prior to week 96, no significant changes in neurocognitive function were observed. CONCLUSION: Subjects with preserved immune function found that neurocognition improved significantly following antiretroviral treatment (ART) discontinuation. The balance between the neurocognitive cost of untreated HIV viremia and the possible toxicities of ART require consideration. Classification of evidence: This study provides Class III evidence that discontinuing ART is associated with an improvement in 2 neuropsychological tests (Trail-Making Test A & B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol subtest) for up to 96 weeks. Resuming ART was not associated with a decline in these scores for up to 45 weeks.

PMID: 20237308 [PubMed - as supplied by publisher]

Evaluating the Substrate-Envelope Hypothesis: Structural Analysis of Novel HIV-1 Protease Inhibitors Designed to be Robust against Drug Resistance.

J Virol. 2010 Mar 17;

Authors: Nalam MN, Ali A, Altman MD, Reddy GS, Chellappan S, Kairys V, Ozen A, Cao H, Gilson MK, Tidor B, Rana TM, Schiffer CA

Drug resistance mutations in HIV-1 protease selectively alter inhibitor binding without significantly affecting substrate recognition and cleavage. This alteration in molecular recognition led us to develop the substrate envelope hypothesis which predicts that HIV-1 protease inhibitors that fit within the overlapping consensus volume of the substrates are less likely to be susceptible to drug-resistant mutations, as a mutation impacting such inhibitors would simultaneously impact the processing of substrates. To evaluate this hypothesis, over 130 HIV-1 protease inhibitors were designed and synthesized with and without substrate-envelope constraints using three different approaches. A subset of 16 representative inhibitors were chosen with binding affinities ranging from 58 nM to 0.8 pM to wild-type protease for crystallographic analysis. The inhibitor-protease complexes revealed that tightly binding inhibitors (picomolar affinity) appear to "lock" into the protease active site by making hydrogen bonds to particular active-site residues. Both this hydrogen bonding pattern and subtle variations in protein-ligand van der Waals interactions distinguish nanomolar from picomolar inhibitors. In general, inhibitors that fit within the substrate envelope, regardless of whether they are picomolar or nanomolar, generally have flatter profiles to drug resistant protease variants than inhibitors that protrude beyond the substrate envelope; this provides a strong rationale for incorporating substrate envelope constraints into structure-based design strategies to develop new HIV-1 protease inhibitors.

PMID: 20237088 [PubMed - as supplied by publisher]

HIV-1 lentiviral vector immunogenicity is mediated by TLR3 and TLR7.

J Virol. 2010 Mar 17;

Authors: Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S, Keyaerts M, Collins M

Lentiviral vectors are promising vaccine vector candidates, which have been extensively tested in pre-clinical models of infectious disease and cancer immunotherapy. They are also used in gene therapy clinical trials, both for the ex vivo modification of cells and for direct in vivo injection. It is therefore critical to understand the mechanism(s) by which such vectors might stimulate the immune system. We evaluated the effect of lentiviral vectors on myeloid dendritic cells (DC), the main target of lentiviral transduction following subcutaneous immunisation. Activation of DC cultures was independent of the lentiviral pseudotype, but dependent on cell entry and reverse transcription. In vivo transduced DC also displayed a mature phenotype, produced TNF-alpha, and stimulated naive CD8+ T cells. Lentiviral activation of DC was TLR-dependent as it was inhibited in TRIF/MyD88 knock out (-/-) DC. TLR3-/- or TLR7-/- DC were less activated, and reverse transcription was important for activation of TLR7-/- DC. Moreover, lentivirally transduced DC lacking TLR3 or TLR7 had an impaired capacity to induce antigen-specific CD8+ T cell responses. In conclusion, we demonstrated TLR-dependent DC activation by lentiviral vectors, explaining their immunogenicity. These data allow the rational development of strategies to manipulate the host's immune response to the transgene.

PMID: 20237085 [PubMed - as supplied by publisher]

Concentration-dependent effects and intracellular accumulation of HIV protease inhibitors in cultured CD4 T cells and primary human lymphocytes.

J Antimicrob Chemother. 2010 Mar 17;

Authors: Janneh O, Bray PG, Jones E, Wyen C, Chiba P, Back DJ, Khoo SH

Background The intracellular and plasma concentrations of HIV protease inhibitors (HPIs) vary widely in vivo. It is unclear whether there is a concentration-dependent effect of HPIs such that at increasing concentration they may either block their own efflux (leading to 'autoboosting') or influx (leading to saturability/decreased intracellular accumulation). Method The effects of various concentrations (0-30 microM) of lopinavir, saquinavir, ritonavir and atazanavir on the accumulation of [(14)C]lopinavir, [(3)H]saquinavir, [(3)H]ritonavir and [(3)H]atazanavir, respectively, were investigated in CEM(parental), CEM(VBL) [P-glycoprotein (ABCB1) overexpressing], CEM(E1000) (MRP1 overexpressing) and in peripheral blood mononuclear cells (PBMCs). We also investigated the effects of inhibitors of ABCB1/ABCG2 (tariquidar), ABCC (MK571) and ABCC1/2 (frusemide), singly and in combination with HPIs, on cellular accumulation. Results In all the cell lines, with increasing concentration of lopinavir, saquinavir and ritonavir, there was a significant increase in the cellular accumulation of [(14)C]lopinavir, [(3)H]saquinavir and [(3)H]ritonavir. Tariquidar, MK571 and frusemide (alone and in combination with lopinavir, saquinavir and ritonavir) significantly increased the accumulation of [(14)C]lopinavir, [(3)H]saquinavir and [(3)H]ritonavir. Ritonavir (alone or in combination with tariquidar) decreased the intracellular accumulation of [(3)H]ritonavir in PBMCs. Atazanavir decreased the accumulation of [(3)H]atazanavir in a concentration-dependent manner in all of the cells tested. Conclusions There are complex and variable drug-specific rather than class-specific effects of the HPIs on their own accumulation.

PMID: 20237075 [PubMed - as supplied by publisher]

Universal access to HIV treatment will not be achieved by 2015 without radical action.

BMJ. 2010;340:c1483

Authors: Moszynski P

PMID: 20236994 [PubMed - in process]

Is it age or HIV that drives the regulatory T-cells expansion that occurs in older HIV-infected persons?

Clin Immunol. 2010 Mar 15;

Authors: Méndez Lagares G, Leal Noval M, Del Pozo Balado MD, León JA, Pacheco YM

PMID: 20236865 [PubMed - as supplied by publisher]

BEST-HNN and 2D-(HN)NH experiments for rapid backbone assignment in proteins.

J Magn Reson. 2010 Feb 20;

Authors: Kumar D, Paul S, Hosur RV

HNN has proven to be an extremely valuable experiment for rapid and unambiguous backbone (H(N), (15)N) assignment in ((13)C, (15)N) labeled proteins. However, low sensitivity of the experiment is often a limiting factor, especially when the transverse relaxation times (T(2)) are short. We show here that BEST modification Schanda et al. (2006) [2] increases the sensitivity per unit time by more than a factor of 2.0 and thus substantially increases the speed of data collection; good 3D data can be collected in 8-10h. Next, we present a simple method for amino-acid type identification based on simple 2D versions of the HNN experiment, labeled here as 2D-(HN)NH. Each of these experiments which produce anchor points for Gly, Ala, Ser/Thr residues, can be recorded in less than an hour. These enable rapid data acquisition, rapid analysis, and consequently rapid assignment of backbone (H(N), (15)N) resonances. The 2D-(HN)NH experiment does not involve aliphatic/aromatic protons and hence can be applied to deuterated protein samples as well, which is an additional advantage. The experiments have been demonstrated with human ubiquitin (76 aa) and acetic-acid denatured HIV-1 protease (99 aa), as representatives of folded and unfolded protein systems, respectively.

PMID: 20236846 [PubMed - as supplied by publisher]

HPLC-MS method for the quantification of nine anti-HIV drugs from dry plasma spot on glass filter and their long term stability in different conditions.

J Pharm Biomed Anal. 2010 Feb 25;

Authors: D'Avolio A, Simiele M, Siccardi M, Baietto L, Sciandra M, Bonora S, Di Perri G

A bioanalytical method for the determination of most commonly prescribed protease inhibitors (saquinavir, atazanavir, amprenavir, darunavir, lopinavir and ritonavir) and non-nucleoside reverse transcriptase inhibitors (etravirine, efavirenz and nevirapine) was developed, modifying our previous HPLC-MS chromatographic run, validated and a complete short and long term stability evaluation was carried out. One hundred microlitres of plasma were distributed on a collection glass paper filter (Glass-Microfibre from Sartorius), then the filter underwent thermal treatment, both for drying and for HIV inactivation, and stored at room temperature, 4 degrees C and -20 degrees C. The analytes were extracted from the filter disc using tert-butylmethylether with basic pH, after the addition of the internal standards quinoxaline. The extract was dried, reconstituted and the chromatographic separation was performed on a reversed-phase C-18 column (150mmx2.0mm) and the analytes were quantified using a single quadrupole mass spectrometer. The method was validated considering the concentration ranges encountered in clinical trials and the routine clinical practice. The assay was linear over the concentration ranges tested. Accuracies ranged from 92.1% to 111.9% and intra-day and inter-day relative standard deviation for all quality control levels ranged from 0.2 to 12.9 and 3.1 to 14.4, respectively. Analytes in dried plasma spots were stable for longer time when dried/inactivation step was carried out before storage compared to samples not dried/inactivated before the analysis. The dried/inactivation step allows shipment of samples at room temperature without any risks, therefore the developed and validated method enables an easy and cheap sample shipment for therapeutic drug monitoring and pharmacokinetic studies.

PMID: 20236784 [PubMed - as supplied by publisher]