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26.  HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation 
AIDS Research and Human Retroviruses  2013;29(11):1401-1406.
Abstract
This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's “Animal Rule” pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine.
doi:10.1089/aid.2012.0337
PMCID: PMC3809608  PMID: 23379343
27.  In Pursuit of an HIV Vaccine: Designing Efficacy Trials in the Context of Partially Effective Nonvaccine Prevention Modalities 
AIDS Research and Human Retroviruses  2013;29(11):1513-1523.
Abstract
The HIV prevention landscape is evolving rapidly, and future efficacy trials of candidate vaccines, which remain the best long-term option for stemming the HIV epidemic, will be conducted in the context of partially effective nonvaccine prevention modalities. It is essential that these trials provide for valid and efficient evaluation of vaccine efficacy and immune correlates. The availability of partially effective prevention modalities presents opportunities to study their interactions with vaccines to maximally reduce HIV incidence. This article proposes an approach for conducting future vaccine efficacy trials in the context of background use of partially effective nonvaccine prevention modalities, and for conducting future vaccine efficacy trials that provide nonvaccine prevention modalities in one or more of the randomized study groups. Strategies are discussed for responding to emerging evidence on nonvaccine prevention modalities during ongoing vaccine trials. Next-generation HIV vaccine efficacy trials will almost certainly be more complex in their design and implementation but may become more relevant to at-risk populations and better suited to the ultimate goal of reducing HIV incidence at the population level.
doi:10.1089/aid.2012.0385
PMCID: PMC3809388  PMID: 23597282
28.  Effect of Combination Antiretroviral Therapy on Chinese Rhesus Macaques of Simian Immunodeficiency Virus Infection 
AIDS Research and Human Retroviruses  2013;29(11):1465-1474.
Abstract
Definitive treatment of HIV infection remains a critical but elusive goal, with persistence of residual virus even in the face of prolonged administration of suppressive combination antiretroviral treatment (cART) providing a source for recrudescent infection if treatment is stopped. Characterization of the residual virus and devising strategies to target it for eradication are key goals in HIV treatment research. Indian rhesus macaques (In-RM) infected with SIVmac have been widely used in such research. However, it has proven challenging to achieve and sustain clinically relevant levels of suppression (<30 vRNA copies/ml plasma) with cART in such models. As ease of viral suppression by cART is related to pretreatment levels of viral replication, and levels of replication of SIVmac239/251 are lower in Chinese rhesus macaques (Ch-RM) than in In-RM, we evaluated cART administration to SIVmac-infected Ch-RM as a potential model for studies of residual virus and eradication strategies. Four SIVmac239-infected Ch-RM received cART including reverse transcriptase inhibitors PMPA/FTC and integrase inhibitor L-870812 daily for 8 weeks. Plasma viral loads were promptly reduced to <30 copies/ml upon initiation of cART. Cell-associated SIV DNA levels in lymphocytes from the gut were also significantly reduced. Jejunal and colonic CCR5+CD4+ mucosal memory T cells increased significantly; restoration of these cells was associated with reductions in immune activation. In conclusion, cART effectively suppressed viral replication to <30 vRNA copies/ml in SIVmac239-infected Ch-RM, reducing immune activation and restoring mucosal immune cell populations. SIVmac239-infected Ch-RM may be a useful model for studying responses to cART and persistent tissue reservoirs and evaluating candidate eradication strategies to cure HIV infection.
doi:10.1089/aid.2012.0378
PMCID: PMC3809389  PMID: 23387294
29.  3-Hydroxyphthalic Anhydride-Modified Human Serum Albumin as a Microbicide Candidate Against HIV Type 1 Entry by Targeting Both Viral Envelope Glycoprotein gp120 and Cellular Receptor CD4 
AIDS Research and Human Retroviruses  2013;29(11):1455-1464.
Abstract
We previously reported that 3-hydroxyphthalic anhydride-modified human serum albumin (HP-HSA) as an anti-HIV microbicide could potently inhibit infection by a broad spectrum of HIV-1 strains; however, its mechanism of action is still elusive. Here, we aimed to identify the target(s) of HP-HSA. HIV-1 envelope glycoprotein (Env)-mediated cell–cell fusion assays were conducted using noninfectious CHO-WT cells or infectious HIV-1IIIB-infected H9 cells as effector cells and MT-2 as target cells. The cell-to-cell transmission and single-round HIV-1 infection assays were performed by measuring luciferase activity. Binding of HP-HSA to CD4 or gp120 was determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry, while binding of HP-HSA to the coreceptor CXCR4 or CCR5 was detected by cell-based ELISA. HP-HSA strongly inhibited HIV-1 Env-mediated cell–cell fusion and blocked infection by HIV-1 pseudoviruses bearing Env of HIV-1HXB2 (X4 strain) or HIV-1SF162 (R5 strain). HP-HSA was also effective in blocking HIV-1BaL transmission from infected to uninfected cells. HP-HSA could strongly bind to HIV-1 Env gp120 and cellular receptor CD4. These results suggest that HP-HSA inhibits HIV-1 entry into the target cell by interacting with viral Env gp120 and/or the cellular CD4 receptor, making it a promising microbicide candidate for preventing HIV-1 sexual transmission.
doi:10.1089/aid.2013.0043
PMCID: PMC3809378  PMID: 23711095
30.  Short Communication: Use of Raltegravir in Late-Presenting HIV-Infected Pregnant Women 
AIDS Research and Human Retroviruses  2013;29(11):1451-1454.
Abstract
The risk of HIV-1 mother-to-child transmission (MTCT) is clearly correlated with the maternal HIV cell-free viral load (VL) at delivery. Preventing MTCT in late-presenting (after 28 weeks) HIV-infected pregnant women remains a clinical challenge, and ensuring a rapid decrease of maternal VL is an important preventive strategy. Raltegravir (RGV) has a higher first and second phase viral decay rate, has a high placental transfer, with a potential preloading effect for neonate, and demonstrates effective accumulation in cervicovaginal secretions. We report 14 cases in which RGV was used late in pregnancy for HIV-1 MTCT prophylaxis. All women were RGV naive and the prophylaxis regimens included RGV plus at least two other antiretroviral agents. At RGV initiation, the median gestational age was 36 weeks (range 34–38) and the median maternal plasma HIV-1 RNA viral load was 35,364 copies/ml (range 636–391,535). At delivery, the median gestational age was 38 weeks (range 37–40). The median exposure time to RGV was 17 days (range 7–32), with a mean maternal VL decay of 2.6 log. At delivery, seven women had undetectable (<50 copies/ml) VL, four had between 64 and 457 copies/ml, and in three VL was not available. All but one infant's HIV-RNA tests were negative at 1 and 3 months (one case of in utero MTCT). Raltegravir-containing antiretroviral regimens induced a rapid HIV-RNA decline in maternal VL at delivery, and were safe and effective in preventing MTCT for late-presenting, HIV-infected women.
doi:10.1089/aid.2013.0059
PMCID: PMC3809937  PMID: 23731224
31.  Issues in Women's Participation in a Phase III Community HIV Vaccine Trial in Thailand 
AIDS Research and Human Retroviruses  2013;29(11):1524-1534.
Abstract
To assess qualities and outcomes of women participating in a large, community-based HIV vaccine trial, the present study was conducted among female participants of the RV 144 prime-boost trial in Thailand from 2003 to 2009. Qualities of participation refer to complete vaccination, retention, and status change. Outcomes of participation refer to incident rate, adverse event, and participation impact event. A total of 6,334 (38.6%) women participated in the trial, of whom about 50% were classified as low risk and 11% as high risk. About 85% of participants completed four vaccinations and 76% were included in the per-protocol analysis of the on-time vaccination schedule. More women (88%) completed 42 months follow-up compared with men (85%). Women aged 21 and above had more adverse events compared to younger age groups. More women (5%) compared with men (3%) reported participation impact events (PIEs). High-risk women had more PIEs and a higher infection rate compared to the low-risk group. Complete vaccination and retention on last follow-up were more common in married women aged above 21, and being a housewife. Female volunteers showed the same qualities and outcomes of participation as males in the HIV vaccine trial. There was no statistically significant difference in vaccine efficacy between men and women, especially among the high-risk and married women. The study highlighted the important behavioral, social, and cultural issues that could be considered for future HIV vaccine trial designs.
doi:10.1089/aid.2012.0265
PMCID: PMC3809940  PMID: 23343395
33.  Isoosmolar Enemas Demonstrate Preferential Gastrointestinal Distribution, Safety, and Acceptability Compared with Hyperosmolar and Hypoosmolar Enemas as a Potential Delivery Vehicle for Rectal Microbicides 
AIDS Research and Human Retroviruses  2013;29(11):1487-1495.
Abstract
Rectally applied antiretroviral microbicides for preexposure prophylaxis (PrEP) of HIV infection are currently in development. Since enemas (rectal douches) are commonly used by men who have sex with men prior to receptive anal intercourse, a microbicide enema could enhance PrEP adherence by fitting seamlessly within the usual sexual practices. We assessed the distribution, safety, and acceptability of three enema types—hyperosmolar (Fleet), hypoosmolar (distilled water), and isoosmolar (Normosol-R)—in a crossover design. Nine men received each enema type in random order. Enemas were radiolabeled [99mTc-diethylene triamine pentaacetic acid (DTPA)] to assess enema distribution in the colon using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Plasma 99mTc-DTPA indicated mucosal permeability. Sigmoidoscopic colon tissue biopsies were taken to assess injury as well as tissue penetration of the 99mTc-DTPA. Acceptability was assessed after each product use and at the end of the study. SPECT/CT imaging showed that the isoosmolar enema had greater proximal colonic distribution (up to the splenic flexure) and greater luminal and colon tissue concentrations of 99mTc-DTPA when compared to the other enemas (p<0.01). Colon biopsies also showed that only the hyperosmolar enema caused sloughing of the colonic epithelium (p<0.05). In permeability testing, the hypoosmolar enema had higher plasma 99mTc-DTPA 24-h area under the concentration-time curve and peak concentration compared to the hyperosmolar and isoosmolar enemas, respectively. Acceptability was generally good with no clear preferences among the three enema types. The isoosmolar enema was superior or similar to the other enemas in all categories and is a good candidate for further development as a rectal microbicide vehicle.
doi:10.1089/aid.2013.0189
PMCID: PMC3809953  PMID: 23885722
34.  Short Communication: A Repeated Simian Human Immunodeficiency Virus Reverse Transcriptase/Herpes Simplex Virus Type 2 Cochallenge Macaque Model for the Evaluation of Microbicides 
AIDS Research and Human Retroviruses  2014;30(11):1117-1124.
Abstract
Epidemiological studies suggest that prevalent herpes simplex virus type 2 (HSV-2) infection increases the risk of HIV acquisition, underscoring the need to develop coinfection models to evaluate promising prevention strategies. We previously established a single high-dose vaginal coinfection model of simian human immunodeficiency virus (SHIV)/HSV-2 in Depo-Provera (DP)-treated macaques. However, this model does not appropriately mimic women's exposure. Repeated limiting dose SHIV challenge models are now used routinely to test prevention strategies, yet, at present, there are no reports of a repeated limiting dose cochallenge model in which to evaluate products targeting HIV and HSV-2. Herein, we show that 20 weekly cochallenges with 2–50 TCID50 simian human immunodeficiency virus reverse transcriptase (SHIV-RT) and 107 pfu HSV-2 results in infection with both viruses (4/6 SHIV-RT, 6/6 HSV-2). The frequency and level of vaginal HSV-2 shedding were significantly greater in the repeated exposure model compared to the single high-dose model (p<0.0001). We used this new model to test the Council's on-demand microbicide gel, MZC, which is active against SHIV-RT in DP-treated macaques and HSV-2 and human papillomavirus (HPV) in mice. While MZC reduced SHIV and HSV-2 infections in our repeated limiting dose model when cochallenging 8 h after each gel application, a barrier effect of carrageenan (CG) that was not seen in DP-treated animals precluded evaluation of the significance of the antiviral activity of MZC. Both MZC and CG significantly (p<0.0001) reduced the frequency and level of vaginal HSV-2 shedding compared to no gel treatment. This validates the use of this repeated limiting dose cochallenge model for testing products targeting HIV and HSV-2.
doi:10.1089/aid.2014.0207
PMCID: PMC4208605  PMID: 25354024
35.  The Immune Space: A Concept and Template for Rationalizing Vaccine Development 
AIDS Research and Human Retroviruses  2014;30(11):1017-1022.
Abstract
Empirical testing of candidate vaccines has led to the successful development of a number of lifesaving vaccines. The advent of new tools to manipulate antigens and new methods and vectors for vaccine delivery has led to a veritable explosion of potential vaccine designs. As a result, selection of candidate vaccines suitable for large-scale efficacy testing has become more challenging. This is especially true for diseases such as dengue, HIV, and tuberculosis where there is no validated animal model or correlate of immune protection. Establishing guidelines for the selection of vaccine candidates for advanced testing has become a necessity. A number of factors could be considered in making these decisions, including, for example, safety in animal and human studies, immune profile, protection in animal studies, production processes with product quality and stability, availability of resources, and estimated cost of goods. The “immune space template” proposed here provides a standardized approach by which the quality, level, and durability of immune responses elicited in early human trials by a candidate vaccine can be described. The immune response profile will demonstrate if and how the candidate is unique relative to other candidates, especially those that have preceded it into efficacy testing and, thus, what new information concerning potential immune correlates could be learned from an efficacy trial. A thorough characterization of immune responses should also provide insight into a developer's rationale for the vaccine's proposed mechanism of action. HIV vaccine researchers plan to include this general approach in up-selecting candidates for the next large efficacy trial. This “immune space” approach may also be applicable to other vaccine development endeavors where correlates of vaccine-induced immune protection remain unknown.
doi:10.1089/aid.2014.0040
PMCID: PMC4208609  PMID: 24857015
36.  Mitochondrial DNA Variation and Changes in Adiponectin and Endothelial Function in HIV-Infected Adults After Antiretroviral Therapy Initiation 
AIDS Research and Human Retroviruses  2013;29(10):1293-1299.
Abstract
Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A>G mtDNA polymorphism (N=8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 μg/ml; p=0.003), greater absolute (−1.9 vs. −0.2 μg/ml) and relative (−33% vs. −3%) adiponectin decreases (p<0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p=0.04). Individual mtDNA haplogroups, including haplogroups H (N=13) and U (N=6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed.
doi:10.1089/aid.2013.0079
PMCID: PMC3785797  PMID: 23944767
37.  A Role for TLR Signaling During B Cell Activation in Antiretroviral-Treated HIV Individuals 
AIDS Research and Human Retroviruses  2013;29(10):1353-1360.
Abstract
The mechanisms underlying B cell activation that persists during antiretroviral therapy (ART) are unknown. Toll-like receptor (TLR) signaling is a critical mediator of innate cell activation and though B cells express TLRs, few studies have investigated a role for TLR signaling in B cell activation during HIV infection. We addressed this question by assessing the activated phenotype and TLR expression/responsiveness of B cells from ART-treated HIV-infected subjects (HIVART+). We evaluated activation markers implicated in B cell-mediated T cell trans infection during HIV pathogenesis. We found no significant difference in TLR expression between B cells of HIVART+ and HIV− subjects. However, B cells of HIVART+ subjects exhibited heightened endogenous expression levels of IL-6 (p=0.0051), T cell cognate ligands CD40 (p=0.0475), CD54 (p=0.0229), and phosphorylated p38 (p<0.0001), a marker of TLR signaling. In vitro, B cells of HIVART+ individuals were less responsive to TLR stimulation compared to B cells of HIV− subjects. The activated phenotype of in vitro TLR-stimulated B cells of HIV− subjects was similar to ex vivo B cells from HIVART+ individuals. TLR2 stimulation was a potent mediator of B cell activation, whereas B cells were least responsive to TLR4 stimulation. Compared to HIV− subjects, the serum level of lipoteichoic acid (TLR2 ligand) in HIVART+ subjects was significantly higher (p=0.0207), correlating positively with viral load (p=0.0127, r=0.6453). Our data suggest that during HIV infection TLR-activated B cells may exert a pathogenic role and B cells from HIVART+ subjects respond to in vitro TLR stimulation, yet exhibit a TLR tolerant phenotype suggesting prior in vivo TLR stimulation.
doi:10.1089/aid.2013.0115
PMCID: PMC3785799  PMID: 23763346
38.  Antiretroviral Therapy-Induced Changes in Plasma Lipids and the Risk of Kidney Dysfunction in HIV-Infected Men 
AIDS Research and Human Retroviruses  2013;29(10):1346-1352.
Abstract
In the context of HIV, the initiation of effective antiretroviral therapy (ART) has been found to increase the risk of dyslipidemia in HIV-infected individuals, and dyslipidemia has been found to be a risk factor for kidney disease in the general population. Therefore, we examined changes in lipid profiles in HIV-infected men following ART initiation and the association with future kidney dysfunction. HIV-infected men from the Multicenter AIDS Cohort Study initiating ART between December 31, 1995 and September 30, 2011 with measured lipid and serum creatinine values pre-ART and post-ART were selected. The associations between changes in total cholesterol or high-density lipoprotein following ART initiation and the estimated change in glomerular filtration rate (eGFR) over time were assessed using piecewise linear mixed effects models. There were 365 HIV-infected men who contributed to the analysis. In the adjusted models, at 3 years post-ART, those with changes in total cholesterol >50 mg/dl had an average decrease in eGFR of 2.6 ml/min/1.73 m2 per year (p<0.001) and at 5 years post-ART, the average decrease was 2.4 ml/min/1.73 m2 per year (p=0.008). This decline contrasted with the estimates for those with changes in total cholesterol ≤50 mg/dl: 1.4 ml/min/1.73 m2 decrease per year (p<0.001) and 0.1 ml/min/1.73 m2 decrease per year (p=0.594) for the same time periods, respectively. Large decreases in high-density lipoprotein (a decline of greater than 5 mg/dl) were not associated with declines in eGFR. These results indicate that large ART-related increases in total cholesterol may be a risk factor for kidney function decline in HIV-infected men. Should these results be generalizable to the broader HIV population, monitoring cholesterol changes following the initiation of ART may be important in identifying HIV-infected persons at risk for kidney disease.
doi:10.1089/aid.2012.0253
PMCID: PMC3785801  PMID: 23758574
39.  Differential Regulatory T Cell Activity in HIV Type 1-Exposed Seronegative Individuals 
AIDS Research and Human Retroviruses  2013;29(10):1321-1329.
Abstract
The potential role of conventional and regulatory T cells (Tregs) in protection from HIV-1 infection remains unclear. To address this question, we analyzed samples from 129 HIV-1-exposed seronegative individuals (HESN) from an HIV-1-serodiscordant couples cohort. To assess the presence of HIV-specific T cell responses and Treg function, we measured the proliferation of T cells in response to HIV-1 peptide pools in peripheral blood mononuclear cells (PBMCs) and PBMCs depleted of Tregs. We identified HIV-specific CD4+ and CD8+ T cell responses and, surprisingly, the overall CD4+ and CD8+ T cell response rate was not increased when Tregs were removed from cell preparations. Of the 20 individuals that had HIV-1-specific CD4+ T cell responses, only eight had Tregs that could suppress this proliferation. When compared with individuals whose Tregs could suppress HIV-1-specific CD4+ T cell proliferation, individuals with Tregs unable to suppress showed a trend toward increased T cell activation and Treg frequency and a significant increase in HIV-1-specific production of microphage inflammatory protein-1β (MIP-1β) by CD4+ T cells, autocrine production of which has been shown to be protective in terms of HIV-1 infection of CD4+ T cells.
doi:10.1089/aid.2013.0075
PMCID: PMC3785803  PMID: 23815575
40.  Nautilus: A Bioinformatics Package for the Analysis of HIV Type 1 Targeted Deep Sequencing Data 
AIDS Research and Human Retroviruses  2013;29(10):1361-1364.
Abstract
The advent of next generation sequencing technologies is providing new insight into HIV-1 diversity and evolution, which has created the need for bioinformatics tools that could be applied to the characterization of viral quasispecies. Here we present Nautilus, a bioinformatics package for the analysis of HIV-1 targeted deep sequencing data. The DeepHaplo module determines the nucleotide base frequency and read depth at each position and computes the haplotype frequencies based on the linkage among polymorphisms in the same next generation sequence read. The Motifs module computes the frequency of the variants in the setting of their sequence context and mapping orientation, which allows for the validation of polymorphisms and haplotypes when strand bias is suspected. Both modules are accessed through a user-friendly GUI, which runs on Mac OS X (version 10.7.4 or later), and are based on Python, JAVA, and R scripts. Nautilus is available from www.hivresearch.org/research.php?ServiceID=5&SubServiceID=6.
doi:10.1089/aid.2013.0175
PMCID: PMC3785804  PMID: 23809062
41.  Effects of Raltegravir on 2-Long Terminal Repeat Circle Junctions in HIV Type 1 Viremic and Aviremic Patients 
AIDS Research and Human Retroviruses  2013;29(10):1365-1369.
Abstract
Although 2-long terminal repeat (2-LTR) circles are only a fraction of the total viral DNA in infected cells, sequence analysis of 2-LTR circles reveals critical information regarding viral DNA synthesis and the nature of actively replicating virus. It was observed that a large proportion of the 2-LTR circular molecules in the peripheral blood mononuclear cell (PBMC) DNA of infected individuals are mutated at the circle junction. The integrase inhibitor raltegravir (RAL) blocks the strand transfer step of the integration of HIV-1; as a consequence of abortive integration a significant increase of episomal 2-LTR circles is observed. Moreover, it was demonstrated that in patients treated with highly active retroviral therapy (HAART) changes in 2-LTR concentration did not affect junction sequences and flanking regions of 2-LTR. Here we evaluated whether RAL therapy could have a differential impact on the 2-LTR circle junctional sequences in patients with different virological profiles at the time of starting RAL therapy. Sequence analysis indicates that RAL acts differently in the two populations.
doi:10.1089/aid.2013.0047
PMCID: PMC3785805  PMID: 23802629
42.  The Majority of HIV Type 1 DNA in Circulating CD4+ T Lymphocytes Is Present in Non-Gut-Homing Resting Memory CD4+ T Cells 
AIDS Research and Human Retroviruses  2013;29(10):1330-1339.
Abstract
Memory CD4+ T lymphocytes in peripheral blood that express integrins α4ß7 preferentially recirculate through gut-associated lymphoid tissue (GALT), a proposed site of significant HIV-1 replication. Tregs and activated CD4+ T cells in GALT could also be particularly susceptible to infection. We therefore hypothesized that infection of these subsets of memory CD4+ T cells may contribute disproportionately to the HIV-1 reservoir. A cross-sectional study of CD4+ T cell subsets of memory CD45RO+ cells in peripheral blood mononuclear cells (PBMCs) was conducted using leukapheresis from eight subjects with untreated chronic HIV-1 infection. Real-time polymerase chain reaction (PCR) was used to quantify total and integrated HIV-1 DNA levels from memory CD4+ T cells sorted into integrin β7+ vs. β7−, CD25+CD127low Treg vs. CD127high, and activated CD38+ vs. CD38−. More than 80% of total HIV-1 DNA was found to reside in the integrin β7-negative non-gut-homing subset of CD45RO+ memory CD4+ T cells. Less than 10% was found in highly purified Tregs or CD38+ activated memory cells. Similarly, integrated HIV-1 DNA copies were found to be more abundant in resting non-gut-homing memory CD4+ T cells (76%) than in their activated counterparts (23%). Our investigations showed that the majority of both total and integrated HIV-1 DNA was found within non-gut-homing resting CD4+ T cells.
doi:10.1089/aid.2012.0351
PMCID: PMC3785810  PMID: 23971972
43.  Graft-Versus-Tumor Effect After Allogeneic Stem Cell Transplantation in HIV-Positive Patients With High-Risk Hematologic Malignancies 
AIDS Research and Human Retroviruses  2013;29(10):1340-1345.
Abstract
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a well-established therapeutic option for hematological malignancies. Combination antiretroviral therapy (cART) has enabled the treatment of medical conditions in patients infected with the human immunodeficiency virus (HIV) in the same way as in the general population. Moreover, improvements in supportive care have allowed HIV-infected patients with life-threatening hematological disorders to be treated with Allo-HSCT. We report on four HIV-infected patients with hematological malignancies receiving an Allo-HSCT in our institution, and on the use of donor lymphocyte infusions to successfully treat post-Allo-HSCT relapse. Of note, one of them is the first HIV+ patient to receive a “dual transplant” (unrelated umbilical cord blood stem cells combined with mobilized T cell-depleted CD34+ stem cells from a mismatched third party donor). cART drugs interactions were satisfactorily managed. This approach provided long-term control of the hematological disease. Nevertheless, despite adequate immune reconstitution, infections were the main cause of morbidity and mortality after Allo-HSCT.
doi:10.1089/aid.2013.0001
PMCID: PMC3785811  PMID: 23800257
44.  Using Antiubiquitin Antibodies to Probe the Ubiquitination State Within rhTRIM5α Cytoplasmic Bodies 
AIDS Research and Human Retroviruses  2013;29(10):1373-1385.
Abstract
The first line of defense protecting rhesus macaques from HIV-1 is the restriction factor rhTRIM5α, which recognizes the capsid core of the virus early after entry and normally blocks infection prior to reverse transcription. Cytoplasmic bodies containing rhTRIM5α have been implicated in the ubiquitin–proteasome pathway, but the specific roles these structures play remain uncharacterized. Here, we examine the ubiquitination status of cytoplasmic body proteins. Using antibodies specific for different forms of ubiquitin, we show that ubiquitinated proteins are present in cytoplasmic bodies, and that this localization is altered after proteasome inhibition. A decrease in polyubiquitinated proteins localizing to cytoplasmic bodies was apparent after 1 h of proteasome inhibition, and greater differences were seen after extended proteasome inhibition. The decrease in polyubiquitin conjugates within cytoplasmic bodies was also observed when deubiquitinating enzymes were inhibited, suggesting that the removal of ubiquitin moieties from polyubiquitinated cytoplasmic body proteins after extended proteasome inhibition is not responsible for this phenomenon. Superresolution structured illumination microscopy revealed finer details of rhTRIM5α cytoplasmic bodies and the polyubiquitin conjugates that localize to these structures. Finally, linkage-specific polyubiquitin antibodies revealed that K48-linked ubiquitin chains localize to rhTRIM5α cytoplasmic bodies, implicating these structures in proteasomal degradation. Differential staining of cytoplasmic bodies seen with different polyubiquitin antibodies suggests that structural changes occur during proteasome inhibition that alter epitope availability. Taken together, it is likely that rhTRIM5α cytoplasmic bodies are involved in recruiting components of the ubiquitin–proteasome system to coordinate proteasomal destruction of a viral or cellular protein(s) during restriction of HIV-1.
doi:10.1089/aid.2013.0029
PMCID: PMC3785812  PMID: 23799296
45.  Coreceptor Usage, Diversity, and Divergence in Drug-Naive and Drug-Exposed Individuals from Malawi, Infected with HIV-1 Subtype C for More Than 20 Years 
Abstract
There are few cohorts of individuals who have survived infection with HIV-1 for more than 20 years, reported and followed in the literature, and even fewer from Africa. Here we present data on a cohort of subtype C-infected individuals from rural northern Malawi. By sequencing multiple clones from long-term survivors at different time points, and using multiple genotyping approaches, we show that 5 of the 11 individuals are predicted as CXCR4 using (by ≥3/5 predictors) but only one individual is predicted as CXCR4 using by all five algorithms. Using any one genotyping approach overestimates the number of predicted CXCR4 sequences. Patterns of diversity and divergence were variable between the HIV-1 long-term survivors with some individuals showing very small amounts of variation and change, and others showing a greater amount; both patterns are consistent with what has been described in the literature.
doi:10.1089/aid.2013.0240
PMCID: PMC4180525  PMID: 24925099
46.  Short Communication: Interferon/Ribavirin Treatment for HCV Is Associated with the Development of Hypophosphatemia in HIV/Hepatitis C Virus-Coinfected Patients 
AIDS Research and Human Retroviruses  2013;29(9):1190-1194.
Abstract
One-third of all HIV-infected individuals in the United States are estimated to be coinfected with the hepatitis C virus (HCV). Treatment of chronic hepatitis C in patients coinfected with HIV is a complex problem associated with toxicities and drug interactions between HIV antiretrovirals and interferon and ribavirin. In recent HCV treatment studies, we observed a previously unreported development of hypophosphatemia in HIV/HCV-coinfected patients treated with interferon/ribavirin (IFN/RBV). To further investigate this observation, we retrospectively reviewed 61 HIV/HCV-coinfected patients on antiretrovirals (ARVs) during treatment with IFN/RBV as well as 154 HIV-infected patients treated with ARVs alone. We found that HIV/HCV-coinfected patients on IFN/RBV therapy were more likely to develop frequent (57% vs. 13%, IFN/RBV-treated patients vs. no IFN/RBV; χ2=0.001) and higher-grade hypophosphatemia (67.0% Grade 2, 33.3% Grade 3 vs. 94.7% Grade 2, 5.3% Grade 3, IFN/RBV-treated patients vs. no IFN/RBV; χ2<0.001) than untreated patients. In addition, we found that the new onset of hypophosphatemia after IFN/RBV treatment initiation was followed by a diminished frequency of this toxicity upon cessation of IFN/RBV, supporting the idea that a drug–drug interaction may increase the risk of this toxicity. To understand the risks of developing this toxicity, we evaluated the association between individual ARV use and hypophosphatemia incidence. Our data suggest that concomitant tenofovir (TDF) use may be a risk factor for the development of hypophosphatemia in HIV/HCV-coinfected patients treated with IFN/RBV. Although the etiology of this abnormality is likely multifactorial, clinicians should be aware of hypophosphatemia as a potential marker of renal toxicity in HIV/HCV-coinfected patients being treated with IFN/RBV regimens.
doi:10.1089/aid.2013.0035
PMCID: PMC3749689  PMID: 23701022
47.  Short Communication: High Prevalence of Vitamin D Deficiency in HIV-Infected and HIV-Uninfected Pregnant Women 
AIDS Research and Human Retroviruses  2013;29(9):1224-1228.
Abstract
Vitamin D deficiency is common in HIV-infected populations. In resource-limited settings, vitamin D deficiency has been shown to affect HIV disease progression and mortality in pregnant women, and also increases mother-to-child HIV transmission and mortality in their infants. This study sought to investigate vitamin D status in HIV-infected women compared to healthy controls in a high-income country setting and determine variables associated with vitamin D deficiency. We prospectively enrolled 40 women/infant pairs (16 HIV-infected women/HIV-exposed infant pairs and 24 uninfected/unexposed pairs). In serum cord blood, 25-hydroxyvitamin D [25(OH)D] concentrations were suboptimal (<30 ng/ml) in 100% of subjects from both groups. White race, non-Hispanic ethnicity was the only variable associated with higher serum 25(OH)D concentrations. This high prevalence of vitamin D deficiency, especially among HIV-infected women and their infants, deserves further investigation, as it may have a negative impact on maternal and infant health.
doi:10.1089/aid.2012.0384
PMCID: PMC3749690  PMID: 23675655
48.  Association of the Veterans Aging Cohort Study Index with Exercise Capacity in HIV-Infected Adults 
AIDS Research and Human Retroviruses  2013;29(9):1218-1223.
Abstract
Physical disability is a major priority in aging, affecting morbidity, mortality, and quality of life. Despite the large number of adults aging with HIV, our understanding of the physiologic and clinical risk factors for disability is limited. Our goal is to determine whether the Veterans Aging Cohort Study (VACS) Index, based on routine clinical blood tests, could serve as a point of care screening tool to identify HIV-infected adults at high risk for physical disability. HIV-infected adults enrolled in the VACS participated in a cross-sectional exercise study with established measures of strength and endurance. The VACS Index was calculated using recent clinical laboratory values and age; a higher score reflects greater mortality risk. Statistical analyses included correlation and linear regression models adjusted for muscle mass. Fifty-five HIV-infected adults, predominantly African-American men, were included with age mean±SD of 52±7 years. Median (IQR) CD4 cell count was 356 cells/mm3 (212–527). The VACS Index was inversely correlated with quadriceps strength (r=−0.45, p<0.01), grip strength (r=−0.28, p=0.04), and 6-min walk distance (r=−0.27, p=0.05). A 20-point increase in VACS Index score was associated with a 10% lower leg strength (p<0.01), which remained significant after adjustment for muscle cross-sectional area (p=0.02). The VACS Index explained 31% of the variance in specific leg strength. In this group of middle-aged adults with well-controlled HIV infection the VACS Index was significantly associated with upper and lower extremity strength. The VACS Index may be valuable for identification of patients at high risk for disability due to muscle weakness.
doi:10.1089/aid.2012.0388
PMCID: PMC3749694  PMID: 23705911
49.  Molecular Characterization of Unique Intersubtype HIV Type 1 A1/C Recombinant Strain Circulating in Pune, India 
AIDS Research and Human Retroviruses  2013;29(9):1245-1253.
Abstract
An increasing number of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) all over the world has necessitated being vigilant about new recombinants. Since the first report of a recombinant virus with an A1/C mosaic in 1998 more and more B/C and A/C recombinant viruses are being reported from India. Here we report the identification and characterization of a unique HIV-1 A1/C recombinant circulating in Western India. Analysis of the full-length genome using RIP, SimPlot, and jpHMM@Gobics has confirmed its mosaic structure with insertion of subtype A1 in the backbone of subtype C at three positions: gag-pol (1973±15–2617±47), pol-vif (4879±37–5582±32), and gp41 (8437±106–8811±8); however, RIP and SimPlot showed one more small insertion in integrase (4343–4519). Phylogenetic analysis confirmed that the recombinant virus has an insertion of clade A1 in the backbone of subtype C, which has come from Indian subtype C.
doi:10.1089/aid.2013.0150
PMCID: PMC3749696  PMID: 23742670
50.  Knowledge of and Opinions on HIV Preexposure Prophylaxis Among Front-Line Service Providers at Canadian AIDS Service Organizations 
AIDS Research and Human Retroviruses  2013;29(9):1183-1189.
Abstract
Oral daily tenofovir/emtricitabine (Truvada) is approved in the United States for HIV preexposure prophylaxis (PrEP) but has generated controversy in the media and within HIV-affected communities. We conducted an online survey about PrEP-related knowledge, experience, opinions, and learning needs, and received 160 responses from service providers at Canadian AIDS Service Organizations. Respondents were cautiously optimistic about PrEP and 48.8% believed that PrEP warranted Health Canada approval. In multivariable logistic regression, support for PrEP approval was associated with more years working in HIV (odds ratio=1.89 per decade, 95% CI=1.10, 3.25), low baseline familiarity with PrEP (OR=3.24, 95% CI=1.01, 14.41), and knowing someone who had used PrEP (OR=4.39, 95% CI=1.28,15.08). Participants major concerns about PrEP were similar to those highlighted in other publications, and some issues specific to certain target populations were raised. Several participants (26.2%) had been asked about PrEP in the past year and 10.6% knew of one or more Canadian who had used PrEP. Despite clients' interest, most participants thought that they (60.6%) or their organization (63.1%) did not have enough current knowledge about PrEP, highlighting the need for further education on this novel HIV prevention strategy.
doi:10.1089/aid.2013.0090
PMCID: PMC3749697  PMID: 23731254

Results 26-50 (596)