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1.  Antiretroviral Therapy Initiated Within 6 Months of HIV Infection Is Associated With Lower T-Cell Activation and Smaller HIV Reservoir Size 
The Journal of Infectious Diseases  2013;208(8):1202-1211.
Background. CD4+/CD8+ T-cell activation levels often remain elevated in chronic human immunodeficiency virus (HIV) infection despite initiation of antiretroviral therapy (ART). T-cell activation predicts early death and blunted CD4+ T-cell recovery during ART and may affect persistent HIV reservoir size. We investigated whether very early ART initiation is associated with lower on-therapy immune activation and HIV persistence.
Methods. From a cohort of patients with early HIV infection (<6 months duration since infection) we identified persons who started ART early (<6 months after infection) or later (≥2 years after infection) and maintained ≥2 years of virologic suppression; at-risk HIV-negative persons were controls. We measured CD4+/CD8+ T-cell activation (percent CD38+/HLA-DR+) and HIV reservoir size (based on HIV DNA and cell-associated RNA levels).
Results. In unadjusted analyses, early ART predicted lower on-therapy CD8+ T-cell activation (n = 34; mean, 22.1%) than achieved with later ART (n = 32; mean, 28.8%; P = .009), although levels in early ART remained elevated relative to HIV-negative controls (P = .02). Early ART also predicted lower CD4+ T-cell activation than with later ART (5.3% vs 7.5%; P = .06). Early ART predicted 4.8-fold lower DNA levels than achieved with later ART (P = .005), and lower cell-associated RNA levels (difference in signal-to-cutoff ratio (S/Co), 3.2; P = .035).
Conclusions. ART initiation <6 months after infection is associated with lower levels of T-cell activation and smaller HIV DNA and RNA reservoir size during long-term therapy.
PMCID: PMC3778965  PMID: 23852127
HIV antiretroviral therapy; early ART; T-cell activation; inflammation; HIVreservoir; HIV eradication; HIV cure
2.  Baseline CD4+ T Cell Counts Correlates with HIV-1 Synonymous Rate in HLA-B*5701 Subjects with Different Risk of Disease Progression 
PLoS Computational Biology  2014;10(9):e1003830.
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral sequences from high-risk progressors (HRPs) and low-risk progressors (LRPs). Posterior distributions of HIV-1 genealogies assuming a Bayesian relaxed molecular clock were used to estimate the absolute rates of nonsynonymous and synonymous substitutions for different set of branches. Rates of viral evolution, as well as in vitro viral replication capacity assessed using a novel phenotypic assay, were correlated with various clinical parameters. HIV-1 synonymous substitution rates were significantly lower in LRPs than HRPs, especially for sets of internal branches. The viral population infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, nor could be explained by differences among subjects in T cell activation or selection pressure. Interestingly, a significant inverse correlation was found between baseline CD4+ T cell counts and mean HIV-1 synonymous rate (which is proportional to the viral replication rate) along branches representing viral lineages successfully propagating through time up to the last sampled time point. The observed lower replication rate in HLA-B*5701 subjects with higher baseline CD4+ T cell counts provides a potential model to explain differences in risk of disease progression among individuals carrying this allele.
Author Summary
The clinical course of HIV-1 infection is characterized by considerable variability in the rate of progression to acquired immunodeficiency syndrome (AIDS) among patients with different genetic background. The human leukocyte antigen (HLA) B*5701 is the host factor most strongly associated with slow HIV-1 disease progression. However, the risk of progression to AIDS also varies among patients carrying this specific allele. To gain a better understanding of the interplay between HIV-1 evolutionary rate variation and risk of disease progression, we followed untreated HLA-B*5701 subjects from early infection up to the onset of AIDS. The analysis of longitudinal viral sequences with advanced computational biology techniques based on coalescent Bayesian methods showed a highly significant association between lower synonymous substitution rates and higher baseline CD4+ T cell counts in HLA-B*5701 subjects. The finding provides a potential model to explain differences in risk of disease progression among individuals carrying this allele and might have translational impact on clinical practice, since synonymous rates, which are proportional to in vivo viral replication rates, could be used as a novel evolutionary marker of disease progression.
PMCID: PMC4154639  PMID: 25187947
3.  Targeting of Conserved Gag-Epitopes in Early HIV Infection Is Associated with Lower Plasma Viral Load and Slower CD4+ T Cell Depletion 
We aimed to investigate whether the character of the immunodominant HIV-Gag peptide (variable or conserved) targeted by CD8+ T cells in early HIV infection would influence the quality and quantity of T cell responses, and whether this would affect the rate of disease progression. Treatment-naive HIV-infected study subjects within the OPTIONS cohort at the University of California, San Francisco, were monitored from an estimated 44 days postinfection for up to 6 years. CD8+ T cells responses targeting HLA-matched HIV-Gag-epitopes were identified and characterized by multicolor flow cytometry. The autologous HIV gag sequences were obtained. We demonstrate that patients targeting a conserved HIV-Gag-epitope in early infection maintained their epitope-specific CD8+ T cell response throughout the study period. Patients targeting a variable epitope showed decreased immune responses over time, although there was no limitation of the functional profile, and they were likely to target additional variable epitopes. Maintained immune responses to conserved epitopes were associated with no or limited sequence evolution within the targeted epitope. Patients with immune responses targeting conserved epitopes had a significantly lower median viral load over time compared to patients with responses targeting a variable epitope (0.63 log10 difference). Furthermore, the rate of CD4+ T cell decline was slower for subjects targeting a conserved epitope (0.85% per month) compared to subjects targeting a variable epitope (1.85% per month). Previous studies have shown that targeting of antigens based on specific HLA types is associated with a better disease course. In this study we show that categorizing epitopes based on their variability is associated with clinical outcome.
PMCID: PMC3581067  PMID: 23140171
4.  Combination of Immune and Viral Factors Distinguishes Low-Risk versus High-Risk HIV-1 Disease Progression in HLA-B*5701 Subjects 
Journal of Virology  2012;86(18):9802-9816.
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8+ T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4+ T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8+ T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8+ T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.
PMCID: PMC3446568  PMID: 22761389
5.  Changes in Seroadaptive Practices from before to after Diagnosis of Recent HIV Infection among Men Who Have Sex with Men 
PLoS ONE  2013;8(2):e55397.
We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices.
We collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred.
A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time.
Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.
PMCID: PMC3566177  PMID: 23405145
6.  Recent HIV Type 1 Infection Among Participants in a Same-Day Mobile Testing Pilot Study in Zimbabwe 
We estimated HIV-1 incidence and characterized risk factors associated with recent infection among participants of a mobile HIV voluntary counseling and testing (VCT) pilot program in two communities in Zimbabwe (N = 1096). HIV-1 infection was diagnosed using a parallel rapid testing algorithm. Recent HIV-1 infections were characterized using the BED immunoglobulin G capture enzyme immunoassay (BED-CEIA). HIV prevalence was 28.9% overall and nearly twice as high in women compared to men (39.5% vs. 21.4%, p < 0.001). HIV-1 incidence was 1.91% and was comparable between men and women (1.99% vs.1.88%; p = 0.626). Although not significant, the proportion of recent infections among all infections was highest among persons ages 25 to 34 years old (10.5%) for both men (11.9%) and women (9.2%). Persons recently infected compared to those with long-term infections were more likely to report STD symptoms (33% vs. 13%; OR = 3.2; p = 0.075) and prior STD treatment (13% vs. 6%; OR = 3.4; p = 0.187) in the previous 6 months. There were no associations found between recent versus long-term HIV infection status and perceived risk or expectation of negative test results. Recent HIV-1 infection detection among mobile VCT participants is a valuable measure for tracking the spread of the epidemic among persons who might otherwise not have access to HIV testing due to practical and logistical barriers. Mobile VCT presents opportunities to expand HIV testing services and evaluate at-risk populations within community settings. Given the challenges of longitudinal cohort studies, recent infection may be a practical endpoint for community-based prevention intervention trials employing mobile testing.
PMCID: PMC3101086  PMID: 21087196
7.  Differential Persistence of Transmitted HIV-1 Drug Resistance Mutation Classes 
The Journal of Infectious Diseases  2011;203(8):1174-1181.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain.
Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model.
Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001).
Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study.
PMCID: PMC3107558  PMID: 21451005
8.  Performance of Risk-Based Criteria for Targeting Acute HIV Screening in San Francisco 
PLoS ONE  2011;6(7):e21813.
Federal guidelines now recommend supplemental HIV RNA testing for persons at high risk for acute HIV infection. However, many rapid HIV testing sites do not include HIV RNA or p24 antigen testing due to concerns about cost, the need for results follow-up, and the impact of expanded venipuncture on clinic flow. We developed criteria to identify patients in a municipal STD clinic in San Francisco who are asymptomatic but may still be likely to have acute infection.
Data were from patients tested with serial HIV antibody and HIV RNA tests to identify acute HIV infection. BED-CEIA results were used to classify non-acute cases as recent or longstanding. Demographics and self-reported risk behaviors were collected at time of testing. Multivariate models were developed and preliminarily evaluated using predictors associated with recent infection in bivariate analyses as a proxy for acute HIV infection. Multivariate models demonstrating ≥70% sensitivity for recent infection while testing ≤60% of patients in this development dataset were then validated by determining their performance in identifying acute infections.
From 2004–2007, 137 of 12,622 testers had recent and 36 had acute infections. A model limiting acute HIV screening to MSM plus any one of a series of other predictors resulted in a sensitivity of 83.3% and only 47.6% of patients requiring testing. A single-factor model testing only patients reporting any receptive anal intercourse resulted in 88.9% sensitivity with only 55.2% of patients requiring testing.
In similar high risk HIV testing sites, acute screening using “supplemental” HIV p24 antigen or RNA tests can be rationally targeted to testers who report particular HIV risk behaviors. By improving the efficiency of acute HIV testing, such criteria could facilitate expanded acute case identification.
PMCID: PMC3130783  PMID: 21755003
9.  HIV RNA level in early infection is predicted by viral load in the transmission source 
AIDS (London, England)  2010;24(7):941-945.
HIV-1 viral load in early infection predicts the risk of subsequent disease progression but the factors responsible for the differences between individuals in viral load during this period have not been fully identified. We sought to determine the relationship between HIV-1 RNA levels in the source partner and recently infected recipient partners within transmission pairs.
We recruited donor partners of persons who presented with acute or recent (< 6 months) HIV infection. Transmission was confirmed by phyologenetic comparison of virus sequence in the donor and recipient partners. We compared viral load in the donor partner and the recipient in the first 6 months of HIV infection.
We identified 24 transmission pairs. The median estimated time from infection to evaluation in acutely/recently infected recipient individuals was 72 days. The viral load in the donor was closely associated with viral load at presentation in the recipient case (r=0.55, P=0.006).
The strong correlation between HIV-1 RNA levels within HIV transmission pairs indicates that virus characteristics are an important determinant of viral load in early HIV infection.
PMCID: PMC2887742  PMID: 20168202
HIV-1 RNA; acute HIV-1 infection; HIV-1 transmission; viral load set-point; HIV-1 pathogenesis
10.  Transmitted Drug Resistance in Persons with Acute/Early HIV-1 in San Francisco, 2002-2009 
PLoS ONE  2010;5(12):e15510.
Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10–20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008–2009.
Methodology/Principal Findings
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005–2007 vs. 2008–2009). From 2003–2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008–2009 compared to 2005–2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31–1.38; p = 0.27).
Our study suggests that transmitted drug resistance rose from 2003–2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008–2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
PMCID: PMC3000814  PMID: 21170322

Results 1-10 (10)