Conflicting data on the role of total virus- and protein-specific cytotoxic-T-lymphocyte (CTL) responses in the control of human immunodeficiency virus (HIV) disease progression exist. We present data generated from a Peruvian cohort of untreated, clade B-infected subjects, demonstrating that the proportion of Gag-specific, and in particular p24-reactive, CTL responses among the total virus-specific CTL activity is associated with individuals' CD4 counts and viral loads. Analyses in a second cohort in the United States confirm these findings and point towards a dominant role of Gag-specific immunity in effective control of HIV infection, providing important guidance for HIV vaccine development.

BackgroundThe efficacy of the CTL component of a future HIV-1 vaccine will depend on the induction of responses with the most potent antiviral activity and broad HLA class I restriction. However, current HIV vaccine designs are largely based on viral sequence alignments only, not incorporating experimental data on T cell function and specificity.MethodsHere, 950 untreated HIV-1 clade B or -C infected individuals were tested for responses to sets of 410 overlapping peptides (OLP) spanning the entire HIV-1 proteome. For each OLP, a "protective ratio" (PR) was calculated as the ratio of median viral loads (VL) between OLP non-responders and responders.ResultsFor both clades, there was a negative relationship between the PR and the entropy of the OLP sequence. There was also a significant additive effect of multiple responses to beneficial OLP. Responses to beneficial OLP were of significantly higher functional avidity than responses to non-beneficial OLP. They also had superior in-vitro antiviral activities and, importantly, were at least as predictive of individuals' viral loads than their HLA class I genotypes.ConclusionsThe data thus identify immunogen sequence candidates for HIV and provide an approach for T cell immunogen design applicable to other viral infections.

Background. Herpes simplex virus type 2 (HSV-2) infection is common among human immunodeficiency virus (HIV)-infected persons, and HSV reactivation increases plasma and genital HIV-1 levels. We studied HIV-1 levels during HSV suppression in coinfected persons in a placebo-controlled crossover trial.Methods. Twenty antiretroviral therapy (ART)-naive HIV-1/HSV-2-seropositive men who have sex with men in Lima, Peru, with CD4 cell counts Ͼ200 cells/L were randomized to receive either valacyclovir at 500 mg twice daily or placebo for 8 weeks, after which they underwent a 2-week washout period and then received the alternative regimen for 8 weeks. Specimens included daily anogenital swabs (for HSV DNA polymerase chain reaction [PCR]), thrice weekly rectal mucosal secretions (for HIV-1 RNA and HSV DNA PCR) obtained by anoscopy, and weekly plasma (for HIV-1 RNA PCR). Outcomes were rectal and plasma HIV-1 RNA levels by treatment arm.Results. HIV-1 was detected in 73% of 844 rectal and 99% of 288 plasma specimens. HSV was detected in 29% and 4% of mucocutaneous specimens obtained during placebo and valacyclovir administration, respectively (P Ͻ .001). Valacyclovir resulted in a 0.16 (95% confidence interval [CI], 0.07-0.25; P ϭ .0008; 33% decrease) log 10 copies/mL lower mean within-subject rectal HIV-1 level and a 0.33 (95% CI, 0.23-0.42; P Ͻ .0001; 53% decrease) log 10 copies/mL lower plasma HIV-1 level, compared with values for placebo.Conclusions. Valacyclovir significantly reduces rectal and plasma HIV-1 levels in HIV-1/HSV-2-coinfected men. HSV suppression may provide clinical benefits to persons not receiving highly active ART as well as public health benefits.Trial registration. ClinicalTrials.gov identifier: NCT00378976.

After acute HIV infection, CD8 + T cells are able to control viral replication to a set point. This control is often lost after superinfection, although the mechanism behind this remains unclear. In this study, we illustrate in an HLA-B27 + subject that loss of viral control after HIV superinfection coincides with rapid recombination events within two narrow regions of Gag and Env. Screening for CD8 + T cell responses revealed that each of these recombination sites ( ‫ف‬ 50 aa) encompassed distinct regions containing two immunodominant CD8 epitopes (B27-KK10 in Gag and Cw1-CL9 in Env). Viral escape and the subsequent development of variant-specifi c de novo CD8 + T cell responses against both epitopes were illustrative of the signifi cant immune selection pressures exerted by both responses. Comprehensive analysis of the kinetics of CD8 responses and viral evolution indicated that the recombination events quickly facilitated viral escape from both dominant WT-and variant-specifi c responses. These data suggest that the ability of a superinfecting strain of HIV to overcome preexisting immune control may be related to its ability to rapidly recombine in critical regions under immune selection pressure. These data also support a role for cellular immune pressures in driving the selection of new recombinant forms of HIV.

All tested centralized antigens provided a similarly potent set of antigenic peptides. However, the significantly broader responses detected using the combination of sets highlight the importance of maximizing coverage of HIV-1 sequence diversity in vaccine preparations, as well as in the evaluation of CTL responses in HIV-1-infected individuals and those vaccinated.