Vaccine-induced gag-specific T cells are associated with reduced viremia after HIV-1 infection

Abstract

The contribution of host T-cell immunity and HLA class I alleles to the control of human immunodeficiency virus (HIV-1) replication in natural infection is widely recognized. We assessed whether vaccine-induced T-cell immunity, or expression of certain HLA alleles, impacted HIV-1 control after infection in the Step MRKAd5/HIV-1 gag/pol/nef study. Vaccine-induced T cells were associated with reduced plasma viremia, with subjects targeting ≥3 gag peptides presenting with half-log lower mean viral loads than subjects without Gag responses. This effect was stronger in participants infected proximal to vaccination and was independent of our observed association of HLA-B*27, -B*57 and -B*58:01 alleles with lower HIV-1 viremia. These findings support the ability of vaccine-induced T-cell responses to influence postinfection outcome and provide a rationale for the generation of T-cell responses by vaccination to reduce viremia if protection from acquisition is not achieved. Clinical trials identifier: NCT00095576.

Keywords: Gag-specific T cells; HIV-1 vaccine; HLA class I alleles; Step study.

Figures

Figure 1.

Pre–antiretroviral therapy log10 HIV-1 RNA copies/ml over time for vaccine and placebo recipients in each HLA group among 154 HIV-1-infected participants. Lines represent estimated means at each week postinfection, based on a weighted generalized estimating equations model that adjusts for baseline participant characteristics and time since HIV-1 infection. There was some indication of a stronger HLA effect in vaccine (red symbols) versus placebo recipients (blue symbols), but this difference was not statistically significant (P = .15). Among placebo recipients, the mean viral load was 0.57 logs lower (95% confidence interval [CI], .19–.95 logs lower) among those with protective HLA alleles and 0.035 logs higher (95% CI, .35 logs lower to .42 logs higher) among those with unfavorable HLA alleles, compared with those with neutral HLA alleles. In the vaccine arm, the mean viral load was 1.00 log lower (95% CI, .55–1.46 logs lower) among those with protective HLA alleles and 0.29 logs higher (95% CI, .02 logs lower to .60 logs higher) among those with unfavorable HLA alleles, compared to those with neutral HLA alleles.

Figure 2.

Number of insert-specific T-cell responses by Ad5 titer stratum. Each bar represents one of 72 participants. Responses were measured pre-infection. Panels show responses by baseline adenovirus 5 (Ad5) neutralizing antibody (nAb) titer: ≤18: n = 31; 19–200: n = 13; 201–1000: n = 18; and >1000: n = 11. The height of each bar represents the number of targeted 15-mer peptides for Gag, Nef, and Pol. Participants with no response to single 15-mers are represented with open grey bars.

Figure 3.

Rate and magnitude of the HIV-1–specific CD8+ T-cell response over time among 74 vaccine recipients who remained HIV-1 uninfected. HIV-1-specific CD8+ T-cell responses were measured by intracellular cytokine staining using Gag, Nef, and Pol peptide pools. A, Response rates were determined for each protein pool separately (Gag: red; Nef: blue; Pol: green), as well as for any pool (black) using established positivity criteria. Response rates and 95% confidence intervals are shown. B, The total magnitude of response across peptide pools for positive (red symbols) and negative (blue symbols) CD8+ T-cell responders. Box plots show medians and interquartile ranges for positive responders; whiskers extend from the upper and lower quartiles to the furthest point within 1.5 times the interquartile range.

Figure 4.

Pre–antiretroviral therapy log10 viral loads over time among HIV-1–infected vaccine recipients, by breadth of the vaccine-induced Gag response (0 vs 1–2 vs ≥3 reactive 15-mers). Lines represent estimated means at each week postinfection, based on a weighted generalized estimating equations model that adjusts for time since HIV-1 infection and HLA group. Estimates are shown based on the 72 vaccine recipients with breadth data (blue) and the subset of 36 vaccine recipients who were infected within 1 year of the last vaccination (red).