AIDSVAX immunization induces HIV-specific CD8+ T-cell responses in high-risk, HIV-negative volunteers who subsequently acquire HIV infection

Abstract

Correlates of immune protection from HIV vaccines remain undefined. The first HIV vaccine efficacy trial in the US and Europe VAX004, was designed to assess whether rgp120 envelope subunits (AIDSVAX B/B, VaxGen) can induce partial or complete protection from HIV-1 infection. No effectiveness in the reduction of either the acquisition of infection or levels of plasma viremia after HIV infection was noted. We found evidence of vaccine-specific CD8+ T cells in volunteers who received the vaccine, regardless of behavioral risk. Surprisingly, the CD8-response is significantly higher in participants who would go on to contract HIV infection. These results suggest that AIDSVAX immunization may boost preexisting immune responses-due to pre-infection exposure, and a vaccine-induced immune profile may serve as a biological marker for HIV susceptibility.

Figure 1

Representative Plot of env-specific CD8 proliferation. CFSE-labeled PBMC were stimulated with ENV peptides for 5 days then assessed for proliferation by flow cytometry. Results are expressed as percent of proliferating CD8+ T-cells as measured by the extent of CFSE dilution. Positive proliferation is defined as >0.1% net and at least twice background.

Figure 2

CMV-specific CD4+ and CD8+ proliferation in VAX004 samples. CFSE- labeled PBMC were stimulated with HCMV peptides then assessed for proliferation after 5 days. No significant difference between the frequency of responses in CD4− and CD8− mediated proliferation was seen between placebo and vaccine recipients (p>0.05)

Figure 3

Representative plots of antigen-specific CD8+ T cells in a vaccine responder. PBMC were stimulated with Env or CMV peptides then stained with anti-CD107a PE, anti-IFN-γ FITC, anti-TNF-α PE-CY7, anti-CD4 PerCP-Cy5.5 anti-IL-2 APC, anti-CD3 AmCyan and anti-CD8 APC-Cy7, and analyzed by flow cytometry. Samples were first gated on the CD3+/CD8+ lymphocyte population then the percent of CD107, TNF-α, IFN-γ, and IL-2 positive CD8+ T cells were determined.

Figure 4

Immune activation in CD4+ and CD8+ lymphocyte subsets in vaccine responders based on subsequent HIV infection status. PBMC were stained with HLADR FITC, CD38 PE, CD3 AmCyan, CD4 APC-CY7, and CD8 PerCP-Cy5.5, and analyzed by flow cytometry. Immune activation was defined as the percentage of CD4+ or CD8+T cells co-expressing HLA DR and CD38. CD8+ immune activation was significantly higher (p=0.014) in vaccine responders who subsequently acquire HIV infection (Infected) compared to vaccine responders who remain HIV negative (Uninfected).