Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study

Abstract

Objectives: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics.

Design: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine.

Methods: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4(+)/CD8(+) activity was assessed by an intracellular cytokine staining assay.

Results: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4(+) interferon-γ producing cells (CA-RNA: r = -0.23, P = 0.03 and CA-DNA: r = -0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4(+) activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4(+) and CD8(+) interferon-γ producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4(+) cells/10(6) lymphocytes, P = 0.03 and 1326 versus 669 CD8(+) cells/10 lymphocytes, P = 0.04). Pre-ATI CA-RNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01).

Conclusion: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics.

Clinical trials registration: NCT00080106.

Figures

Figure 1. Association between HIV-specific CD4+ activity and HIV reservoir levels at baseline

(A) CA-RNA and (B) CA-DNA at baseline are associated with the number of HIV-specific CD4+ IFN-γ-producing cells. CA-RNA, cell-associated HIV RNA; CA-DNA, cell-associated HIV DNA.

Figure 2. Therapeutic HIV vaccination was not associated with changes in CA-RNA or CA-DNA levels

(A) CA-RNA and (B) CA-DNA levels in participants of A5197 pre- (wk 0) and post-vaccination (wk 8 and 38). Bars represent median values. CA-RNA, cell-associated HIV RNA; CA-DNA, cell-associated HIV DNA.

Figure 3. Baseline HIV reservoir levels differ by HLA group

(A) Residual viremia by single-copy assay, (B) CA-RNA, and (C) CA-DNA levels in PBMC in participants of A5197 stratified by the presence of unfavorable, neutral, or protective HLA alleles. SCA, single-copy assay; CA-RNA, cell-associated HIV RNA; CA-DNA, cell-associated HIV DNA; HLA, human leukocyte antigen; PBMC, peripheral blood mononuclear cell.

Figure 4. Pre-ATI CA-RNA and CA-DNA predict viral load set point

Pre-ATI week 38 (A) CA-RNA and (B) CA-DNA levels were both significantly correlated with post-ATI viral load set point. ATI, analytic treatment interruption; CA-RNA, cell-associated HIV RNA; CA-DNA, cell-associated HIV DNA.