Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02

Abstract

Background: HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA-presented HIV-1 epitopes that are recognized by CD8(+) T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent.

Methods: Viral loads, CD4(+) T-cell counts, and enzyme-linked immunospot assay-determined anti-HIV-1 CD8(+) T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed.

Results: Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4(+) T-cell count of <350 cells/mm(3) (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/10(6) peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients.

Conclusions: In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4(+) T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition.

Clinical trials registration: NCT00413725, DOH-27-0207-1539.

Keywords: Gag-specific CD8+ T cells; HIV-1 vaccine; HLA class I; Phambili trial.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.

Longitudinal viremia levels, CD4+ T-cell counts, and CD8+ T-cell responses in the 60 infected vaccinees and placebo recipients, irrespective of HLA. A, Chronic viral set point (defined for each individual as the median of all measurements from >3 months after diagnosis). Each patient's set point is shown as a circle (vaccine recipients) or triangle (placebo recipients), and horizontal lines and numbers denote median values. Statistical analysis was performed by the Mann–Whitney U test. B, Examination of the effect of vaccination on longitudinal viremia levels before antiretroviral therapy initiation. The slopes (thick lines) generated from a linear mixed-effects model are plotted on top of data points and viral load trajectories for individual patients (thin lines). Statistical analysis was performed by analysis of variance. C, Kaplan–Meier curves showing time to reach a CD4+ T-cell count of <350 cells/mm3 in vaccinees and placebo recipients. Statistical analysis was performed by the log-rank test. D, Breadth and magnitude of CD8+ T-cell responses at the second time point in vaccinees and placebo recipients. In Tukey box plots, horizontal lines indicate median values, boxes show interquartile ranges, and whiskers show minimum and maximum values. Statistical analysis was performed by the Mann–Whitney U test. The column termed “Total” shows the combined values of responses to all proteins; the column termed “Other” includes responses to Env, Rev, Tat, Vpu, Vif, and Vpr. Abbreviations: IFN-γ, interferon γ; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cells.

Figure 2.

Chronic viral set point and CD4+ T-cell counts in infected Phambili subjects expressing protective HLA-B*57/58:01/81:01 or disease-susceptible HLA-B*58:02 alleles. A–C, Data for the participants expressing protective alleles (12 vaccinees and 3 placebo recipients). D–F, Data for the participants expressing HLA-B*58:02 (7 vaccinees and 7 placebo recipients). A and C, Chronic viral set point (defined for each individual as the median of all measurements from >3 months after diagnosis) is shown at left. Each patient's set point is shown as circles (vaccine recipients) or triangles (placebo recipients). Horizontal lines and numbers denote median values for vaccine and placebo groups. Statistical analysis was performed by the Mann–Whitney U test. Examination of the effect of vaccination on longitudinal viral load values before antiretroviral therapy initiation is shown at right. The slopes (thick lines) generated from a linear mixed-effects model are plotted on top of data points and viral load trajectories (thin lines) for individual patients. Statistical analysis was performed by analysis of variance. B and D, Kaplan–Meier curves showing time to reach a CD4+ T-cell count of <350 cells/mm3 in vaccinees and placebo recipients. Statistical analysis was performed by the log-rank test.

Figure 3.

Chronic viral set point and CD4+ T-cell counts in the infected Phambili subjects expressing neither protective nor disease-susceptible HLA alleles. A and B, Data for the participants expressing neither protective nor disease-susceptible alleles overall (18 vaccinees and 13 placebo recipients). C and D, Example of a subset of the subjects from panels A and B who express HLA-B*44:03 and for whom there were sufficient subject numbers to compare vaccine (n = 6) and placebo (n = 6) groups. A and C, Chronic viral set point (defined for each individual as the median of all measurements from >3 months after diagnosis) is shown at left. Each patient's set point is shown as a circle (vaccine recipients) or triangle (placebo recipients), and horizontal lines and numbers denote median values for vaccine and placebo groups. Statistical analysis was performed by the Mann–Whitney U test. Examination of the effect of vaccination on longitudinal viral load values before antiretroviral therapy initiation is shown at right. The slopes (thick lines) generated from a linear mixed-effects model are plotted on top of the data points and viral load trajectories (thin lines) for individual patients. Statistical analysis was performed by analysis of variance. B and D, Kaplan–Meier curves showing the time to reach a CD4+ T-cell count of <350 cells/mm3 in vaccinees and placebo recipients. Statistical analysis was performed by the log-rank test. Abbreviation: NS, not significant.

Figure 4.

CD8+ T-cell responses in the infected Phambili subjects expressing disease-susceptible HLA-B*58:02 or those expressing neither protective nor disease-susceptible alleles or those expressing protective HLA alleles. A, Breadth and magnitude of CD8+ T-cell responses at the second time point in HLA-B*58:02–positive vaccinees, placebo recipients, and C clade chronically infected unvaccinated B*58:02-positive individuals. B, Breadth and magnitude of CD8+ T-cell responses at the second time point in vaccinees and placebo recipients expressing neither protective nor disease-susceptible HLA-B alleles. C, Breadth and magnitude of CD8+ T-cell responses at the second time point in vaccinees and placebo recipients expressing protective HLA-B alleles. In Tukey box plots, horizontal lines indicate median values, boxes show interquartile ranges, and whiskers show minimum and maximum values. Statistical analysis was performed by the Kruskal–Wallis and Mann–Whitney U tests. The column termed “Total” shows the combined values of responses to all proteins; the column termed “Other” includes responses to Env, Rev, Tat, Vpu, Vif, and Vpr. Abbreviations: IFN-γ, interferon γ; NS, not significant; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cells.

Figure 5.

HLA-dependent differential immunodominance hierarchy of CD8+ T-cell responses in chronically C clade–infected, antiretroviral-naive, South African adults. CD8+ T-cell immunodominance hierarchy in subjects in the 3 HLA groups (allele frequency ≥5%), expressing protective HLA, neither protective nor disease-susceptible HLA, and disease-susceptible HLA. Targeting frequency denotes the percentage of subjects making detectable responses in interferon γ enzyme-linked immunospot assays to the named human immunodeficiency virus type 1 peptide. Numbers on the x-axis refer to the particular overlapping peptide (of 410 spanning the C clade proteome) to which a response was detected. The x in each column denotes the median viral load of responders to that peptide.