Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys

Abstract

Vaccine-induced cellular immunity controls virus replication in simian immunodeficiency virus (SIV)-infected monkeys only transiently, leading to the question of whether such vaccines for AIDS will be effective. We immunized monkeys with plasmid DNA and replication-defective adenoviral vectors encoding SIV proteins and then challenged them with pathogenic SIV. Although these monkeys demonstrated a reduction in viremia restricted to the early phase of SIV infection, they showed a prolonged survival. This survival was associated with preserved central memory CD4+ T lymphocytes and could be predicted by the magnitude of the vaccine-induced cellular immune response. These immune correlates of vaccine efficacy should guide the evaluation of AIDS vaccines in humans.

Fig. 1

Peak cellular immune responses elicited by vaccination. Groups of monkeys were immunized at weeks 0, 4, and 8 with plasmid DNA expressing the indicated gene products and at week 40 with recombinant adenoviruses carrying the same genes. Two weeks later, cellular immune responses were assessed in peripheral blood mononuclear cells (PBMC) by IFN-γ Elispot assay. Data are expressed as spot-forming cells (SFC) per 10⁶ PBMC.

Fig. 2

Plasma viral RNA levels after SIVmac251 challenge. The monkeys were challenged by intravenous route with pathogenic SIVmac251, and plasma viral RNA levels were assessed prospectively. (A) Plasma viral RNA data are shown for each individual monkey, with the data from the control monkeys shown in red. (B)Data were assessed at each time point by the Wilcoxon rank sum test to determine whether vaccinated monkeys differed from the group of control monkeys in their plasma viral RNA levels. The P value for that comparison is shown for each data set, and the horizontal line indicates a P value of approximately 0.05.

Fig. 3

Differences between control and experimentally vaccinated monkeys in survival and plasma viral RNA levels after challenge. (A) Kaplan-Meier survival curves for the control and experimentally vaccinated monkeys after SIVmac251 challenge. The comparison of survival in these groups of monkeys has been done using a log-rank test (16). (B) Comparison of area under the curve calculations for the plasma viral RNA levels in the control and experimentally vaccinated monkeys between days 3 and 126 after challenge. The comparison was analyzed using the Wilcoxon rank sum test.

Fig. 4

Survival is associated with the preservation of peripheral blood central memory CD4⁺ T lymphocytes and vaccine-elicited cellular immune responses. (A) Plasma viral RNA levels and (B) percent of naïve (CD28⁺CD95⁻) CD4⁺ T cells, (C) effector memory (CD28⁻CD95⁺) CD4⁺ T cells, and (D) central memory (CD28⁺CD95⁺) CD4⁺ T cells were compared in the experimentally vaccinated and control monkeys on day 126 after challenge using the Wilcoxon rank sum test (16) (fig. S1). For panels (B) to (D), the percentage values are based on a denominator of total CD4⁺ T cells. Kaplan-Meier survival curves for all monkeys after challenge divided into thirds based on (E) absolute number of peripheral blood CD4⁺ T lymphocytes or (F) central memory CD4⁺ T lymphocytes. The 16 monkeys that received a Gag immunogen were divided into halves based on magnitude of vaccine-elicited peak (G) total Gag-specific IFN-γ Elispot responses or (H) CD4⁺ T lymphocyte Gag-stimulated intracellular IFN-γ expression. The comparisons of survival in these groups of monkeys were done using a log-rank test.