In vivo CD8+ T cell control of immunodeficiency virus infection in humans and macaques

Abstract

Forty million people are estimated to be infected with HIV-1, and only a small fraction of those have access to life-prolonging antiretroviral treatment. As the epidemic grows there is an urgent need for effective therapeutic and prophylactic vaccines. Nonhuman primate models of immunodeficiency virus infection are essential for the preclinical evaluation of candidate vaccines. To interpret the results of these trials, comparative studies of the human and macaque immune responses are needed. Despite the widespread use of macaques to evaluate vaccines designed to elicit a CD8(+) cytotoxic T lymphocyte (CTL) response, the efficiency with which CTL control immunodeficiency virus infections has not been compared between humans and macaques, largely because of difficulties in assaying the functional CTL response. We recently developed a method for estimating the rate at which CTLs kill cells productively infected with HIV-1 in humans in vivo. Here, using the same technique, we quantify the rate at which CTLs kill infected cells in macaque models of HIV infection. We show that CTLs kill productively infected cells significantly faster (P = 0.004) and that escape variants have significantly higher fitness costs (P = 0.003) in macaques compared with humans. These results suggest that it may be easier to elicit a protective CTL response in macaques than in humans and that vaccine studies conducted in macaques need to be interpreted accordingly.

Fig. 1.

Estimating lower bounds on the rate of escape. If CTL escape is too rapid to be fully captured by the frequency of observations (i.e., there are less than two points when the fraction of sequences bearing the escape variant is not 0% or 100%) then the escape rate calculated (solid line) will be a lower bound on the escape rate. The true escape rate could be considerably faster (dashed line) but not slower. ■, experimental data points; solid line, slowest escape consistent with the data (gives estimated lower bound on the rate of escape); dashed line, faster escape, also consistent with the experimental data.

Fig. 2.

Rate of escape from natural CTL responses in humans and macaques. The rate of escape from a single, natural CTL response is plotted as a function of the mean time interval between observations. Data from humans are shown in black, and data from macaques are in gray. Estimates that are lower bounds are denoted by open symbols. The x axis is cropped at 350 days. ■, rate of escape in humans; □, lower bound on the rate of escape in humans; gray circle, rate of escape in macaques; ○, lower bound on the rate of escape in macaques. The rate of escape was significantly faster in macaques than in humans (P = 0.004; Fisher's χ² two-tailed test) despite the fact that the majority of estimates in macaques were only lower bounds. The lines are predicted values from an analysis of covariance with log-transformed escape rates as the dependent variable and time interval and species as the two independent variables (solid line, humans; dashed line, macaques).

Fig. 3.

Rate of reversion in humans and macaques. The fitness cost of a CTL escape variant is equal to the rate of reversion of the variant to the WT on transmission to a host who does not possess the MHC class I allele to bind the WT epitope. The rate of reversion was significantly faster in macaques (P = 0.003; Wilcoxon–Mann–Whitney two-tailed, exact); the difference was still significant even if the four fastest rates of reversion observed in macaques (which seem to form a separate group of outliers) were excluded (P = 0.048; Wilcoxon–Mann–Whitney two-tailed, exact). ■, rate of reversion in humans; □, lower bound on the rate of reversion in humans; gray circle, rate of reversion in macaques; ○, lower bound on the rate of reversion in macaques.