In vivoCD8⁺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.human immunodeficiency virus ͉ simian immunodeficiency virus ͉ cytotoxic T lymphocyte ͉ vaccine ͉ viral escape S imian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection of nonhuman primates, notably rhesus macaques (Macaca mulatta) and pigtail macaques (Macaca nemestrina), reproduce many of the key elements of HIV infection of humans, including CD4 ϩ cell depletion and an AIDS-like syndrome. Importantly, for appraising vaccine efficacy, macaques and humans have similar immune systems (1). However, it has been difficult to compare immune control of immunodeficiency viruses in humans and macaques. A number of commonly used SHIV strains (SHIV-89.6P, SHIV-DH12R, and SHIV-KU) are more susceptible to antibody neutralization than HIV-1, and it has therefore been suggested that they are poor systems for testing vaccines designed to elicit an antibody response (2). The efficiency with which CD8 ϩ cytotoxic T lymphocytes (CTLs) control immunodeficiency virus infections has not been compared between humans and macaques, largely because of difficulties in assaying the functional CTL response (3). A method for quantifying CTL lytic function in vivo (4, 5) now makes this comparison possible. ResultsThe rate at which a CTL escape variant grows out and replaces the wild-type (WT) strain, ''the rate of escape,'' is determined by the balance between the rate of CTL killing evaded by the escape variant and the fitness cost of the variant (see Methods). By quantifying the rate of escape and the fitness cost of known CTL escape variants the rate of killing of prod...

Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8+T Cells from the Dynamics of Viral Immune Escape

“…There are several previous studies that have estimated the killing rate of virus-infected cells for HIV-or SIV-specific CD8 ϩ T cells (4,5,15,45,52). While our estimates of the killing rate at peak CTL levels are very similar to other estimates of the killing rate made early during the acute infection phase (15,45), they are much higher (ϳ5-to 100-fold) than those estimated from later in the infection (4,52).…”

HLA-Associated Clinical Progression Correlates with Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection

“…The role of other forms of host immunity (e.g., neutralizing antibodies, natural killer cells, and macrophages) has, to some extent, been pursued with less intensity in light of persuasive evidence that CTLs can control retrovirus infection (46). The extent to which the simian model mirrors HIV infection has been questioned (5) and, despite exhaustive cellular assays of T-cell functionfrom gamma interferon enzyme-linked immunospot assays (1,27,38) to polyfunctional cytokine matrices (2, 6)-no CTL function correlates robustly with HIV plasma viral load or viral dynamics. Moreover, analyses of evolutionary data suggest that CTLs are inefficient at killing HIV-infected cells (4).…”

Novel vaccines and adjuvant systems: The utility of animal models for predicting immunogenicity in humans

“…23 The pathological differences between SIV in non-human primates and HIV in humans have long been known, but it has been shown more recently that it is easier to induce a protective CTL response in monkeys than humans; these factors together make it very difficult to extrapolate results from testing vaccines in monkeys to humans. 24 Similarly, several small and large animal models have been developed for visceral leishmaniases, but none closely mimic what happens in humans, 25 making it difficult to assess vaccine efficacy.…”