Antiviral Inhibitory Capacity of CD8+ T cells Predicts the Rate of CD4+ T-Cell Decline in HIV-1 Infection

CD8+ T-cell–based vaccines against human immunodeficiency virus type 1 (HIV-1) aim to induce responses that abort or limit early viral replication and thus delay disease progression and reduce transmission risk. Recombinant DNA and attenuated viral vector vaccines showed promise because of their capacity to induce high frequencies of interferon γ (IFN-γ)–secreting and/or polyfunctional T cells in healthy volunteers [1, 2]. However, the disappointing results of the Step Study, in which there was no effect of vaccine-induced T-cell responses on viral replication after seroconversion, highlighted the need for a reliable immunological correlate of virus control [3]. CD8+ T-cell depletion experiments in macaques with simian immunodeficiency virus (SIV) infection and vaccine strategies to induce T-cell responses against SIV have demonstrated unequivocally that CD8+ T cells suppress AIDS virus replication, with the most promising results to date being achieved by vaccination with a rhesus cytomegalovirus–vectored vaccine [4–8]. CD8+ T cells are induced early during primary HIV-1 infection, in tandem with peak viremia and prior to the appearance of neutralizing antibodies, but in the majority of cases these early CD8+ T cells fail to attenuate viral replication [9, 10]. Patients who spontaneously control HIV-1 (ie, long-term nonprogressors [LTNPs] and/or controllers), who represent <5% of all infected individuals, differ from typical progressors in functional aspects of their antiviral CD8+ T-cell responses, which suggests that the quality of these responses may influence the course of HIV-1 infection [11–13]. However, these observations are derived largely from cross-sectional studies. Thus, it is unclear whether preserved CD8+ T-cell function is a consequence rather than a cause of effectively suppressed viral replication. In support of the former notion, viremic individuals followed longitudinally showed loss of CD8+ T-cell functions over time [14]. Assessment of CD8+ T-cell–mediated inhibition of viral replication in vitro may provide a more accurate indication of immune control in vivo than other, more established measures of HIV-specific T-cell function, as it relies on the recognition of endogenously generated viral peptides within CD4+ T cells, in contrast to the loading of target cells with exogenous peptides at nonphysiological concentrations [15]. This is supported by studies showing that CD8+ T cells from HIV-1 LTNP/controllers show efficient inhibition of HIV-1 replication in vitro [16–18]. However, interpretation of these data is also limited by the cross-sectional study design. To address this, we measured the antiviral inhibitory capacity of ex vivo CD8+ T cells from 50 HIV-1–seropositive individuals and investigated its relationship to the rate of CD4+ T-cell decline in retrospective and prospective cohorts.