Kinetics of antiviral activity by human immunodeficiency virus type 1-specific cytotoxic T lymphocytes (CTL) and rapid selection of CTL escape virus in vitro

Identification of immune responses that may limit progression toward AIDS and may eliminate infected cells that persist despite effective antiviral therapy (6, 20, 30) is a major goal for current research aimed at the development of vaccines and immunotherapies against AIDS (1). It is generally assumed that an effective vaccine against human immunodeficiency virus type 1 (HIV-1) should elicit an antiviral immune response which includes virus-specific major histocompatibility complex class I-restricted CD8+ cytotoxic T lymphocytes (CTL), because their presence is associated with the control of primate lentivirus replication and they have been detected in individuals exposed to but apparently uninfected with HIV (reviewed in reference 8). Furthermore, CTL have been shown to exert pressure on virus replication in vivo (2, 9) and in vitro (3, 27, 32). CTL clones directed against the late viral proteins Gag, reverse transcriptase (RT), and Env, have been shown to lyse HIV-1-infected cells before peak virus production (31) and to suppress HIV-1 replication in immortalized CD4+ T-cell lines such as H9 and T1 (32). Env-specific CTL have been shown to eliminate HIV-1-infected CD4+ peripheral blood mononuclear cells (PBMC) and H9 cells (32), indicating that inhibition of HIV-1 replication involved cytolytic mechanisms. In addition to exerting cytolytic activity, HIV-specific CTL have been shown to suppress virus replication by the excretion of soluble factors (3, 32). Although CTL against late viral proteins do exhibit antiviral activity, elimination of nonproductively infected cells with still incomplete protein expression (18) and suppression of low-level virus replication (20) may require CTL directed against the regulatory viral proteins Tat and Rev. These proteins are translated early in the replication cycle of HIV-1 and are necessary for transcription (Tat) or expression of the intermediate and late proteins (Rev) (14, 15). Consistent with such a protective role of CTL against Rev and Tat, we have shown previously that CTL with these specificities were preferentially found in individuals who experienced a long-term asymptomatic course of disease progression (28). In contrast, CTL responses against the late proteins Gag and RT did not correlate with the rate of disease progression (28). Here we present a detailed analysis of the Rev-specific CTL response in one individual who has been infected for more than 12 years without developing symptoms. Rev-specific CTL clones were generated, and a minimal epitope as well as the HLA class I restriction of its recognition were identified. It is shown that both Rev- and RT-specific CTL can suppress HIV-1 production before they exert cytolytic activity and that Rev-specific CTL-mediated inhibition of virus replication in PBMC leads to the rapid selection of virus mutated in the CTL epitope.