SUPPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION BY CD8(- EVIDENCE FOR HLA CLASS I-RESTRICTED TRIGGERING OF CYTOLYTIC AND NONCYTOLYTIC MECHANISMS() CELLS )

Although CD8(+) lymphocytes in human immunodeficiency virus type 1 (HI V-1)-infected individuals have been demonstrated to suppress viral rep lication, the mechanisms of inhibition have not been defined precisely . A large body of evidence indicates that these cells act via soluble inhibitory factors, but the potential role of HLA class I-restricted c ytolysis has remained controversial. Here we demonstrate that HIV-1-sp ecific cytotoxic T lymphocytes (CTL) mediate antiviral suppression by both cytolytic and noncytolytic mechanisms. The predominant mechanism requires direct contact of CTL with the infected cells, is HLA class I restricted, and can achieve complete elimination of detectable virus in infected cell cultures. Inhibition occurs even at high multipliciti es of infection or at ratios of CTL to CD4 cells as low as 1:1,000. Th e other mechanism is mediated by soluble inhibitory factors which are triggered in an antigen-specific and HLA-restricted fashion but then a ct without HLA restriction. These include MIP-1 alpha, MIP-1 beta, and RANTES as well as a distinct factor(s) capable of inhibiting HIV-1 st rains insensitive to these chemokines. These data indicate that HIV-1- specific CTL are potent mediators of HIV-1 suppression at cell ratios existing in vivo and demonstrate an antigen-specific trigger for CD8() cell-derived soluble inhibitory factors. These results suggest that CTL play an important role in the observed antiviral activity of CD8() cells from infected individuals.