Suppression of HIV-1 Replication by HIV-1-Irrelevant CD8 + Cytotoxic T Lymphocytes Resulting in Preservation of Persistently HIV-1-Infected Cells In Vitro

Abstract

CD8⁺ cells of asymptomatic HIV-1 carriers (AC) contain HIV-1-specific cytotoxic T lymphocytes (CTLs) but suppress HIV-1 replication in a class I major histocompatibility complex (MHC-I)-unrestricted manner. In order to selectively investigate the HIV-1-suppressive function of CTLs apart from HIV-1-specific cytotoxicity, HIV-1-irrelevant allo-specific CTLs were established from an HIV-1-uninfected individual and their HIV-1-suppressive activity against autologous CD4⁺ peripheral blood mononuclear cells (PBMC) was examined. We found that these CTLs significantly suppressed both R5 and X4-HIV-1 replication in either acutely or persistently infected autologous PBMC. Although these CTLs partially killed HIV-1-infected PBMC through Fas ligand, CTLs still suppressed late steps of HIV-1 replication in the presence of neutralizing antibodies to Fas ligand. HIV-1 replication in PBMC that had been suppressed by CTLs was reversible following depletion of CTLs from culture, analogous to the previous observation for CD8⁺ cell-depleted PBMC of AC. Induction of HIV-1 replication by CTL-depletion was amplified by addition of newly prepared CD4⁺ cells or activation with staphylococcal enterotoxin B. Our results indicate that CTLs can suppress HIV-1 replication in PBMC in an antigen-nonspecific manner and preserve infected cells in a state capable of restarting HIV-1 replication and transmission.