Strong Ability of Nef-Specific CD4+ Cytotoxic T Cells To Suppress Human Immunodeficiency Virus Type 1 (HIV-1) Replication in HIV-1-Infected CD4+ T Cells and Macrophages

A restricted number of studies have shown that human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic CD4(+) T cells are present in HIV-1-infected individuals. However, the roles of this type of CD4(+) T cell in the immune responses against an HIV-1 infection remain unclear. In this study, we identified novel Nef epitope-specific HLA-DRB1*0803-restricted cytotoxic CD4(+) T cells. The CD4(+) T-cell clones specific for Nef187-203 showed strong gamma interferon production after having been stimulated with autologous B-lymphoblastoid cells infected with recombinant vaccinia virus expressing Nef or pulsed with heat-inactivated virus particles, indicating the presentation of the epitope antigen through both exogenous and endogenous major histocompatibility complex class II processing pathways. Nef187-203-specific CD4(+) T-cell clones exhibited strong cytotoxic activity against both HIV-1-infected macrophages and CD4(+) T cells from an HLA-DRB1*0803(+) donor. In addition, these Nef-specific cytotoxic CD4(+) T-cell clones exhibited strong ability to suppress HIV-1 replication in both macrophages and CD4(+) T cells in vitro. Nef187-203-specific cytotoxic CD4(+) T cells were detected in cultures of peptide-stimulated peripheral blood mononuclear cells (PBMCs) and in ex vivo PBMCs from 40% and 20% of DRB1*0803(+) donors, respectively. These results suggest that HIV-1-specific CD4(+) T cells may directly control HIV-1 infection in vivo by suppressing virus replication in HIV-1 natural host cells.