JVI Accepts, published online ahead of print on 20 May 2009

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J. Virol. doi:10.1128/JVI.00513-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Strong ability of Nef-specific CD4⁺ cytotoxic T cells to suppress HIV-1 replication in HIV-1-infected CD4⁺ T cells and macrophages

Nan Zheng, Mamoru Fujiwara, Takamasa Ueno, Shinichi Oka, and Masafumi Takiguchi^*

Division of Viral Immunology and Division of Infectious Disease, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811; and AIDS Clinical Center, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku, Tokyo 162-8655, Japan

^* To whom correspondence should be addressed. Email: masafumi{at}kumamoto-u.ac.jp.

A restricted number of studies have shown that 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 IFN- production after having been stimulated with autologous B-LCLs infected with Nef recombinant vaccinia virus or pulsed with heat-inactivated virus particles, indicating the presentation of the epitope antigen through both exogenous and endogenous MHC 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 in CD4⁺ T cells in vitro. Nef187-203-specific cytotoxic CD4⁺ T cells were detected in cultures of peptide-stimulated PBMC and in ex vivo PBMC 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.