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Journal of Virology, August 2009, p. 7668-7677, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00513-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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{triangledown}

Nan Zheng,1 Mamoru Fujiwara,1 Takamasa Ueno,1 Shinichi Oka,2,3 and Masafumi Takiguchi1*

Division of Viral Immunology,1 Division of Infectious Disease, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811,2 AIDS Clinical Center, International Medical Center of Japan, 1-21-1, Toyama, Shinjuku, Tokyo 162-8655, Japan3

Received 12 March 2009/ Accepted 12 May 2009

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.

* Corresponding author. Mailing address: Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. Phone: 81-96-373-6529. Fax: 81-96-373-6532. E-mail: masafumi{at}kumamoto-u.ac.jp

{triangledown} Published ahead of print on 20 May 2009.

Journal of Virology, August 2009, p. 7668-7677, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00513-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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