The Journal of Experimental Medicine
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Published 15 December 2003. doi:10.1084/jem.20031598
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© Rockefeller University Press, 0022-1007/2003/12/1909 $5.00
The Journal of Experimental Medicine, Volume 198, Number 12, 1909-1922

HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity

Souheil-Antoine Younes1, Bader Yassine-Diab1, Alain R. Dumont1,3, Mohamed-Rachid Boulassel2, Zvi Grossman4, Jean-Pierre Routy2 and Rafick-Pierre Sékaly1,2,3

1 Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
2 Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
3 Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal H3A 1A1, Canada
4 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69972, Israel

Address correspondence to Rafick-Pierre Sékaly, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montréal H3T 1J4, Canada. Phone: (514) 343-6284; Fax: (514) 343-5858; email: rafick-pierre.sekaly{at}umontreal.ca

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-{gamma}. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-{gamma}. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-{gamma}–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-{gamma} only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-{gamma} only–producing cells that lack self-renewal capacity.

Key Words: T cell memory • T cell proliferation • primary HIV-1 infection • HAART

Abbreviations used in this paper: CFSE, 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester; HAART, highly active antiretroviral therapy; ICS, intracellular cytokine staining; LCMV, lymphocytic choriomeningitis virus; SIV, simian immunodeficiency virus; Tcm, central memory CD4+ T cell(s); Tem, effector memory CD4+ T cell(s).


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