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)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. 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-γ–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-γ 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-γ only–producing cells that lack self-renewal capacity.
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15 December 2003
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December 15 2003
HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity
Souheil-Antoine Younes,
Souheil-Antoine Younes
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
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Bader Yassine-Diab,
Bader Yassine-Diab
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
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Alain R. Dumont,
Alain R. Dumont
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
3Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal H3A 1A1, Canada
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Mohamed-Rachid Boulassel,
Mohamed-Rachid Boulassel
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
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Zvi Grossman,
Zvi Grossman
4Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69972, Israel
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Jean-Pierre Routy,
Jean-Pierre Routy
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
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Rafick-Pierre Sékaly
Rafick-Pierre Sékaly
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
3Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal H3A 1A1, Canada
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Souheil-Antoine Younes
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
Bader Yassine-Diab
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
Alain R. Dumont
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
3Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal H3A 1A1, Canada
Mohamed-Rachid Boulassel
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
Zvi Grossman
4Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69972, Israel
Jean-Pierre Routy
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
Rafick-Pierre Sékaly
1Laboratoire d'Immunologie, Département de Microbiologie et Immunologie, and Centre de Recherche du CHUM, Université de Montréal, Montréal H3T 1J4, Canada
2Immunodeficiency Service and Division of Hematology, Royal Victoria Hospital, McGill University Health Centre
3Faculty of Medicine, Division of Experimental Medicine, McGill University, Montréal H3A 1A1, Canada
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: [email protected]
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).
Received:
September 16 2003
Accepted:
October 28 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (12): 1909–1922.
Article history
Received:
September 16 2003
Accepted:
October 28 2003
Citation
Souheil-Antoine Younes, Bader Yassine-Diab, Alain R. Dumont, Mohamed-Rachid Boulassel, Zvi Grossman, Jean-Pierre Routy, Rafick-Pierre Sékaly; HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity . J Exp Med 15 December 2003; 198 (12): 1909–1922. doi: https://doi.org/10.1084/jem.20031598
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