HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity.
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.
Younes
Souheil-Antoine
SA
Département de Microbiologie et Immunologie, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montréal H3T 1J4, Canada.
Yassine-Diab
Bader
B
Dumont
Alain R
AR
Boulassel
Mohamed-Rachid
MR
Grossman
Zvi
Z
Routy
Jean-Pierre
JP
Sekaly
Rafick-Pierre
RP
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology*; D000595:Amino Acid Sequence; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000032:analysis; D014766:Viremia / Q000276:immunology*
C515370:CCR7 protein, human; D007376:Interleukin-2; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens