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The Journal of Immunology, 2005, 175: 6948-6958.
Copyright © 2005 by The American Association of Immunologists

Expansion and Contraction of HIV-Specific CD4 T Cells with Short Bursts of Viremia, but Physical Loss of the Majority of These Cells with Sustained Viral Replication1

Nilufer Seth*, Daniel Kaufmann{dagger},||, Timothy Lahey{dagger},{ddagger},§,||, Eric S. Rosenberg{dagger},|| and Kai W. Wucherpfennig2,*,#,**

* Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston MA 02115; {dagger} Infectious Disease Unit, Massachusetts General Hospital, Boston, MA 02114; {ddagger} Infectious Diseases and International Health, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03755; § Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA 02215; and Department of Pathology, || Department of Medicine, and # Department of Neurology and ** Program in Immunology, Harvard Medical School, Boston, MA 02115

Chronic infection with the HIV results in poor HIV-specific CD4 T cell proliferation, but more recent analyses using intracellular cytokine staining demonstrated that IFN-{gamma}-producing, HIV-specific CD4 T cells can be detected for years in HIV-infected subjects. Because it is not known whether the majority of HIV-specific T cells are lost or become dysfunctional, we examined the kinetics of the T cell response over an extended period of time using a panel of 10 HLA-DR tetramers loaded with HIV p24 peptides. Tetramer+ CD4 T cells were present at a relatively high frequency during acute infection, but the size of these populations substantially contracted following suppression of viral replication. Short-term cessation of antiretroviral therapy resulted in a burst of viral replication and concomitant expansion of tetramer+ CD4 T cells, and these populations again contracted following reinitiation of therapy. The kinetics with which these cell populations contracted were characteristic of effector T cells, a conclusion that was supported by their phenotypic (CCR7CD45RA) and functional properties (IFN-{gamma}+). Continued high-level viremia resulted in the physical loss of the majority of tetramer+ CD4 T cells, and the decline of HIV p24-specific CD4 T cells occurred more rapidly and was more substantial than the reduction of total CD4 T cell numbers. We conclude that the population of HIV p24-specific CD4 T cells is initially responsive to changes in the levels of viral Ags, but that the majority of these cells are lost in a setting of chronic viremia.


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