The Journal of Experimental Medicine
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Published 20 September 2004. doi:10.1084/jem.20041270
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 6, 701-712
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Loss of HIV-1–specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-induced HIV-1–specific CD4+ T Cells

Mathias Lichterfeld1, Daniel E. Kaufmann1, Xu G. Yu1, Stanley K. Mui1, Marylyn M. Addo1, Mary N. Johnston1, Daniel Cohen2, Gregory K. Robbins1, Eunice Pae2, Galit Alter1, Alysse Wurcel1,3, David Stone3, Eric S. Rosenberg1, Bruce D. Walker1,4, and Marcus Altfeld1

1 Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, MA 02129
2 Fenway Community Health Care Center, Boston, MA 02115
3 Lemuel Shattuck Hospital, Boston, MA 02130
4 Howard Hughes Medical Institute, Chevy Chase, MD 20815

Address correspondence to Marcus Altfeld, Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Boston, MA 02129. Phone: (617) 724-2461; Fax: (617) 724-8586; email: maltfeld{at}partners.org

Virus-specific CD8+ T cells are associated with declining viremia in acute human immunodeficiency virus (HIV)1 infection, but do not correlate with control of viremia in chronic infection, suggesting a progressive functional defect not measured by interferon {gamma} assays presently used. Here, we demonstrate that HIV-1–specific CD8+ T cells proliferate rapidly upon encounter with cognate antigen in acute infection, but lose this capacity with ongoing viral replication. This functional defect can be induced in vitro by depletion of CD4+ T cells or addition of interleukin 2–neutralizing antibodies, and can be corrected in chronic infection in vitro by addition of autologous CD4+ T cells isolated during acute infection and in vivo by vaccine-mediated induction of HIV-1–specific CD4+ T helper cell responses. These data demonstrate a loss of HIV-1–specific CD8+ T cell function that not only correlates with progressive infection, but also can be restored in chronic infection by augmentation of HIV-1–specific T helper cell function. This identification of a reversible defect in cell-mediated immunity in chronic HIV-1 infection has important implications for immunotherapeutic interventions.

Key Words: HIV-1 • CD8+ T cells • CD4+ T cells • vaccine • protective immunity

Abbreviations used in this paper: CFSE, carboxyfluorescein succinimidyl ester; FSC, forward scatter; SFC, spot-forming cell; SSC, side scatter.


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