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Journal of Virology, August 2000, p. 7320-7330, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Human Immunodeficiency Virus-Specific Circulating CD8 T Lymphocytes Have Down-Modulated CD3zeta and CD28, Key Signaling Molecules for T-Cell Activation

Linda A. Trimble,1,dagger Premlata Shankar,1 Mark Patterson,1 Johanna P. Daily,2 and Judy Lieberman1,*

The Center for Blood Research, Harvard Medical School,1 and Department of Medicine, Brigham and Women's Hospital,2 Boston, Massachusetts 02115

Received 14 February 2000/Accepted 17 May 2000

Although human immunodeficiency virus (HIV)-infected subjects without AIDS have a high frequency of HIV-specific CD8 T lymphocytes, cellular immunity is unable to control infection. Freshly isolated lymphocytes often do not lyse HIV-infected targets in 4-h cytotoxicity assays. A large fraction of circulating CD8 T cells from HIV-infected donors down-modulate CD3zeta , the signaling component of the T-cell receptor complex, which is reexpressed in vitro coincident with the return of cytotoxic function. To investigate further the link between CD3zeta down-modulation and possible CD8 T-cell functional defects, we used flow cytometry to characterize further the properties of the CD3zeta -down-modulated subset. HIV-specific CD8 T cells, identified by tetramer staining, are CD3zeta -. CD8 T cells with down-modulated CD3zeta also do not express the key costimulatory receptor CD28 and have the cell surface phenotype of activated or memory T cells (HLA-DR+ CD62L-). After T-cell activation, CD3zeta -down-modulated cells express the activation marker CD69 but not the high-affinity interleukin 2 (IL-2) receptor alpha -chain CD25 and produce gamma interferon but not IL-2. Therefore HIV-specific CD8 T cells have down-modulated key signaling molecules for T-cell activation and costimulation and require exogenous cytokine stimulation. The typical impairment of HIV-specific CD4 T helper cells, which would normally provide specific CD8 T-cell stimulation, means that in vivo CTL function in vivo is compromised in most HIV-infected individuals. In AIDS patients, the functional defect is more severe, since CD3zeta is not reexpressed even after IL-2 exposure.

* Corresponding author. Mailing address: The Center for Blood Research, 800 Huntington Ave., Boston, MA 02115. Phone: (617) 278-3381. Fax: (617) 278-3493. E-mail: lieberman{at}cbr.med.harvard.edu.

dagger Present address: Dana Farber Cancer Institute, Boston, MA 02115.

Journal of Virology, August 2000, p. 7320-7330, Vol. 74, No. 16
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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