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HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism

Gandhi, Rajesh T. and Chen, Benjamin K. and Straus, Stephen E. and Dale, Janet K. and Lenardo, Michael J. and Baltimore, David (1998) HIV-1 Directly Kills CD4+ T Cells by a Fas-independent Mechanism. Journal of Experimental Medicine, 187 (7). pp. 1113-1122. ISSN 0022-1007.

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The mechanism by which HIV-1 induces CD4+ T cell death is not known. A fundamental issue is whether HIV-1 primarily induces direct killing of infected cells or indirectly causes death of uninfected bystander cells. This question was studied using a reporter virus system in which infected cells are marked with the cell surface protein placental alkaline phosphatase (PLAP). Infection by HIV-PLAP of peripheral blood mononuclear cells (PBMCs) and T cell lines leads to rapid depletion of CD4+ T cells and induction of apoptosis. The great majority of HIV-induced T cell death in vitro involves direct loss of infected cells rather than indirect effects on uninfected bystander cells. Because of its proposed role in HIV-induced cell death, we also examined the Fas (CD95/Apo1) pathway in killing of T cells by HIV-1. Infected PBMCs or CEM cells display no increase in surface Fas relative to uninfected cells. In addition, HIV-1 kills CEM and Jurkat T cells in the presence of a caspase inhibitor that completely blocks Fas-mediated apoptosis. HIV-1 also depletes CD4+ T cells in PBMCs from patients who have a genetically defective Fas pathway. These results suggest that HIV-1 induces direct apoptosis of infected cells and kills T cells by a Fas-independent mechanism.

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Baltimore, David0000-0001-8723-8190
Additional Information:Copyright © 1998 by the Rockefeller University Press. Received for publication 31 December 1997 and in revised form 23 January 1998. R.T. Gandhi is a recipient of a Howard Hughes Postdoctoral Research Fellowship for Physicians and a National Institutes of Health (NIH) Mentored Clinical Scientist Development Award (1 K08 AI-01443-01). B.K. Chen was supported by a Medical Scientist Training Program Award (GM07739). D. Baltimore is an American Cancer Society Research Professor and is supported at MIT by funds from the Ivan R. Cottrell Chair and grants from the NIH. We thank George Cohen for critical comments on the manuscript and members of the Baltimore laboratory for advice and assistance. R.T. Gandhi wishes to thank Bonnie A. Southworth and Marshall A. Wolf.
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Deposited On:16 Dec 2006
Last Modified:06 Nov 2017 23:19

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