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Rajesh T. Gandhi^*,, Benjamin K. Chen^*,, Stephen E. Straus^||, Janet K. Dale^||, Michael J. Lenardo^¶, and David Baltimore^**

From the ^* Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; the Dana Farber Cancer Institute, Boston, Massachusetts 02115; The Rockefeller University, New York 10021; the ^|| Laboratory of Clinical Investigation and the ^¶ Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; and the ^** California Institute of Technology, Pasadena, California 91125

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.

¹Abbreviations used in this paper: ALPS, autoimmune lymphoproliferative syndrome; FasL, Fas ligand; hFasL, human FasL; HXBnPLAP, PLAP-expressing HXB2; NL-PI, PLAP-expressing NL43; PLAP, placental alkaline phosphatase; TUNEL, TdT-mediated dUTP nick end labeling.

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.

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