HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism.
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.
Gandhi
R T
RT
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Chen
B K
BK
Straus
S E
SE
Dale
J K
JK
Lenardo
M J
MJ
Baltimore
D
D
D000469:Alkaline Phosphatase; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000821:virology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D015415:Biomarkers; D015853:Cysteine Proteinase Inhibitors; D058851:GPI-Linked Proteins; D007527:Isoenzymes; D019014:fas Receptor; D000469:Alkaline Phosphatase; C019839:alkaline phosphatase, placental