Apoptotic cell death upon contact of CD4+ T lymphocytes with HIV glycoprotein-expressing cells is mediated by caspases but bypasses CD95 (Fas/Apo-1) and TNF receptor 1.
Loss of CD4+ T helper lymphocytes is central to the development of immunodeficiency after infection with HIV. In this study, we demonstrate that contact of primary uninfected CD4+ T lymphocytes with HIV-infected or HIV envelope glycoprotein-expressing cells results in apoptotic cell death of both uninfected and infected cells. Apoptosis was blocked by inhibitors of caspases/IL-1beta-converting enzyme-like proteases. This finding provides conclusive evidence that cytotoxicity upon contact of HIV-infected and uninfected primary cells is an active process and represents another example for the role of caspases in the induction of apoptosis. Prevention of apoptosis by inhibition of caspases did not block the formation of syncytia, indicating that apoptosis occurs either in a subpopulation of cells or in syncytia. Cell death was not mediated by the CD95 (Fas/Apo-1) or TNF receptor 1 molecules, which indicates a different pathway of apoptosis induction. The data indicate that initiation of apoptosis significantly shortens the life span of uninfected CD4+ T cells upon contact with HIV-infected cells and may represent a factor that contributes to the destruction of CD4+ T lymphocytes in vitro. Elucidation of the mechanism that initiates apoptosis in this situation will add to our understanding of both HIV pathogenesis and apoptotic signaling.
Ohnimus
H
H
Institute for Virology and Immunobiology, Julius Maximilians University, Wurzburg, Germany.
Heinkelein
M
M
Jassoy
C
C
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D053938:DNA Fragmentation; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D009842:Oligopeptides / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D015853:Cysteine Proteinase Inhibitors; D015699:HIV Envelope Protein gp120; D009842:Oligopeptides; D018124:Receptors, Tumor Necrosis Factor; C108637:aspartyl-glutamyl-valyl-aspartal; D019014:fas Receptor