title: HIV type 1 Tat protein enhances activation-but not Fas (CD95)-induced peripheral blood T cell apoptosis in healthy individuals.
abstract: T cell apoptosis may play an important role in the depletion and functional defects of T cells in HIV disease. A number of investigators have shown that peripheral blood T cells in HIV disease undergo spontaneous and activation-induced apoptosis. We found recently that peripheral blood T cells from HIV+ individuals undergo apoptosis when stimulated through Fas. Also, a number of investigators have shown that Tat protein from HIV-1 can increase spontaneous and activation-induced apoptosis. In the present study we examined the effect of HIV type 1 Tat protein on spontaneous, activation-induced and Fas-induced apoptosis of peripheral blood T cells from HIV- individuals. We find that Tat protein has no effect on spontaneous apoptosis but does enhance activation-induced apoptosis of both CD4+ and CD8+ T cells. Tat, however, failed to enhance Fas-induced apoptosis of CD4+ and CD8+ T cells. Examining the mechanisms by which Tat induces apoptosis, we found that inhibitors of reactive oxygen intermediate (ROI) generation or neutralizers of ROI, such as rotenone, a potent inhibitor of mitochondrial complex I of the respiratory chain, and 3,3,5,5-tetramethylpyrroline N-oxide (TMPO), an electron spin trap, could both enhance the spontaneous apoptosis induced by Tat. This enhancement of Tat-induced apoptosis by rotenone and TMPO was independent of ICE activation as it could not be inhibited by the tripeptide z-VAD-fmk, an irreversible inhibitor of ICE/ced-3 protease homologs. These findings suggest that Tat induced enhancement of activation-induced cell death may involve complex mechanisms, some of which are ROI independent. These results indicate that a HIV-specific mechanism other than Tat is responsible for the previously observed increased susceptibility of peripheral blood T cells from HIV-infected individuals to undergo apoptosis in response to Fas stimulation.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, CA 94305, USA.
authors.forename: P D
authors.initials: PD
authors.lastname: Katsikis
authors.forename: M E
authors.initials: ME
authors.lastname: García-Ojeda
authors.forename: J F
authors.initials: JF
authors.lastname: Torres-Roca
authors.forename: D R
authors.initials: DR
authors.lastname: Greenwald
authors.forename: L A
authors.initials: LA
authors.lastname: Herzenberg
authors.forename: L A
authors.initials: LA
authors.lastname: Herzenberg
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D015696:Gene Products, tat / Q000276:immunology* / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000276:Adjuvants, Immunologic; D015696:Gene Products, tat; D019014:fas Receptor; D054322:tat Gene Products, Human Immunodeficiency Virus; D013481:Superoxides