ro-24-7429 and Acquired-Immunodeficiency-Syndrome

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Benzodiazepines; Drug Evaluation; Drug Industry; Gene Products, tat; HIV; Humans; Pyrroles; tat Gene Products, Human Immunodeficiency Virus; United States

CD4+ T-cell depletion in AIDS patients involves induction of apoptosis in human immunodeficiency virus (HIV)-infected and noninfected T cells. The HIV type 1 (HIV-1)-transactivating protein Tat enhances apoptosis and activation-induced cell death (AICD) of human T cells. This effect is mediated by the CD95 (APO-1/Fas) receptor-CD95 ligand (CD95L) system and may be linked to the induction of oxidative stress by Tat. Here we show that HIV-1 Tat-induced oxidative stress is necessary for sensitized AICD in T cells caused by CD95L expression. Tat-enhanced apoptosis and CD95L expression in T cells are inhibited by neutralizing anti-Tat antibodies, antioxidants, and the Tat inhibitor Ro24-7429. Chimpanzees infected with HIV-1 show viral replication resembling early infection in humans but do not show T-cell depletion or progression towards AIDS. The cause for this discrepancy is unknown. Here we show that unlike Tat-treated T cells in humans, Tat-treated chimpanzee T cells do not show downregulation of manganese superoxide dismutase or signs of oxidative stress. Chimpanzee T cells are also resistant to Tat-enhanced apoptosis, AICD, and CD95L upregulation.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antigens, Surface; Antiviral Agents; Apoptosis; Benzodiazepines; Cell Death; Cell Line; Disease Susceptibility; Fas Ligand Protein; Gene Products, tat; Humans; Immunoglobulin M; Lymphocyte Activation; Membrane Glycoproteins; Oxidative Stress; Pan troglodytes; Pyrroles; RNA, Messenger; Species Specificity; Superoxide Dismutase; T-Lymphocytes; tat Gene Products, Human Immunodeficiency Virus; Transcription, Genetic; Tumor Cells, Cultured

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Benzodiazepines; Gene Products, tat; Genes, tat; HIV; Humans; Pyrroles; tat Gene Products, Human Immunodeficiency Virus

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Benzodiazepines; Drug Industry; Humans; National Institutes of Health (U.S.); Pyrroles; Research Support as Topic; United States