Resistance of chimpanzee T cells to human immunodeficiency virus type 1 Tat-enhanced oxidative stress and apoptosis.
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.
Ehret
A
A
Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
Westendorp
M O
MO
Herr
I
I
Debatin
K M
KM
Heeney
J L
JL
Frank
R
R
Krammer
P H
PH
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004198:Disease Susceptibility; D053222:Fas Ligand Protein; D015696:Gene Products, tat / Q000378:metabolism*; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D018384:Oxidative Stress; D002679:Pan troglodytes; D011758:Pyrroles; D012333:RNA, Messenger / Q000096:biosynthesis; D013045:Species Specificity; D013482:Superoxide Dismutase / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology* / Q000821:virology*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D054322:tat Gene Products, Human Immunodeficiency Virus
D000954:Antigens, Surface; D000998:Antiviral Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015696:Gene Products, tat; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D011758:Pyrroles; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus; D001569:Benzodiazepines; C070024:Ro 24-7429; D013482:Superoxide Dismutase