A major human immunodeficiency virus type 1-initiated killing pathway distinct from apoptosis.
We have investigated the relative contribution of apoptosis or programmed cell death (PCD) to cell killing during acute infection with T-cell-tropic, cytopathic human immunodeficiency virus type 1 (HIV-1), by employing diverse strategies to inhibit PCD or to detect its common end-stage sequelae. When Bcl-2-transfected cell lines were infected with HIV-1, their viability was only slightly higher than that of control infections. Although the adenovirus E1B 19-kDa protein has been reported to be a stronger competitor of apoptosis than Bcl-2, it did not inhibit HIV-mediated cell death better than Bcl-2 protein. Competition for Fas ligand or inactivation of the Fas pathway secondary to intracellular mutation (MOLT-4 T cells) also had modest effects on overall cell death during acute HIV infection. In contrast to these observations with HIV infection or with HIV envelope-initiated cell death, Tat-expressing cell lines were much more susceptible (200% enhancement) to Fas-induced apoptosis than controls and Bcl-2 overexpression strongly (75%) inhibited this apoptotic T-cell death. PCD associated with FasR ligation resulted in the cleavage of common interleukin-1beta-converting enzyme (ICE)-protease targets, poly(ADP-ribose) polymerase (PARP) and pro-ICE, whereas cleaved products were not readily detected during HIV infection of peripheral blood mononuclear cells or T-cell lines even during periods of extensive cell death. These results indicate that one important form of HIV-mediated cell killing proceeds by a pathway that lacks the characteristics of T-cell apoptosis. Our observations support the conclusion that at least two HIV genes (env and tat) can kill T cells by distinct pathways and that an envelope-initiated process of T-cell death can be discriminated from apoptosis by many of the properties most closely associated with apoptotic cell death.
Kolesnitchenko
V
V
Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
King
L
L
Riva
A
A
Tani
Y
Y
Korsmeyer
S J
SJ
Cohen
D I
DI
D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D020730:Guanine Nucleotide Dissociation Inhibitors; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus
D017501:Adenovirus E1B Proteins; D002087:Butyrates; D015696:Gene Products, tat; D020730:Guanine Nucleotide Dissociation Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D054322:tat Gene Products, Human Immunodeficiency Virus; D020148:Butyric Acid; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D019204:GTP-Binding Proteins