title: The HIV-1 vpr protein acts as a negative regulator of apoptosis in a human lymphoblastoid T cell line: possible implications for the pathogenesis of AIDS.
abstract: Although apoptosis is considered one of the major mechanisms of CD4(+) T cell depletion in HIV-infected patients, the virus-infected cells somehow appear to be protected from apoptosis, which generally occurs in bystander cells. Vpr is an auxiliary HIV-1 protein, which, unlike the other regulatory gene products, is present at high copy number in virus particles. We established stable transfectants of CD4+ T Jurkat cells constitutively expressing low levels of vpr. These clones exhibited cell cycle characteristics similar to those of control-transfected cells. Treatment of control clones with apoptotic stimuli (i.e., cycloheximide/tumor necrosis factor alpha (TNF-alpha), anti-Fas antibody, or serum starvation) resulted in a massive cell death by apoptosis. In contrast, all the vpr-expressing clones showed an impressive protection from apoptosis independently of the inducer. Notably, vpr antisense phosphorothioate oligodeoxynucleotides render vpr-expressing cells as susceptible to apoptosis induced by cycloheximide and TNF-alpha as the control clones. Moreover, the constitutive expression of HIV-1 vpr resulted in the upregulation of bcl-2, an oncogene endowed with antiapoptotic activities, and in the downmodulation of bax, a proapoptotic factor of the bcl-2 family. Altogether, these results suggest that low levels of the endogenous vpr protein can interfere with the physiological turnover of T lymphocytes at early stages of virus infection, thus facilitating HIV persistence and, subsequently, viral spread. This might explain why apoptosis mostly occurs in bystander uninfected cells in AIDS patients.
authors.affiliation: Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Conti
authors.forename: G
authors.initials: G
authors.lastname: Rainaldi
authors.forename: P
authors.initials: P
authors.lastname: Matarrese
authors.forename: B
authors.initials: B
authors.lastname: Varano
authors.forename: R
authors.initials: R
authors.lastname: Rivabene
authors.forename: S
authors.initials: S
authors.lastname: Columba
authors.forename: A
authors.initials: A
authors.lastname: Sato
authors.forename: F
authors.initials: F
authors.lastname: Belardelli
authors.forename: W
authors.initials: W
authors.lastname: Malorni
authors.forename: S
authors.initials: S
authors.lastname: Gessani
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000209:etiology*; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002453:Cell Cycle; D003513:Cycloheximide / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics; D016336:Gene Products, vpr / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D019169:Jurkat Cells / Q000166:cytology / Q000821:virology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014764:Viral Proteins / Q000032:analysis / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000276:immunology; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D000906:Antibodies; C494826:BAX protein, human; D016336:Gene Products, vpr; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D054325:vpr Gene Products, Human Immunodeficiency Virus; D003513:Cycloheximide