title: The role of Vpr in HIV-1 disease progression is independent of its G2 arrest induction function.
abstract: Vpr (viral protein R) is a vital HIV-1 accessory protein with multiple functions in the viral life cycle, including nuclear import of preintegration complex, induction of apoptosis and G(2) cell cycle arrest. The cell cycle perturbation activity of Vpr requires activation of the ATR (Ataxia-Telangiectasia and Rad3-related) pathway and the integrity of Vpr C-terminal motif that is crucial for chromatin binding. Recent studies also demonstrated Vpr as one of the viral factors that influence HIV disease progression, as mutations in Vpr were overrepresented in some cohorts of long-term nonprogressors (LTNP). The LTNP-associated mutations of Vpr are frequently observed in the C-terminal domain. This raises the question whether the LTNP phenotype of Vpr is the result of the loss its ability to induce G(2) arrest. Here we report that the LTNP-associated mutants of Vpr function normally in the induction of G(2) arrest. No defects in ATR activation and direct binding to chromatin are observed. These mutants also show similar levels of apoptosis induction as wild-type Vpr. These data differentiate the LTNP-associated mutations of Vpr with those defective in inducing G(2) arrest. We propose that the G(2) arrest function of Vpr is separated from the LTNP phenotype, and the role of Vpr in HIV disease progression may involve other functions of Vpr.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, and Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Maoyi
authors.initials: M
authors.lastname: Lai
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D018450:Disease Progression; D016195:G2 Phase; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015658:HIV Infections / Q000473:pathology*; D020276:HIV Long-Term Survivors; D015497:HIV-1 / Q000737:chemistry* / Q000472:pathogenicity; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014162:Transfection; D054325:vpr Gene Products, Human Immunodeficiency Virus
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D016336:Gene Products, vpr; D054325:vpr Gene Products, Human Immunodeficiency Virus; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases