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J Virol. Nov 1995; 69(11): 6705–6711.
PMCID: PMC189580

Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity.

Abstract

The Vpr accessory gene product of human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus is believed to play a role in permitting entry of the viral core into the nucleus of nondividing cells. A second role for Vpr was recently suggested by Rogel et al. (M. E. Rogel, L. I. Wu, and M. Emerman, J. Virol. 69:882-888, 1995), who showed that Vpr prevents the establishment in vitro of chronically infected HIV producer cell lines, apparently by causing infected cells to arrest in the G2/M phase of the cell cycle. In cycling cells, progression from G2 to M phase is driven by activation of the p34cdc2/cyclin B complex, an event caused, in part, by dephosphorylation of two regulatory amino acids of p34cdc2 (Thr-14 and Tyr-15). We show here that Vpr arrests the cell cycle in G2 by preventing the activation of the p34cdc2/cyclin B complex. Vpr expression in cells caused p34cdc2 to remain in the phosphorylated, inactive state, p34cdc2/cyclin B complexes immunoprecipitated from cells expressing Vpr were almost completely inactive in a histone H1 kinase assay. Coexpression of a constitutively active mutant p34cdc2 molecule with Vpr relieved the G2 arrest. These findings strongly suggest that Vpr arrests cells in G2 by preventing the activation of the p34cdc2/cyclin B complex that is required for entry into M phase. In vivo, Vpr might, by preventing p34cdc2 activation, delay or prevent apoptosis of infected cells. This would increase the amount of virus each infected cell produced.

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Selected References

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  • Adachi A, Ono N, Sakai H, Ogawa K, Shibata R, Kiyomasu T, Masuike H, Ueda S. Generation and characterization of the human immunodeficiency virus type 1 mutants. Arch Virol. 1991;117(1-2):45–58. [PubMed]
  • Akari H, Sakuragi J, Takebe Y, Tomonaga K, Kawamura M, Fukasawa M, Miura T, Shinjo T, Hayami M. Biological characterization of human immunodeficiency virus type 1 and type 2 mutants in human peripheral blood mononuclear cells. Arch Virol. 1992;123(1-2):157–167. [PubMed]
  • Antoni BA, Sabbatini P, Rabson AB, White E. Inhibition of apoptosis in human immunodeficiency virus-infected cells enhances virus production and facilitates persistent infection. J Virol. 1995 Apr;69(4):2384–2392. [PMC free article] [PubMed]
  • Balliet JW, Kolson DL, Eiger G, Kim FM, McGann KA, Srinivasan A, Collman R. Distinct effects in primary macrophages and lymphocytes of the human immunodeficiency virus type 1 accessory genes vpr, vpu, and nef: mutational analysis of a primary HIV-1 isolate. Virology. 1994 May 1;200(2):623–631. [PubMed]
  • Chen C, Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. [PMC free article] [PubMed]
  • Chen G, Shi L, Litchfield DW, Greenberg AH. Rescue from granzyme B-induced apoptosis by Wee1 kinase. J Exp Med. 1995 Jun 1;181(6):2295–2300. [PMC free article] [PubMed]
  • Cohen EA, Terwilliger EF, Jalinoos Y, Proulx J, Sodroski JG, Haseltine WA. Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr. 1990;3(1):11–18. [PubMed]
  • Coleman TR, Dunphy WG. Cdc2 regulatory factors. Curr Opin Cell Biol. 1994 Dec;6(6):877–882. [PubMed]
  • Connor RI, Chen BK, Choe S, Landau NR. Vpr is required for efficient replication of human immunodeficiency virus type-1 in mononuclear phagocytes. Virology. 1995 Feb 1;206(2):935–944. [PubMed]
  • Dedera D, Hu W, Vander Heyden N, Ratner L. Viral protein R of human immunodeficiency virus types 1 and 2 is dispensable for replication and cytopathogenicity in lymphoid cells. J Virol. 1989 Jul;63(7):3205–3208. [PMC free article] [PubMed]
  • Gibbs JS, Lackner AA, Lang SM, Simon MA, Sehgal PK, Daniel MD, Desrosiers RC. Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995 Apr;69(4):2378–2383. [PMC free article] [PubMed]
  • Greenberg AH, Litchfield DW. Granzymes and apoptosis: targeting the cell cycle. Curr Top Microbiol Immunol. 1995;198:95–119. [PubMed]
  • Groux H, Torpier G, Monté D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. [PMC free article] [PubMed]
  • Gu Y, Rosenblatt J, Morgan DO. Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. EMBO J. 1992 Nov;11(11):3995–4005. [PMC free article] [PubMed]
  • Heinzinger NK, Bukrinsky MI, Haggerty SA, Ragland AM, Kewalramani V, Lee MA, Gendelman HE, Ratner L, Stevenson M, Emerman M. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311–7315. [PMC free article] [PubMed]
  • Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. [PubMed]
  • Jha MN, Bamburg JR, Bedford JS. Cell cycle arrest by Colcemid differs in human normal and tumor cells. Cancer Res. 1994 Sep 15;54(18):5011–5015. [PubMed]
  • Jowett JB, Planelles V, Poon B, Shah NP, Chen ML, Chen IS. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2 + M phase of the cell cycle. J Virol. 1995 Oct;69(10):6304–6313. [PMC free article] [PubMed]
  • Krek W, Marks J, Schmitz N, Nigg EA, Simanis V. Vertebrate p34cdc2 phosphorylation site mutants: effects upon cell cycle progression in the fission yeast Schizosaccharomyces pombe. J Cell Sci. 1992 May;102(Pt 1):43–53. [PubMed]
  • Krek W, Nigg EA. Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites. EMBO J. 1991 Feb;10(2):305–316. [PMC free article] [PubMed]
  • Krek W, Nigg EA. Mutations of p34cdc2 phosphorylation sites induce premature mitotic events in HeLa cells: evidence for a double block to p34cdc2 kinase activation in vertebrates. EMBO J. 1991 Nov;10(11):3331–3341. [PMC free article] [PubMed]
  • Landau NR, Page KA, Littman DR. Pseudotyping with human T-cell leukemia virus type I broadens the human immunodeficiency virus host range. J Virol. 1991 Jan;65(1):162–169. [PMC free article] [PubMed]
  • Lang SM, Weeger M, Stahl-Hennig C, Coulibaly C, Hunsmann G, Müller J, Müller-Hermelink H, Fuchs D, Wachter H, Daniel MM, et al. Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus. J Virol. 1993 Feb;67(2):902–912. [PMC free article] [PubMed]
  • Lenburg ME, Landau NR. Vpu-induced degradation of CD4: requirement for specific amino acid residues in the cytoplasmic domain of CD4. J Virol. 1993 Dec;67(12):7238–7245. [PMC free article] [PubMed]
  • Levy DN, Fernandes LS, Williams WV, Weiner DB. Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell. 1993 Feb 26;72(4):541–550. [PubMed]
  • Meikrantz W, Gisselbrecht S, Tam SW, Schlegel R. Activation of cyclin A-dependent protein kinases during apoptosis. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3754–3758. [PMC free article] [PubMed]
  • Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131–134. [PubMed]
  • Morgenstern JP, Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. [PMC free article] [PubMed]
  • Nishioka WK, Welsh RM. Susceptibility to cytotoxic T lymphocyte-induced apoptosis is a function of the proliferative status of the target. J Exp Med. 1994 Feb 1;179(2):769–774. [PMC free article] [PubMed]
  • Norbury CJ, Nurse P. Control of the higher eukaryote cell cycle by p34cdc2 homologues. Biochim Biophys Acta. 1989 Jul 28;989(1):85–95. [PubMed]
  • Ogawa K, Shibata R, Kiyomasu T, Higuchi I, Kishida Y, Ishimoto A, Adachi A. Mutational analysis of the human immunodeficiency virus vpr open reading frame. J Virol. 1989 Sep;63(9):4110–4114. [PMC free article] [PubMed]
  • Paxton W, Connor RI, Landau NR. Incorporation of Vpr into human immunodeficiency virus type 1 virions: requirement for the p6 region of gag and mutational analysis. J Virol. 1993 Dec;67(12):7229–7237. [PMC free article] [PubMed]
  • Pear WS, Nolan GP, Scott ML, Baltimore D. Production of high-titer helper-free retroviruses by transient transfection. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8392–8396. [PMC free article] [PubMed]
  • Pirruccello SJ, LeBien TW. The human B cell-associated antigen CD24 is a single chain sialoglycoprotein. J Immunol. 1986 May 15;136(10):3779–3784. [PubMed]
  • Rogel ME, Wu LI, Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J Virol. 1995 Feb;69(2):882–888. [PMC free article] [PubMed]
  • Rosenblatt J, Gu Y, Morgan DO. Human cyclin-dependent kinase 2 is activated during the S and G2 phases of the cell cycle and associates with cyclin A. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2824–2828. [PMC free article] [PubMed]
  • Schmid I, Uittenbogaart CH, Giorgi JV. A gentle fixation and permeabilization method for combined cell surface and intracellular staining with improved precision in DNA quantification. Cytometry. 1991;12(3):279–285. [PubMed]
  • Shen Y, Shenk TE. Viruses and apoptosis. Curr Opin Genet Dev. 1995 Feb;5(1):105–111. [PubMed]
  • Shi L, Nishioka WK, Th'ng J, Bradbury EM, Litchfield DW, Greenberg AH. Premature p34cdc2 activation required for apoptosis. Science. 1994 Feb 25;263(5150):1143–1145. [PubMed]
  • Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM, Krammer PH. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature. 1995 Jun 8;375(6531):497–500. [PubMed]
  • White E, Sabbatini P, Debbas M, Wold WS, Kusher DI, Gooding LR. The 19-kilodalton adenovirus E1B transforming protein inhibits programmed cell death and prevents cytolysis by tumor necrosis factor alpha. Mol Cell Biol. 1992 Jun;12(6):2570–2580. [PMC free article] [PubMed]
  • Zhu L, Anasetti C. Cell cycle control of apoptosis in human leukemic T cells. J Immunol. 1995 Jan 1;154(1):192–200. [PubMed]

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