Abstract
We previously reported that expression of human immunodeficiency virus type 1 strain NL4-3 (HIV-1(NL4-3))vpr causes cells to arrest in the G2 phase of the cell cycle. We examined the induction of cell cycle arrest by other HIV-1 isolates and by primary lentiviruses other than HIV-1. We demonstrate that the vpr genes from tissue culture-adapted or primary isolates of HIV-1 are capable of inducing G2 arrest. In addition, we demonstrate that induction of cell cycle arrest is a conserved function of members of two other groups of primate lentiviruses, HIV-2/simian immunodeficiency virus strain sm (SIVsm)/SIVmac and SIVagm. vpr from HIV-1, HIV-2, and SIVmac induced cell cycle arrest when transfected in human (HeLa) and monkey (CV-1) cells. vpx from HIV-2 and SIVmac did not induce detectable cell cycle arrest in either cell type, and SIVagm vpx was capable of inducing arrest in CV-1 but not HeLa cells. These results indicate that induction of cell cycle perturbation is a general property of lentiviruses that infect primates. The conservation of this viral function throughout evolution suggests that it plays a key role in virus-host relationships, and elucidation of its mechanism may reveal important clues about pathology induced by primary lentiviruses.
Full Text
The Full Text of this article is available as a PDF (318.2 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Adachi A., Gendelman H. E., Koenig S., Folks T., Willey R., Rabson A., Martin M. A. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J Virol. 1986 Aug;59(2):284–291. doi: 10.1128/jvi.59.2.284-291.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Balotta C., Lusso P., Crowley R., Gallo R. C., Franchini G. Antisense phosphorothioate oligodeoxynucleotides targeted to the vpr gene inhibit human immunodeficiency virus type 1 replication in primary human macrophages. J Virol. 1993 Jul;67(7):4409–4414. doi: 10.1128/jvi.67.7.4409-4414.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen E. A., Dehni G., Sodroski J. G., Haseltine W. A. Human immunodeficiency virus vpr product is a virion-associated regulatory protein. J Virol. 1990 Jun;64(6):3097–3099. doi: 10.1128/jvi.64.6.3097-3099.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen E. A., Terwilliger E. F., Jalinoos Y., Proulx J., Sodroski J. G., Haseltine W. A. Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr. 1990;3(1):11–18. [PubMed] [Google Scholar]
- Franchini G., Reitz M. S., Jr Phylogenesis and genetic complexity of the nonhuman primate retroviridae. AIDS Res Hum Retroviruses. 1994 Sep;10(9):1047–1060. doi: 10.1089/aid.1994.10.1047. [DOI] [PubMed] [Google Scholar]
- Fukasawa M., Miura T., Hasegawa A., Morikawa S., Tsujimoto H., Miki K., Kitamura T., Hayami M. Sequence of simian immunodeficiency virus from African green monkey, a new member of the HIV/SIV group. Nature. 1988 Jun 2;333(6172):457–461. doi: 10.1038/333457a0. [DOI] [PubMed] [Google Scholar]
- Gibbs J. S., Lackner A. A., Lang S. M., Simon M. A., Sehgal P. K., Daniel M. D., Desrosiers R. C. Progression to AIDS in the absence of a gene for vpr or vpx. J Virol. 1995 Apr;69(4):2378–2383. doi: 10.1128/jvi.69.4.2378-2383.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guyader M., Emerman M., Montagnier L., Peden K. VPX mutants of HIV-2 are infectious in established cell lines but display a severe defect in peripheral blood lymphocytes. EMBO J. 1989 Apr;8(4):1169–1175. doi: 10.1002/j.1460-2075.1989.tb03488.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guyader M., Emerman M., Sonigo P., Clavel F., Montagnier L., Alizon M. Genome organization and transactivation of the human immunodeficiency virus type 2. Nature. 1987 Apr 16;326(6114):662–669. doi: 10.1038/326662a0. [DOI] [PubMed] [Google Scholar]
- Hattori N., Michaels F., Fargnoli K., Marcon L., Gallo R. C., Franchini G. The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages. Proc Natl Acad Sci U S A. 1990 Oct;87(20):8080–8084. doi: 10.1073/pnas.87.20.8080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- He J., Choe S., Walker R., Di Marzio P., Morgan D. O., Landau N. R. Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J Virol. 1995 Nov;69(11):6705–6711. doi: 10.1128/jvi.69.11.6705-6711.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzinger N. K., Bukrinsky M. I., Haggerty S. A., Ragland A. M., Kewalramani V., Lee M. A., Gendelman H. E., 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. doi: 10.1073/pnas.91.15.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henderson L. E., Sowder R. C., Copeland T. D., Benveniste R. E., Oroszlan S. Isolation and characterization of a novel protein (X-ORF product) from SIV and HIV-2. Science. 1988 Jul 8;241(4862):199–201. doi: 10.1126/science.3388031. [DOI] [PubMed] [Google Scholar]
- Hirsch V. M., Dapolito G., Johnson P. R., Elkins W. R., London W. T., Montali R. J., Goldstein S., Brown C. Induction of AIDS by simian immunodeficiency virus from an African green monkey: species-specific variation in pathogenicity correlates with the extent of in vivo replication. J Virol. 1995 Feb;69(2):955–967. doi: 10.1128/jvi.69.2.955-967.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirsch V. M., Johnson P. R. Pathogenic diversity of simian immunodeficiency viruses. Virus Res. 1994 May;32(2):183–203. doi: 10.1016/0168-1702(94)90041-8. [DOI] [PubMed] [Google Scholar]
- Hoch J., Lang S. M., Weeger M., Stahl-Hennig C., Coulibaly C., Dittmer U., Hunsmann G., Fuchs D., Müller J., Sopper S. vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys. J Virol. 1995 Aug;69(8):4807–4813. doi: 10.1128/jvi.69.8.4807-4813.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jin M. J., Hui H., Robertson D. L., Müller M. C., Barré-Sinoussi F., Hirsch V. M., Allan J. S., Shaw G. M., Sharp P. M., Hahn B. H. Mosaic genome structure of simian immunodeficiency virus from west African green monkeys. EMBO J. 1994 Jun 15;13(12):2935–2947. doi: 10.1002/j.1460-2075.1994.tb06588.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jowett J. B., Planelles V., Poon B., Shah N. P., Chen M. L., Chen I. S. 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. doi: 10.1128/jvi.69.10.6304-6313.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kappes J. C., Conway J. A., Lee S. W., Shaw G. M., Hahn B. H. Human immunodeficiency virus type 2 vpx protein augments viral infectivity. Virology. 1991 Sep;184(1):197–209. doi: 10.1016/0042-6822(91)90836-z. [DOI] [PubMed] [Google Scholar]
- Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
- Lavallée C., Yao X. J., Ladha A., Göttlinger H., Haseltine W. A., Cohen E. A. Requirement of the Pr55gag precursor for incorporation of the Vpr product into human immunodeficiency virus type 1 viral particles. J Virol. 1994 Mar;68(3):1926–1934. doi: 10.1128/jvi.68.3.1926-1934.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee M. G., Nurse P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2. Nature. 1987 May 7;327(6117):31–35. doi: 10.1038/327031a0. [DOI] [PubMed] [Google Scholar]
- Levy D. N., Fernandes L. S., Williams W. V., Weiner D. B. Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell. 1993 Feb 26;72(4):541–550. doi: 10.1016/0092-8674(93)90073-y. [DOI] [PubMed] [Google Scholar]
- Norbury C., Nurse P. Animal cell cycles and their control. Annu Rev Biochem. 1992;61:441–470. doi: 10.1146/annurev.bi.61.070192.002301. [DOI] [PubMed] [Google Scholar]
- O'Brien W. A., Koyanagi Y., Namazie A., Zhao J. Q., Diagne A., Idler K., Zack J. A., Chen I. S. HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain. Nature. 1990 Nov 1;348(6296):69–73. doi: 10.1038/348069a0. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1128/jvi.63.9.4110-4114.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paxton W., Connor R. I., Landau N. R. 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. doi: 10.1128/jvi.67.12.7229-7237.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Planelles V., Bachelerie F., Jowett J. B., Haislip A., Xie Y., Banooni P., Masuda T., Chen I. S. Fate of the human immunodeficiency virus type 1 provirus in infected cells: a role for vpr. J Virol. 1995 Sep;69(9):5883–5889. doi: 10.1128/jvi.69.9.5883-5889.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Planelles V., Haislip A., Withers-Ward E. S., Stewart S. A., Xie Y., Shah N. P., Chen I. S. A new reporter system for detection of retroviral infection. Gene Ther. 1995 Aug;2(6):369–376. [PubMed] [Google Scholar]
- Re F., Braaten D., Franke E. K., Luban J. Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin B. J Virol. 1995 Nov;69(11):6859–6864. doi: 10.1128/jvi.69.11.6859-6864.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Regier D. A., Desrosiers R. C. The complete nucleotide sequence of a pathogenic molecular clone of simian immunodeficiency virus. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1221–1231. doi: 10.1089/aid.1990.6.1221. [DOI] [PubMed] [Google Scholar]
- Rogel M. E., Wu L. I., Emerman M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J Virol. 1995 Feb;69(2):882–888. doi: 10.1128/jvi.69.2.882-888.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schmid I., Uittenbogaart C. H., Giorgi J. V. 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. doi: 10.1002/cyto.990120312. [DOI] [PubMed] [Google Scholar]
- Spurr N. K., Gough A. C., Lee M. G. Cloning of the mouse homologue of the yeast cell cycle control gene cdc2. DNA Seq. 1990;1(1):49–54. doi: 10.3109/10425179009041346. [DOI] [PubMed] [Google Scholar]
- Tristem M., Marshall C., Karpas A., Hill F. Evolution of the primate lentiviruses: evidence from vpx and vpr. EMBO J. 1992 Sep;11(9):3405–3412. doi: 10.1002/j.1460-2075.1992.tb05419.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson I. A., Niman H. L., Houghten R. A., Cherenson A. R., Connolly M. L., Lerner R. A. The structure of an antigenic determinant in a protein. Cell. 1984 Jul;37(3):767–778. doi: 10.1016/0092-8674(84)90412-4. [DOI] [PubMed] [Google Scholar]
- Wu X., Conway J. A., Kim J., Kappes J. C. Localization of the Vpx packaging signal within the C terminus of the human immunodeficiency virus type 2 Gag precursor protein. J Virol. 1994 Oct;68(10):6161–6169. doi: 10.1128/jvi.68.10.6161-6169.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang L., Farin C. E. Identification of cDNAs encoding bovine cyclin B and Cdk1/Cdc2. Gene. 1994 Apr 20;141(2):283–286. doi: 10.1016/0378-1119(94)90586-x. [DOI] [PubMed] [Google Scholar]
- Yu X. F., Matsuda M., Essex M., Lee T. H. Open reading frame vpr of simian immunodeficiency virus encodes a virion-associated protein. J Virol. 1990 Nov;64(11):5688–5693. doi: 10.1128/jvi.64.11.5688-5693.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yu X. F., Yu Q. C., Essex M., Lee T. H. The vpx gene of simian immunodeficiency virus facilitates efficient viral replication in fresh lymphocytes and macrophage. J Virol. 1991 Sep;65(9):5088–5091. doi: 10.1128/jvi.65.9.5088-5091.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yuan X., Matsuda Z., Matsuda M., Essex M., Lee T. H. Human immunodeficiency virus vpr gene encodes a virion-associated protein. AIDS Res Hum Retroviruses. 1990 Nov;6(11):1265–1271. doi: 10.1089/aid.1990.6.1265. [DOI] [PubMed] [Google Scholar]