1887

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Volume 95, Issue 3

Human immunodeficiency virus type 1 Vpr polymorphisms associated with progressor and nonprogressor individuals alter Vpr-associated functions Free

Abstract

Following infection with (HIV-1) there is a remarkable variation in virus replication and disease progression. Both host and viral factors have been implicated in the observed differences in disease status. Here, we focus on understanding the contribution of HIV-1 viral protein R (Vpr) by evaluating the disease-associated Vpr polymorphism and its biological functions from HIV-1 positive rapid progressor (RP) and long-term nonprogressor (LTNP) subjects. Results presented here show distinct variation in phenotypes of Vpr alleles from LTNP and RP subjects. Most notably, the polymorphism of Vpr at R36W and L68M associated with RP shows higher levels of oligomerization, and increased virus replication, whereas R77Q exhibits poor replication kinetics. Interestingly, we did not observe correlation with cell cycle arrest function. Together these results indicate that polymorphisms in Vpr in part may contribute to altered virus replication kinetics leading to the observed differences in disease progression in LTNP and RP groups.

  • Received:
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© 2014 SGM
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2014-03-01
2024-04-24
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References

  1. Andreoni M. 2004; Viral phenotype and fitness. New Microbiol 27:Suppl. 171–76[PubMed]
     [Google Scholar]
  2. Bimber B. N., Chugh P., Giorgi E. E., Kim B., Almudevar A. L., Dewhurst S., O’Connor D. H., Lee H. Y. 2009; Nef gene evolution from a single transmitted strain in acute SIV infection. Retrovirology 6:57 [View Article][PubMed]
     [Google Scholar]
  3. Caly L., Saksena N. K., Piller S. C., Jans D. A. 2008; Impaired nuclear import and viral incorporation of Vpr derived from a HIV long-term non-progressor. Retrovirology 5:67 [View Article][PubMed]
     [Google Scholar]
  4. Cavert W., Webb C. H., Balfour H. H. Jr 2004; Alterations in the C-terminal region of the HIV-1 accessory gene vpr do not confer clinical advantage to subjects receiving nucleoside antiretroviral therapy. J Infect Dis 189:2181–2184 [View Article][PubMed]
     [Google Scholar]
  5. Chui C., Cheung P. K., Brumme C. J., Mo T., Brumme Z. L., Montaner J. S., Badley A. D., Harrigan P. R. 2006; HIV VprR77Q mutation does not influence clinical response of individuals initiating highly active antiretroviral therapy. AIDS Res Hum Retroviruses 22:615–618 [View Article][PubMed]
     [Google Scholar]
  6. Cohen E. A., Dehni G., Sodroski J. G., Haseltine W. A. 1990; Human immunodeficiency virus vpr product is a virion-associated regulatory protein. J Virol 64:3097–3099[PubMed]
     [Google Scholar]
  7. Fang G., Burger H., Chappey C., Rowland-Jones S., Visosky A., Chen C. H., Moran T., Townsend L., Murray M., Weiser B. 2001; Analysis of transition from long-term nonprogressive to progressive infection identifies sequences that may attenuate HIV type 1. AIDS Res Hum Retroviruses 17:1395–1404 [View Article][PubMed]
     [Google Scholar]
  8. Fritz J. V., Didier P., Clamme J.-P., Schaub E., Muriaux D., Cabanne C., Morellet N., Bouaziz S., Darlix J.-L. other authors 2008; Direct Vpr–Vpr interaction in cells monitored by two photon fluorescence correlation spectroscopy and fluorescence lifetime imaging. Retrovirology 5:87 [View Article][PubMed]
     [Google Scholar]
  9. Gummuluru S., Emerman M. 1999; Cell cycle- and Vpr-mediated regulation of human immunodeficiency virus type 1 expression in primary and transformed T-cell lines. J Virol 73:5422–5430[PubMed]
     [Google Scholar]
  10. Holzmayer V., Aitken C., Skinner C., Ryall L., Devare S. G., Hackett J. Jr 2009; Characterization of genetically diverse HIV type 1 from a London cohort: near full-length genomic analysis of a subtype H strain. AIDS Res Hum Retroviruses 25:721–726 [View Article][PubMed]
     [Google Scholar]
  11. Hrimech M., Yao X. J., Bachand F., Rougeau N., Cohen E. A. 1999; Human immunodeficiency virus type 1 (HIV-1) Vpr functions as an immediate-early protein during HIV-1 infection. J Virol 73:4101–4109[PubMed]
     [Google Scholar]
  12. Iijima S., Nitahara-Kasahara Y., Kimata K., Zhong Zhuang W., Kamata M., Isogai M., Miwa M., Tsunetsugu-Yokota Y., Aida Y. 2004; Nuclear localization of Vpr is crucial for the efficient replication of HIV-1 in primary CD4+ T cells. Virology 327:249–261 [View Article][PubMed]
     [Google Scholar]
  13. Levy J. A. 2006; HIV pathogenesis: knowledge gained after two decades of research. Adv Dent Res 19:10–16 [View Article][PubMed]
     [Google Scholar]
  14. Levy D. N., Refaeli Y., Weiner D. B. 1995; Extracellular Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J Virol 69:1243–1252[PubMed]
     [Google Scholar]
  15. Lum J. J., Cohen O. J., Nie Z., Weaver J. G., Gomez T. S., Yao X.-J., Lynch D., Pilon A. A., Hawley N. other authors 2003a; Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. J Clin Invest 111:1547–1554[PubMed] [CrossRef]
     [Google Scholar]
  16. Lum J. J., Cohen O. J., Nie Z., Weaver J. G., Gomez T. S., Yao X. J., Lynch D., Pilon A. A., Hawley N. other authors 2003b; Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis. J Clin Invest 111:1547–1554[PubMed] [CrossRef]
     [Google Scholar]
  17. Mahalingam S., Ayyavoo V., Patel M., Kieber-Emmons T., Weiner D. B. 1997; Nuclear import, virion incorporation, and cell cycle arrest/differentiation are mediated by distinct functional domains of human immunodeficiency virus type 1 Vpr. J Virol 71:6339–6347[PubMed]
     [Google Scholar]
  18. Majumder B., Venkatachari N. J., Srinivasan A., Ayyavoo V. 2009; HIV-1 mediated immune pathogenesis: spotlight on the role of viral protein R (Vpr). Curr HIV Res 7:169–177 [View Article][PubMed]
     [Google Scholar]
  19. Mologni D., Citterio P., Menzaghi B., Poma B. Z., Riva C., Broggini V., Sinicco A., Milazzo L., Adorni F. other authors 2006; Vpr and HIV-1 disease progression: R77Q mutation is associated with long-term control of HIV-1 infection in different groups of patients. AIDS 20:567–574 [View Article][PubMed]
     [Google Scholar]
  20. Morellet N., Bouaziz S., Petitjean P., Roques B. P. 2003; NMR structure of the HIV-1 regulatory protein VPR. J Mol Biol 327:215–227 [View Article][PubMed]
     [Google Scholar]
  21. Morellet N., Roques B. P., Bouaziz S. 2009; Structure–function relationship of Vpr: biological implications. Curr HIV Res 7:184–210 [View Article][PubMed]
     [Google Scholar]
  22. Nitahara-Kasahara Y., Kamata M., Yamamoto T., Zhang X., Miyamoto Y., Muneta K., Iijima S., Yoneda Y., Tsunetsugu-Yokota Y., Aida Y. 2007; Novel nuclear import of Vpr promoted by importin α is crucial for human immunodeficiency virus type 1 replication in macrophages. J Virol 81:5284–5293 [View Article][PubMed]
     [Google Scholar]
  23. Pham T. N. Q., Richard J., Gerard F. C. A., Power C., Cohen É. A. 2011; Modulation of NKG2D-mediated cytotoxic functions of natural killer cells by viral protein R from HIV-1 primary isolates. J Virol 85:12254–12261 [View Article][PubMed]
     [Google Scholar]
  24. Poon B., Chen I. S. 2003; Human immunodeficiency virus type 1 (HIV-1) Vpr enhances expression from unintegrated HIV-1 DNA. J Virol 77:3962–3972 [View Article][PubMed]
     [Google Scholar]
  25. Popov S., Rexach M., Ratner L., Blobel G., Bukrinsky M. 1998; Viral protein R regulates docking of the HIV-1 preintegration complex to the nuclear pore complex. J Biol Chem 273:13347–13352 [View Article][PubMed]
     [Google Scholar]
  26. Reinis M., Weiser B., Kuiken C., Dong T., Lang D., Nachman S., Zhang Y., Rowland-Jones S., Burger H. 2007; Genomic analysis of HIV type 1 strains derived from a mother and child pair of long-term nonprogressors. AIDS Res Hum Retroviruses 23:309–315 [View Article][PubMed]
     [Google Scholar]
  27. Rhodes D. I., Ashton L., Solomon A., Carr A., Cooper D., Kaldor J., Deacon N. Australian Long-Term Nonprogressor Study Group 2000; Characterization of three nef-defective human immunodeficiency virus type 1 strains associated with long-term nonprogression. J Virol 74:10581–10588 [View Article][PubMed]
     [Google Scholar]
  28. Rodés B., Toro C., Paxinos E., Poveda E., Martinez-Padial M., Benito J. M., Jimenez V., Wrin T., Bassani S., Soriano V. 2004; Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection. AIDS 18:1109–1116 [View Article][PubMed]
     [Google Scholar]
  29. Romani B., Glashoff R., Engelbrecht S. 2009; Molecular and phylogenetic analysis of HIV type 1 vpr sequences of South African strains. AIDS Res Hum Retroviruses 25:357–362 [View Article][PubMed]
     [Google Scholar]
  30. Saksena N. K., Ge Y. C., Wang B., Xiang S. H., Dwyer D. E., Randle C., Palasanthiran P., Ziegler J., Cunningham A. L. 1996; An HIV-1 infected long-term non-progressor (LTNP): molecular analysis of HIV-1 strains in the vpr and nef genes. Ann Acad Med Singapore 25:848–854[PubMed]
     [Google Scholar]
  31. Shen C., Gupta P., Wu H., Chen X., Huang X., Zhou Y., Chen Y. 2008; Molecular characterization of the HIV type 1 vpr gene in infected Chinese former blood/plasma donors at different stages of diseases. AIDS Res Hum Retroviruses 24:661–666 [View Article][PubMed]
     [Google Scholar]
  32. Sherman M. P., de Noronha C. M. C., Heusch M. I., Greene S., Greene W. C. 2001; Nucleocytoplasmic shuttling by human immunodeficiency virus type 1 Vpr. J Virol 75:1522–1532 [View Article][PubMed]
     [Google Scholar]
  33. Shioda T., Nakayama E. E. 2006; Human genetic polymorphisms affecting HIV-1 diseases. Int J Hematol 84:12–17 [View Article][PubMed]
     [Google Scholar]
  34. Somasundaran M., Sharkey M., Brichacek B., Luzuriaga K., Emerman M., Sullivan J. L., Stevenson M. 2002; Evidence for a cytopathogenicity determinant in HIV-1 Vpr. Proc Natl Acad Sci U S A 99:9503–9508 [View Article][PubMed]
     [Google Scholar]
  35. Tungaturthi P. K., Sawaya B. E., Singh S. P., Tomkowicz B., Ayyavoo V., Khalili K., Collman R. G., Amini S., Srinivasan A. 2003; Role of HIV-1 Vpr in AIDS pathogenesis: relevance and implications of intravirion, intracellular and free Vpr. Biomed Pharmacother 57:20–24 [View Article][PubMed]
     [Google Scholar]
  36. Tzitzivacos D. B., Tiemessen C. T., Stevens W. S., Papathanasopoulos M. A. 2009; Viral genetic determinants of nonprogressive HIV type 1 subtype C infection in antiretroviral drug-naive children. AIDS Res Hum Retroviruses 25:1141–1148 [View Article][PubMed]
     [Google Scholar]
  37. Venkatachari N. J., Majumder B., Ayyavoo V. 2007; Human immunodeficiency virus (HIV) type 1 Vpr induces differential regulation of T cell costimulatory molecules: direct effect of Vpr on T cell activation and immune function. Virology 358:347–356 [View Article][PubMed]
     [Google Scholar]
  38. Venkatachari N. J., Walker L. A., Tastan O., Le T., Dempsey T. M., Li Y., Yanamala N., Srinivasan A., Klein-Seetharaman J. other authors 2010; Human immunodeficiency virus type 1 Vpr: oligomerization is an essential feature for its incorporation into virus particles. Virol J 7:119 [View Article][PubMed]
     [Google Scholar]
  39. Wang B., Ge Y. C., Palasanthiran P., Xiang S. H., Ziegler J., Dwyer D. E., Randle C., Dowton D., Cunningham A., Saksena N. K. 1996; Gene defects clustered at the C-terminus of the vpr gene of HIV-1 in long-term nonprogressing mother and child pair: in vivo evolution of vpr quasispecies in blood and plasma. Virology 223:224–232 [View Article][PubMed]
     [Google Scholar]
  40. Zhao L. J., Zhu H. 2004; Structure and function of HIV-1 auxiliary regulatory protein Vpr: novel clues to drug design. Curr Drug Targets Immune Endocr Metabol Disord 4:265–275 [View Article][PubMed]
     [Google Scholar]
  41. Zhao Y., Chen M., Wang B., Yang J., Elder R. T., Song X. Q., Yu M., Saksena N. K. 2002; Functional conservation of HIV-1 Vpr and variability in a mother–child pair of long-term non-progressors. Virus Res 89:103–121 [View Article][PubMed]
     [Google Scholar]
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Human immunodeficiency virus type 1 Vpr polymorphisms associated with progressor and nonprogressor individuals alter Vpr-associated functions
J. Gen. Virol. 95, 700 (2014); https://doi.org/10.1099/vir.0.059576-0
/content/journal/jgv/10.1099/vir.0.059576-0
/content/journal/jgv/10.1099/vir.0.059576-0
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