Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Evidence for a newly discovered cellular anti-HIV-1 phenotype

Abstract

Animal cells have developed many ways to suppress viral replication, and viruses have evolved diverse strategies to resist these. Here we provide evidence that the virion infectivity factor protein of human immunodeficiency virus type 1 (HIV-1) functions to counteract a newly discovered activity in human cells that otherwise inhibits virus replication. This anti-viral phenotype is shown by human T cells, the principal in vivo targets for HIV-1, and, based on our present understanding of virion infectivity factor action, is presumed to act by interfering with a late step(s) in the virus life cycle. These observations indicate that the inhibition of virion infectivity factor function in vivo may prevent HIV-1 replication by 'unmasking' an innate anti-viral phenotype.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Vif is required for HIV-1 infectivity in HUT78 cells, but not in CEM-SS or 293T cells.
Figure 2: Strategy for the production of HIV-1 from transient T cell-293T heterokaryons.
Figure 3: Infectivities of HIV-1/Δvif and HIV-1 produced from heterokaryons.
Figure 4: Effects of time and cell ratio on Vif function in heterokaryons.

Similar content being viewed by others

References

  1. Steeves, R. & Lilly, F. Interactions between host and viral genomes in mouse leukemia. Ann. Rev. Genet. 11, 277–296 (1977).

    Article  CAS  PubMed  Google Scholar 

  2. Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–725 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Smith, M. et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Science 277, 959–965 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Winkler, C. et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 279, 389– 393 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Simon, J. H. M. et al. The regulation of primate immunodeficiency virus infectivity by Vif is cell species restricted: a role for Vif in determining virus host range and cross-species transmission. EMBO J. 17, 1259–1267 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fisher, A. G. et al. The sor gene of HIV-1 is required for efficient virus transmission in vitro. Science 237, 888– 893 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. Strebel, K. et al. The HIV "A" (sor) gene product is essential for virus infectivity. Nature 328, 728– 730 (1987).

    Article  CAS  PubMed  Google Scholar 

  9. Gabuzda, D. H. et al. Role of vif in replication of human immunodeficiency virus type 1 in + T lymphocytes. J. Virol. 66, 6489–6495 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. von Schwedler, U., Song, J., Aiken, C. & Trono, D. vif is crucial for human immunodeficiency virus type 1 proviral DNA synthesis in infected cells. J. Virol. 67, 4945– 4955 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Tomonaga, K. et al. Identification of a feline immunodeficiency virus gene which is essential for cell-free virus infectivity. J. Virol. 66, 6181–6185 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Simon, J.H.M., Southerling, T.E., Peterson, J.C., Meyer, B.E. & Malim, M.H. Complementation of vif-defective human immunodeficiency virus type 1 by primate, but not nonprimate, lentivirus vif genes. J. Virol. 69, 4166– 4172 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Reddy, T.R. et al. Comparative analyses of human immunodeficiency virus type 1 (HIV-1) and HIV-2 Vif mutants. J. Virol. 69, 3549–3553 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Harmache, A. et al. Requirement of caprine arthritis encephalitis virus vif gene for in vivo replication. Virology 224, 246–255 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Desrosiers, R. C. et al. Identification of highly attenuated mutants of simian immunodeficiency virus. J. Virol. 72, 1431– 1437 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Fan, L. & Peden, K. Cell-free transmission of Vif mutants of HIV-1. Virology 190, 19– 29 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. Sakai, H. et al. Cell-dependent requirement of human immunodeficiency virus type 1 Vif protein for maturation of virus particles. J. Virol. 67, 1663–1666 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Sova, P. & Volsky, D.J. Efficiency of viral DNA synthesis during infection of permissive and nonpermissive cells with vif-negative human immunodeficiency virus type 1. J. Virol. 67, 6322–6326 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Simon, J.H.M. & Malim, M.H. The human immunodeficiency virus type 1 Vif protein modulates the postpenetration stability of viral nucleoprotein complexes. J. Virol. 70, 5297– 5305 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fouchier, R.A.M., Simon, J.H.M., Jaffe, A.B. & Malim, M.H. Human immunodeficiency virus type 1 Vif does not influence expression or virion incorporation of gag-, pol- and env-encoded proteins. J. Virol. 70, 8263–8269 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bouyac, M. et al. Phenotypically Vif human immunodeficiency virus type 1 is produced by chronically infected restrictive cells. J. Virol. 71, 2473–2477 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mèvel-Ninio, M. & Weiss, M.C. Immunofluorescence analysis of the time-course of extinction, reexpression, and activation of albumin production in rat hepatoma-mouse fibroblast heterokaryons and hybrids. J. Cell. Biol. 90, 339– 350 (1981).

    Article  PubMed  Google Scholar 

  23. Beggs, A.H., Frisque, R.J. & Scangos, G.A. Extinction of JC virus tumor-antigen expression in glial cell-fibroblast hybrids. Proc. Natl. Acad. Sci. USA 85, 7632–7636 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Goncalves, J., Korin, Y., Zack, J. & Gabuzda, D. Role of Vif in human immunodeficiency virus type 1 reverse transcription. J. Virol. 70, 8701–8709 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Simon, J.H.M. et al. The Vif and Gag proteins of human immunodeficiency virus type 1 colocalize in infected human T cells. J. Virol. 71, 5259–5267 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Marrack, P. & Kappler, J. Subversion of the immune system by pathogens. Cell 76, 323– 332 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Smith, G.L. Virus proteins that bind cytokines, chemokines or interferons. Curr. Opin. Immunol. 8, 467–471 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Ploegh, H.L. Viral strategies of immune evasion. Science 280, 248–253 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Moss, B. in Fields Virology (eds Fields, B.N., Knipe, D.M. & Howley, P.M.) 2637–2671 (Lippincott-Raven, Philadelphia, 1996).

    Google Scholar 

  30. Bertin, J. et al. Death effector domain-containing herpes-virus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc. Natl. Acad. Sci. USA 94, 1172–1176 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hu, S., Vincenz, C., Buller, M. & Dixit, V.M. A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis. J. Biol. Chem. 272, 9621–9624 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517– 521 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Katze, M.G. Regulation of the interferon-induced PKR: can viruses cope? Trends Microbiol. 3, 75–78 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Mathews, M.B. Structure, function and evolution of adenovirus virus-associated RNAs. Curr. Top. Microbiol. Immunol. 199, 173– 187 (1995).

    CAS  PubMed  Google Scholar 

  35. Best, S., Le Tissier, P., Towers, G. & Stoye, J.P. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 382, 826–829 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. DesGroseillers, L. & Jolicoeur, P. Physical mapping of the Fv-1 tropism host range determinant of BALB/c murine leukemia viruses. J. Virol. 48, 685–696 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dubay, J.W., Roberts, S.J., Hahn, B.H. & Hunter, E. Truncation of the human immunodeficiency virus type 1 transmembrane glycoprotein cytoplasmic domain blocks virus infectivity. J. Virol. 66, 6616–6625 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Felber, B.K. & Pavlakis, G.N. A quantitative bioassay for HIV-1 based on trans-activation. Science 239, 184–187 (1988).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank P. Bates, T. Kadesch, V. Pollard and A. Sheehy for discussions, and L. Zimmerman for secretarial support. N.C.G. is a National Science Foundation pre-doctoral fellow. This work was supported by the Howard Hughes Medical Institute and US Public Service grant AI38715 from NIAID.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael H. Malim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simon, J., Gaddis, N., Fouchier, R. et al. Evidence for a newly discovered cellular anti-HIV-1 phenotype. Nat Med 4, 1397–1400 (1998). https://doi.org/10.1038/3987

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/3987

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing