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Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein

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Abstract

Viruses have developed diverse non-immune strategies to counteract host-mediated mechanisms that confer resistance to infection. The Vif (virion infectivity factor) proteins are encoded by primate immunodeficiency viruses, most notably human immunodeficiency virus-1 (HIV-1). These proteins are potent regulators of virus infection and replication and are consequently essential for pathogenic infections in vivo1,2,3,4,5,6. HIV-1 Vif seems to be required during the late stages of virus production3,6 for the suppression of an innate antiviral phenotype that resides in human T lymphocytes7,8. Thus, in the absence of Vif, expression of this phenotype renders progeny virions non-infectious. Here, we describe a unique cellular gene, CEM15, whose transient or stable expression in cells that do not normally express CEM15 recreates this phenotype, but whose antiviral action is overcome by the presence of Vif. Because the Vif:CEM15 regulatory circuit is critical for HIV-1 replication, perturbing the circuit may be a promising target for future HIV/AIDS therapies.

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Figure 1: Replication of HIV-1 in non-permissive and permissive T cells.
Figure 2: Northern analysis of CEM15 expression in non-permissive and permissive cells.
Figure 3: Expression of CEM15 in permissive cells inhibits the infectivity of HIV-1/Δvif.
Figure 4: Stable expression of CEM15 in CEM-SS cells selectively inhibits HIV-1/Δvif replication.
Figure 5: Incorporation of CEM15 into virions.
Figure 6: Amino-acid sequence of CEM15.

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References

  1. 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 

  2. 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  ADS  CAS  PubMed  Google Scholar 

  3. Gabuzda, D. H. et al. Role of vif in replication of human immunodeficiency virus type 1 in CD4+ T lymphocytes. J. Virol. 66, 6489–6495 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  6. 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 

  7. Madani, N. & Kabat, D. An endogenous inhibitor of human immunodeficiency virus in human lymphocytes is overcome by the viral Vif protein. J. Virol. 72, 10251–10255 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Simon, J. H. M., Gaddis, N. C., Fouchier, R. A. M. & Malim, M. H. Evidence for a newly discovered cellular anti-HIV-1 phenotype. Nature Med. 4, 1397–1400 (1998)

    Article  CAS  PubMed  Google Scholar 

  9. Foley, G. E. et al. Loss of neoplastic properties in vitro. II. Observations on KB sublines. Cancer Res. 25, 1254–1261 (1965)

    CAS  PubMed  Google Scholar 

  10. Nara, P. L. & Fischinger, P. J. Quantitative infectivity assay for HIV-1 and -2. Nature 332, 469–470 (1988)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Hassaine, G. et al. The tyrosine kinase Hck is an inhibitor of HIV-1 replication counteracted by the viral vif protein. J. Biol. Chem. 276, 16885–16893 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Camaur, D. & Trono, D. Characterization of human immunodeficiency virus type 1 Vif particle incorporation. J. Virol. 70, 6106–6111 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Liu, H. et al. The Vif protein of human and simian immunodeficiency viruses is packaged into virions and associates with viral core structures. J. Virol. 69, 7630–7638 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Teng, B., Burant, C. F. & Davidson, N. O. Molecular cloning of an apolipoprotein B messenger RNA editing protein. Science 26, 1816–1819 (1993)

    Article  ADS  Google Scholar 

  16. Madsen, P. et al. Psoriasis upregulated phorbolin-1 shares structural but not functional similarity to the mRNA-editing protein apobec-1. J. Invest. Dermatol. 113, 162–169 (1999)

    Article  CAS  PubMed  Google Scholar 

  17. Bhattacharya, S., Navaratnam, N., Morrison, J. R., Scott, J. & Taylor, W. R. Cytosine nucleoside/nucleotide deaminases and apolipoprotein B mRNA editing. Trends Biochem. Sci. 19, 105–106 (1994)

    Article  CAS  PubMed  Google Scholar 

  18. MacGinnitie, A. J., Anant, S. & Davidson, N. O. Mutagenesis of apobec-1, the catalytic subunit of the mammalian apolipoprotein B mRNA editing enzyme, reveals distinct domains that mediate cytosine nucleoside deaminase, RNA binding, and RNA editing activity. J. Biol. Chem. 270, 14768–14775 (1995)

    Article  CAS  PubMed  Google Scholar 

  19. Smith, A. A., Carlow, D. C., Wolfenden, R. & Short, S. A. Mutations affecting transition-state stabilization by residues coordinating zinc at the active site of cytidine deaminase. Biochemistry 33, 6468–6474 (1994)

    Article  CAS  PubMed  Google Scholar 

  20. Dettenhofer, M., Cen, S., Carlson, B. A., Kleiman, L. & Yu, X.-F. Association of human immunodeficiency virus type 1 Vif with RNA and its role in reverse transcription. J. Virol. 74, 8938–8945 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Khan, M. A. et al. Human immunodeficiency virus type 1 Vif protein is packaged into the nucleoprotein complex through an interaction with viral genomic RNA. J. Virol. 75, 7252–7265 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, H., Pomerantz, R. J., Dornadula, G. & Sun, Y. Human immunodeficiency virus type 1 Vif protein is an integral component of an mRNP complex of viral RNA and could be involved in the viral RNA folding and packaging process. J. Virol. 74, 8252–8261 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Courcoul, M. et al. Peripheral blood mononuclear cells produce normal amounts of defective Vif- human immunodeficiency virus type 1 particle which are restricted for the preretrotranscription steps. J. Virol. 69, 2068–2074 (1995)

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 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 

  25. 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 

  26. Pryciak, P. M. & Varmus, H. E. Fv-1 restriction and its effects on murine leukemia virus integration in vivo and in vitro. J. Virol. 66, 5959–5966 (1992)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Towers, G. et al. A conserved mechanism of retrovirus restriction in mammals. Proc. Natl Acad. Sci. USA 97, 12295–12299 (2000)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fouchier, R. A. M., Meyer, B. E., Simon, J. H. M., Fischer, U. & Malim, M. H. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J. 16, 4531–4539 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pear, W. S. et al. Efficient and rapid induction of a chronic myelogenous leukemia-like myeloproliferative disease in mice receiving P210 bcr/abl-transduced bone marrow. Blood 92, 3780–3792 (1998)

    CAS  PubMed  Google Scholar 

  30. 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 

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Acknowledgements

We thank D. Gabuzda for the CEM cells. This work was supported by Research Grants from the National Institutes of Health (M.H.M. and A.M.S.), the National Science Foundation (N.C.G.) and the UK Medical Research Council (M.H.M.). M.H.M. is an Elizabeth Glaser Scientist supported by the Elizabeth Glaser Pediatric AIDS Foundation.

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Authors and Affiliations

  1. Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA

    Ann M. Sheehy, Nathan C. Gaddis & Michael H. Malim

  2. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA

    Jonathan D. Choi

  3. Department of Infectious Diseases, Guy's, King's and St Thomas' School of Medicine, King's College London, SE1 9RT, London, UK

    Michael H. Malim

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  1. Ann M. Sheehy
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Correspondence to Michael H. Malim.

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Sheehy, A., Gaddis, N., Choi, J. et al. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418, 646–650 (2002). https://doi.org/10.1038/nature00939

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