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HIV accessory proteins as therapeutic targets

Nature Medicine volume 3, pages 389–394 (1997)Cite this article

Abstract

Viral regulatory proteins represent new targets for therapeutic and prevention strategies against HIV.

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References

  1. Pantaleo, G. & Fauci, A.S. Immunopathogenesis of HIV infection. Annu. Rev. Microbiol. 50, 825–854 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Richman, D.D. Clinical significance of drug resistance in human immunodeficiency virus. Clin. Infect. Dis. 21 (Suppl. 2), S166–169 (1995).

    Article  PubMed  Google Scholar 

  3. Kestler, H.W. et al. Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65, 651–662 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Wyand, M.S., Manson, K.H., Garcia-Moll, M., Montefiori, D. & Desrosiers, R.C. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. J. Virol. 70, 3724–3733 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Heinzinger, N.K. et al. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc. Natl. Acad. Sci USA 91, 7311–7315 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yao, X.-J. et al. Mutagenic analysis of human immunodeficiency virus type 1 Vpr: Role of a predicted N-terminal alpha-helical structure in Vpr nuclear localization and virion incorporation. J. Virol. 69, 7032–7044 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Dubrovsky, L. et al. Nuclear localization signal of HIV-1 as a novel target for therapeutic intervention. Mol. Med. 1, 217–230 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jowett, J.B.M. et al. The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2+M phase of the cell cycle. J. Virol. 69, 6304–6313 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. He, J. et al. 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. 69, 6705–6711 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Re, F., Braaten, D., Franke, E.K. & Luban, J. Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 inhibiting the activation of p34cdc2-cyclin B. J. Virol. 69, 6859–6864 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. DiMarzio, P., Choe, S., Ebright, M., Knoblauch, R. & Landau, N.R. Mutational analysis of cell cycle arrest, nuclear localization, and virion packaging of human immunodeficiency virus type 1 Vpr. J. Virol. 69, 7909–7916 (1995).

    CAS  Google Scholar 

  12. Bartz, S.R., Rogel, M.E. & Emerman, M. Human immunodeficiency virus type 1 cell cycle control: Vpr is cytostatic and mediates G2 accumulation by a mechanism which differs from DNA damage checkpoint control. J. Virol. 70, 2324–2331 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wei, X. et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 373, 117–122 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Ho, D.D. et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 373, 123–126 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Levy, D.N., Fernandes, L.S., Williams, W.V. & Weiner, D.B. Induction of cell differentiation by human immunodeficiency virus 1 Vpr. Cell 72, 541–550 (1993.

    Article  CAS  PubMed  Google Scholar 

  16. Maldarelli, F., Chen, M.Y., Willey, R.L. & Strebel, K. Human immunodeficiency virus type 1 Vpu protein is an oligomeric type 1 integral membrane protein. J. Virol. 67, 5056–5061 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Willey, R.L., Maldrelli, F., Martin, M.A. & Strebel, K. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J. Virol. 66, 7193–7200 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bour, S., Schubert, U. & Strebel, K. The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: Implications for the mechanism of degradation. J. Virol. 69, 1510–1520 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Yao, X.-J. et al. Degradation of CD4 induced by human immunodeficiency virus type 1 Vpu protein: A predicted alpha-helix structure in the proximal cytoplasmic region of CD4 contributes to Vpu sensitivity. Virology 209, 615–623 (1995).

    Article  CAS  PubMed  Google Scholar 

  20. Göttlinger, H.G., Dorfman, T., Cohen, E.A. & Haseltine, W.A. Vpu protein of human immunodeficiency virus type 1 enhances the release of capsids produced by gag gene constructs of widely divergent retroviruses. Proc. Natl. Acad. Sci. USA 90, 7381–7385 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ewart, G.D., Sutherland, T., Gage, P.W. & Cox, G.B., Vpu protein of human immunodeficiency virus type 1 forms cation-selective ion channels. J. Virol. 70, 7108–7115 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Schubert, U. et al. Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1 infected cells. FEBS Let. 398, 12–18 (1996).

    Article  CAS  Google Scholar 

  23. Schubert, U. et al. The two biological activities of human immunodeficiency virus type 1 Vpu protein involve two separable structural domains. J. Virol. 70, 809–819 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Goncalves, J., Jallepalli, P. & Gabuzda, D.H., Subcellular localization of the Vif protein of human immunodeficiency virus type 1. J. Virol. 68, 704–712 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang, X., Goncalves, J. & Gabuzda, D. Phosphorylation of Vif and its role in HIV-1 replication. J. Biol. Chem. 271, 10121–10129 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Karczewski, M.K. & Strebel, K. Cytoskeleton association and virion incorporation of the human immunodeficiency virus type 1 Vif protein. J. Virol. 70, 494–507 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. 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 

  29. 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 

  30. Franchini, G., Robert-Guroff, M., Ghrayeb, J., Chang, N.T. & Wong-Staal, F. Cytoplasmic localization of the HTLV-III 3′ orf protein in cultured T cells. Virology 155, 593–599 (1986).

    Article  CAS  PubMed  Google Scholar 

  31. Aiken, C., Konner, J., Landau, N.R., Lenburg, M.E. & Trono, D. Nef induces CD4 endocytosis: Requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76, 853–864 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Miller, M.D., Warmerdam, M.T., Gaston, I., Greene, W.C. & Feinberg, M.B. The human immunodeficiency virus-1 nef gene product: A positive factor for viral infection and replication in primary lymphocytes and macrophages. J. Exp. Med. 179, 101–113 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Spina, C.A., Kwoh, T.J., Chowers, M.Y., Guatelli, J.C. & Richman, D.D. The importance of nef in the induction of human immunodeficiency virus type 1 replication from primary quiescent CD4 lymphocytes. J. Exp. Med. 179, 115–123 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Goldsmith, M.A., Warmerdam, M.T., Atchison, R.E., Miller, M.D. & Greene, W. Dissociation of the CD4 downregulation and viral infectivity enhancement functions of human immunodeficiency virus type 1 Nef. J. Virol. 69, 4112–4121 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Welker, R., Kottler, H., Kalbitzer, H.R. & Krausslich, H.-G. Human immunodeficiency virus type 1 Nef protein is incorporated into virus particles and specifically cleaved by the viral proteinase. Virology 219, 228–236 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Pandori, M.W. et al. Producer-cell modification of human immunodeficiency virus type 1: Nef is a virion protein. J. Virol. 70, 4283–4290 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Bukovsky, A.A., Dorfman, T., Weimann, A. & Gottlinger, H.G. Nef association with human immunodeficiency virus type 1 virions and cleavage by the viral protease. J. Virol. 71, 1013–1018 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sawai, E.T., Baur, A.S., Peterlin, B.M., Levy, J.A. & Cheng-Mayer, C. A conserved domain and membrane targeting of Nef from HIV and SIV are required for association with a cellular serine kinase activity. J. Biol.Chem. 270, 15307–15314 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Nunn, M.F. & Marsh, J.W. Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family. J. Virol. 70, 6157–6161 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Deacon, N.J. et al. Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270, 988–991 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Refaeli, Y., Levy, D.N. & Weiner, D.B. The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc. Natl. Acad. Sci. USA 92, 3621–3625 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee, C.-H., Saksela, K., Mirza, U.A., Chait, B.T. & Kuriyan, J. Crystal structure of the conserved core of HIV-1 Nef complexed with a Src family SH3 domain. Cell 85, 931–942 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Grzesiek, S. et al. The solution structure of HIV-1 Nef reveals an unexpected fold and permits delineation of the binding surface for the SH3 domain of Hck tyro-sine kinase. Nature Struct. Biol. 3, 340–345 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Grzesiek, S., Stahl, S.J., Wingfield, P.T. & Bax, A. The CD4 determinant for down-regulation by HIV-1 Nef binding surface by NMR. Biochemistry 35, 10256–10261 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Lu, Y.-L., Bennett, R.P., Wills, J.W., Gorelick, R. & Ratner, L. A leucine triplet repeat sequence (LXX)4 in p6gag is important for Vpr incorporation into human immunodeficiency virus type 1 particles. J. Virol. 69, 6873–6879 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Kondo, E. & Gottlinger, H.G. A conserved LXXLF sequence is the major determinant in p6gagrequired for the incorporation of human immunodeficiency virus type 1 Vpr. J. Virol. 70, 159–164 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu, X. et al. Targeting foreign proteins to human immunodeficiency virus particles via fusion with Vpr and Vpx. J. Virol. 69, 3389–3398 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Woffendin, C., Ranga, U., Yang, Z., Xu, L. & Nabel, G. Expression of a protective gene prolongs survival of T cells in human immunodeficiency virus-infected patients. Proc. Natl. Acad. Sci. USA 93, 2889–2894 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bridges, S.H. & Sarver, N. Gene therapy and immune restoration for HIV disease. Lancet 345, 427–432 (1995).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Targeted Interventions Branch, Basic Sciences Program, Division of AIDS, National Institute of Allergy and Infectious Diseases Correspondance should be addressed to R.M. at DAIDS, NIAID, Solar Building, Room 2C36A, 6003 Executive Boulevard, MSC 7620, Bethesda, Maryland, 20892-7620, USA

    Roger H. Miller & Nava Sarver

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Miller, R., Sarver, N. HIV accessory proteins as therapeutic targets. Nat Med 3, 389–394 (1997). https://doi.org/10.1038/nm0497-389

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