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HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor κB

Nature Medicine volume 3, pages 1117–1123 (1997)Cite this article

Abstract

The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation. We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation. However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids. In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis. This regulation of apoptosis is linked to Vpr suppression of NF-κB activity via the induction of IκB, an inhibitor of NF-κB. Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNFα and IL-4, all of which are NF-κB-dependent. The effects of Vpr could be reversed by RU486. Our finding that Vpr can regulate NF-κB supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.

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References

  1. Cohen, E.A. et al. Identification of HIV-1 Vpr product and function. J. Acquired Immune DeficSyndr. 3, 11–18 (1990).

    CAS  Google Scholar 

  2. Heinzinger, N.K. et al. The HIV-1 Vpr protein influences nuclear targeting of viral nucleic acids in non-dividing cells. Proc. Natl. Acad. Sci. USA 91, 7311–7315 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fletcher, T. et al. Nuclear import and cell cycle arrest functions of the HIV-1 Vpr protein are encoded by two separate genes in HIV-2/SIVsm. EMBO J. 15, 6155–6165 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Connor, R.I., Chen, B.K., Choe, S., Landau, N.R. Vpr is required for efficient replication of human immunodeficiency virus type 1 in mononuclear phagocytes. Virology 206, 936–94 (1995).

    Article  Google Scholar 

  5. Levy, D.N., Rafaeli, Y., & Weiner, D.B. Vpr protein increases cellular permissiveness to human immunodeficiency virus replication and reactivates virus from latency. J. Virol. 69, 1243–1252 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Levy, D.N. et al. Induction of cell differentiation by human immunodeficiency virus 1 vpr. Cell 72, 541–550 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. He, J. et al. Human immunodeficiency virus type 1 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 

  8. Rafaeli, 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  Google Scholar 

  9. Parrillo, J.E., Fauci, A.S. Mechanisms of glucocorticoid action on immune processes. Annu. Rev. Pharmacol. Toxicol. 19, 179–201 (1979).

    Article  CAS  PubMed  Google Scholar 

  10. Gonzalo, J.A., Gonzalez-Garcia, A., Martinez, C. & Kroemer, G. Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo. J. Exp. Med. 177, 1239–1246 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Wyllie, A.H. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284, 555–556 (1980).

    Article  CAS  PubMed  Google Scholar 

  12. Von Knebel Doeberitz, M. et al. Glucocorticoid hormones reduce the expression of major histocompatibility class I antigens on human epithelial cells. Eur. J. Immunol. 20, 35–40 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Fauci, A.S. Host factors and the pathogenesis of HIV-induced disease. Nature 384, 529–534 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Byron, K.A., Varigos, G. & Wootton, A. Hydrocortisone inhibition of human interleukin-4. Immunology 77, 624–626 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Gillis, S. et al. Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect of mitogen-induced lymphocyte proliferation. J. Immunol. 123, 1624–1631 (1979).

    CAS  PubMed  Google Scholar 

  16. Philibert, D. RU38486: An original multifaceted antihormone in vivo, in Adrenal Steroid Antagonism. (ed. Agarwal, M.K.) 77–101 (de Gruyter, Berlin and New York, 1984).

    Google Scholar 

  17. Tobler, A. et al. Glucocorticoids downregulate gene expression of GM-CSF, NAP-1/IL-8, and IL-6 but not of M-CSF in human fibroblasts. Blood 79, 45–51 (1992).

    CAS  PubMed  Google Scholar 

  18. Ucker, D.S. Cytotoxic T lymphocytes and glucocorticoids activate an endogenous suicide process in target cells. Nature 327, 62–64 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Helmberg, A. et al. Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor. Embo J. 14, 452–460 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Grimm, S. et al. Bcl-2 down regulates the activity of transcription factor NF-kappa B induced upon apoptosis. J. Cell Biol. 134, 13–23 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Lin, K.I. et al. Thiol agents and Bcl-2 identify an alphavirus-induced apoptotic pathway that requires activation of the transcription factor NF-kappa B. J. Cell Biol. 131, 1149–1161 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Fotedar, A. et al. Fine specificity of antigen recognition by T cell hybridoma clones specific for poly-18: A synthetic polypeptide antigen of defined sequence and conformation. J. Immunol. 135, 3028–3033 (1985).

    CAS  PubMed  Google Scholar 

  23. Lu, W. et al. Glucocorticoids rescue CD4 T lymphocytes from activation-induced apoptosis triggered by HIV-1: Implications for pathogenesis and therapy. AIDS 9, 35–42 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Zhao, Y. et al. Calcineurin activation protects T cells from glucocorticoid-induced apoptosis. J. Immunol. 154, 6346–6354 (1995).

    CAS  PubMed  Google Scholar 

  25. Beg, A.A. & Baltimore, D. An essential role of NF-kappaB in preventing TNFa induced cell death. Science 274, 782–784 (1996).

    Article  CAS  PubMed  Google Scholar 

  26. Van Antwerp, D.J. et al. Suppression of TNFα induced apoptosis by NF-kappaB. Science 274, 787–789 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Wang, C., Mayo, M.W. & Baldwin, A.S., Jr. TNF and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-kappaB. Science 274, 784–787 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Auphan, N. et al. Immunosuppression by glucocorticoids: Inhibition of NF-κB activity through induction of 1κB synthesis. Science 270, 286–290 (1996).

    Article  Google Scholar 

  29. Scheinman, R.I., Cogswell, P.C., Lofquist, A.K. & Baldwin, A.S., Jr., Role of transcriptional activation of IKBα inmediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1996).

    Article  Google Scholar 

  30. Mahalingam, S., Velpandi, A., Patel, M., Kieber-Emmons, T. & Weiner, D.B. Nuclear import, virion incorporation and cell cycle arrest/differentiation are mediated by distinct functional domains of HIV-1 Vpr. J. Virol. 71, 6339–6347 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Paul, W.E. & Seder, R.A. Lymphocyte responses and cytokines. Cell 76, 241–251 (1994).

    Article  CAS  PubMed  Google Scholar 

  32. Arya, S.K., Wong-Stall, F. & Gallo, R.C. Dexamethasone-mediated inhibition of human T cell growth factor and γ-interferon messenger RNA. J. Immunol. 133, 273–276 (1984).

    CAS  PubMed  Google Scholar 

  33. Graziosi, C. et al. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science 265, 248–252 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Graziosi, C. et al. Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection. Proc. Natl. Acad. Sci. USA 93, 4386–4391 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Poli, G. & Fauci, A.S. Role of cytokines in the pathogenesis of HIV disease. in Human Cytokines: Their Role in Disease and Therapy. (eds. Aggarwal, B.B. & Puri, R.K.) 421–449 (Blackwell Scientific Publ., Cambridge, MA, 1995).

    Google Scholar 

  36. Levy, D.N. et al. Serum vpr regulates productive infection and latency of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. USA 91, 10873–10877 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ameisen, J.C. & Capron, A. Cell dysfunction and depletion in AIDS: The programmed Cell death hypothesis. Immunol. Today 12, 102–105 (1991).

    Article  CAS  PubMed  Google Scholar 

  38. Finkel, T.H. et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV-and SIV-infected lymph nodes. Nature Med. 1, 129–134 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Lang, S.M. et al. Importance of vpr function of rhesus monkeys with simian immunodeficiency virus. J. Virol. 67, 902–912 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wang, B. et al. 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 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Rogel, M.E., Wu, L.I. & Emerman, M. The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J. Virol. 69, 882–888 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 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 

  43. Mahalingam, S. et al. Mutagenesis of the putative a-helical domain of the Vpr protein of human immunodeficiency virus type 1: Effect on stability and virion incorporation. Proc. Natl. Acad. Sci. USA 92, 3794–3798 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Fujita, T. et al. Independent modes of transcriptional activation by the p50 and p65 subunits of NF-kappa B. Genes Dev. 6, 775–787 (1992).

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 505 Steller-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania, 19104, USA

    Velpandi Ayyavoo, S. Mahalingam, Sagar Kudchodkar & David B. Weiner

  2. La Jolla Institute of Allergy and Immunology, 10355 Science Center Drive, San Diego, California, 92121, USA

    Artin Mahboubi & Douglas R. Green

  3. Roche Institute of Molecular Biology, Roche Research Center, Nutley, New Jersey, 07110, USA

    R. Ramalingam

  4. Department of Rheumatology, University of Pennsylvania, 912 Steller-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania, 19104, USA

    Williams V. Williams

  5. Pulmonary Research Laboratories, Cornell Medical Center, 1300 York Avenue, F-1401, New York, New York, 10021, USA

    R. Ramalingam

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  1. Velpandi Ayyavoo
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Ayyavoo, V., Mahboubi, A., Mahalingam, S. et al. HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor κB. Nat Med 3, 1117–1123 (1997). https://doi.org/10.1038/nm1097-1117

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