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HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell

Abstract

In vivo infection of lymphatic tissues by the human immunodeficiency virus type 1 (HIV-1) leads to enhanced apoptosis, which prominently involves uninfected bystander cells1,2,3. Increased killing of such bystander cells is mediated in part through Nef induction of Fas ligand (FasL) expression4,5,6 on the surface of the virally infected T cells. The subsequent interaction of FasL with Fas (CD95) displayed on neighbouring cells, including HIV-1-specific cytotoxic T lymphocytes, may lead to bystander cell killing and thus forms an important mechanism of immune evasion. As HIV-1 also enhances Fas expression on virally infected cells7,8,9, it is unclear how these hosts avoid rapid cell-autonomous apoptosis mediated through cis ligation of Fas by FasL. Here we show that HIV-1 Nef associates with and inhibits apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that forms a common and key signalling intermediate in the Fas and tumour-necrosis factor-α (TNFα) death-signalling pathways10,11,12. The interaction of Nef with ASK1 inhibits both Fas- and TNFα-mediated apoptosis, as well as the activation of the downstream c-Jun amino-terminal kinase. Our findings reveal a strategy by which HIV-1 Nef promotes the killing of bystander cells through the induction of FasL, while simultaneously protecting the HIV-1-infected host cell from these same pro-apoptotic signals through its interference with ASK1 function.

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Figure 1: HIV-1 Nef interacts with the serine/threonine kinase ASK1.
Figure 2: HIV-1 Nef inhibits the intrinsic catalytic activity of ASK1 by preventing thioredoxin release and impairs ASK1- and Fas-mediated induction of JNK1.
Figure 3: HIV-1 Nef inhibits TNF-α- and Fas-induced apoptosis.
Figure 4: Expression of Nef during HIV-1 infection inhibits TNF-α- and Fas-induced apoptosis.
Figure 5: Mechanistic model.

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References

  1. Jaworowski, A. & Crowe, S. M. Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis? Immunol. Cell Biol. 77, 90–98 (1999).

    Article  CAS  Google Scholar 

  2. Muro-Cacho, C. A., Pantaleo, G. & Fauci, A. S. Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J. Immunol. 154, 5555–5566 (1995).

    CAS  PubMed  Google Scholar 

  3. 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  Google Scholar 

  4. Xu, X. N. et al. Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells. J. Exp. Med. 186, 7–16 (1997).

    Article  CAS  Google Scholar 

  5. Xu, X. N. et al. Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J. Exp. Med. 189, 1489–1496 (1999).

    Article  CAS  Google Scholar 

  6. Hodge, S., Novembre, F. J., Whetter, L., Gelbard, H. A. & Dewhurst, S. Induction of fas ligand expression by an acutely lethal simian immunodeficiency virus, SIVsmmPBj14. Virology 252, 354–363 (1998).

    Article  CAS  Google Scholar 

  7. Debatin, K. M. et al. High expression of APO-1 (CD95) on T lymphocytes from human immunodeficiency virus-1-infected children. Blood 83, 3101–3103 (1994).

    CAS  PubMed  Google Scholar 

  8. Katsikis, P. D., Wunderlich, E. S., Smith, C. A. & Herzenberg, L. A. Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J. Exp. Med. 181, 2029–2036 (1995).

    Article  CAS  Google Scholar 

  9. Sloand, E. M. et al. Role of Fas ligand and receptor in the mechanism of T-cell depletion in acquired immunodeficiency syndrome: effect on CD4+ lymphocyte depletion and human immunodeficiency virus replication. Blood 89, 1357–1363 (1997).

    CAS  PubMed  Google Scholar 

  10. Chang, H. Y., Nishitoh, H., Yang, X., Ichijo, H. & Baltimore, D. Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Science 281, 1860–1863 (1998).

    Article  ADS  CAS  Google Scholar 

  11. Ichijo, H. et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90–94 (1997).

    Article  CAS  Google Scholar 

  12. Nishitoh, H. et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol. Cell 2, 389–395 (1998).

    Article  CAS  Google Scholar 

  13. Badley, A. D. et al. Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J. Exp. Med. 185, 55–64 (1997).

    Article  CAS  Google Scholar 

  14. Herbein, G. et al. Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4. Nature 395, 189–194 (1998).

    Article  ADS  CAS  Google Scholar 

  15. Mitra, D., Steiner, M., Lynch, D. H., Staiano-Coico, L. & Laurence, J. HIV-1 upregulates Fas ligand expression in CD4+ T cells in vitro and in vivo: association with Fas-mediated apoptosis and modulation by aurintricarboxylic acid. Immunology 87, 581–585 (1996).

    Article  CAS  Google Scholar 

  16. Badley, A. D. et al. Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J. Virol. 70, 199–206 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Saitoh, M. et al. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 17, 2596–2606 (1998).

    Article  CAS  Google Scholar 

  18. Liu, H., Nishitoh, H., Ichijo, H. & Kyriakis, J. M. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Mol. Cell. Biol. 20, 2198–2208 (2000).

    Article  CAS  Google Scholar 

  19. 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  Google Scholar 

  20. 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  Google Scholar 

  21. Mangasarian, A., Piguet, V., Wang, J. K., Chen, Y. L. & Trono, D. Nef-induced CD4 and major histocompatibility complex class I (MHC-I) down-regulation are governed by distinct determinants: N-terminal alpha helix and proline repeat of Nef selectively regulate MHC-I trafficking. J. Virol. 73, 1964–1973 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Greenberg, M. E., Iafrate, A. J. & Skowronski, J. The SH3 domain-binding surface and an acidic motif in HIV-1 Nef regulate trafficking of class I MHC complexes. EMBO J. 17, 2777–2789 (1998).

    Article  CAS  Google Scholar 

  23. Bresnahan, P. A. et al. A dileucine motif in HIV-1 Nef acts as an internalization signal for CD4 downregulation and binds the AP-1 clathrin adaptor. Curr. Biol. 8, 1235–1238 (1998).

    Article  CAS  Google Scholar 

  24. Greenberg, M., DeTulleo, L., Rapoport, I., Skowronski, J. & Kirchhausen, T. A dileucine motif in HIV-1 Nef is essential for sorting into clathrin-coated pits and for downregulation of CD4. Curr. Biol. 8, 1239–1242 (1998).

    Article  CAS  Google Scholar 

  25. Craig, H. M., Pandori, M. W. & Guatelli, J. C. Interaction of HIV-1 Nef with the cellular dileucine-based sorting pathway is required for CD4 down-regulation and optimal viral infectivity. Proc. Natl Acad. Sci. USA 95, 11229–11234 (1998).

    Article  ADS  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. Asada, M. et al. Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J. 18, 1223–1234 (1999).

    Article  CAS  Google Scholar 

  28. Zhang, L., Chen, J. & Fu, H. Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc. Natl Acad. Sci. USA 96, 8511–8515 (1999).

    Article  ADS  CAS  Google Scholar 

  29. Taylor, D. R., Shi, S. T., Romano, P. R., Barber, G. N. & Lai, M. M. Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. Science 285, 107–110 (1999).

    Article  CAS  Google Scholar 

  30. Orth, K. et al. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285, 1920–1923 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. C. Wynant of the Stanford University Beckman Center Protein and Nucleic Acid Facility for protein digests and mass spectrometry analysis. We thank E. Verdin, M. Jenkins, V. Linquist-Stepps and T. Liegler for helpful discussions and sharing unpublished data; S. Ferrell, P. Defecheureux, P. Bresnahan, L. Gibson, J. Lorens, J. Bogenberger and E. Wieder for technical advice and assistance; J. Carroll, N. Shea, S. Gonzales and C. Goodfellow for preparing figures; S. Ordway and G. Howard for editorial assistance; and R. Givens for preparation of the manuscript. We also thank the following individuals for expression vectors: G. Johnson for MEKK1; M. Karin for Flag–JNK1; M. Jenkins and M. McCune for human Fas; J. Pomerantz and D. Baltimore for murine Fas; and J. Bauer and V. Dixit for CrmA. W.C.G. acknowledges support from the NIH and the UCSF-GIVI Center for AIDS Research.

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Correspondence to Warner C. Greene.

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Geleziunas, R., Xu, W., Takeda, K. et al. HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410, 834–838 (2001). https://doi.org/10.1038/35071111

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