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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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 We thank E. Verdin, M. Jenkins, V. Linquist-Stepps and T. Liegler for helpful discussions and sharing unpublished data; S. Ferrell, P. Defecheureux, P. Bresnahan, L. Gibson, J. Lorens, J. Bogenberger and E. Wieder for technical advice and assistance; J. Carroll, N. Shea,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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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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DOI: https://doi.org/10.1038/35071111
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