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J. Exp. Med.,
Volume 189, Number 9, May 3, 1999 1489-1496
Chain
By
From the * Medical Research Council Human Immunology Unit, Institute of Molecular Medicine,
John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; the During HIV/SIV infection, there is widespread programmed cell death in infected and, perhaps more importantly, uninfected cells. Much of this apoptosis is mediated by Fas-Fas ligand
(FasL) interactions. Previously we demonstrated in macaques that induction of FasL expression
and apoptotic cell death of both CD4+ and CD8+ T cells by SIV is dependent on a functional
nef gene. However, the molecular mechanism whereby HIV-1 induces the expression of FasL
remained poorly understood. Here we report a direct association of HIV-1 Nef with the Institute of Clinical and
Molecular Virology, University of Erlangen/Nürnberg, 91054 Erlangen, Germany; and § Genzentrum, Ludwig-Maximilians-Universität München, 81377 München, Germany
chain of the T cell receptor (TCR) complex and the requirement of both proteins for HIV-mediated upregulation of FasL. Expression of FasL through Nef depended upon the integrity of
the immunoreceptor tyrosine-based activation motifs (ITAMs) of the TCR chain. Conformation for the importance of for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of but not CD3
was both required and sufficient to promote activation and binding of the Nef-associated kinase (NAK/p62). Our data imply that Nef
can form a signaling complex with the TCR, which bypasses the requirement of antigen to initiate T cell activation and subsequently upregulation of FasL expression. Thus, our study may
provide critical insights into the molecular mechanism whereby the HIV-1 accessory protein
Nef contributes to the pathogenesis of HIV.
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