Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain.

Journal article

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 zeta 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 zeta chain. Conformation for the importance of zeta for Nef-mediated signaling in T cells came from an independent finding. A single ITAM motif of zeta but not CD3epsilon 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.

Authors: Xu, X; Laffert, B; Screaton, G; Kraft, M; Wolf, D

• Publication status: Published
• Journal: Journal of experimental medicine
• Volume: 189
• Issue: 9
• Pages: 1489-1496
• Publication date: 1999-05-01
• DOI: 10.1084/jem.189.9.1489
• EISSN: 1540-9538
• ISSN: 0022-1007
• Language: English
• Keywords: Up-Regulation; Humans; Membrane Proteins; Protein-Serine-Threonine Kinases; HIV-1; Gene Products, nef; Receptors, Antigen, T-Cell; Membrane Glycoproteins; Jurkat Cells; Fas Ligand Protein; nef Gene Products, Human Immunodeficiency Virus; Protein Kinases; p21-Activated Kinases