AEGiS-12IAC: The HIV-1 Nef protein induces CD4+ T cell apoptosis through functional upregulation of the CD95/CD95L pathway.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

The HIV-1 Nef protein induces CD4+ T cell apoptosis through functional upregulation of the CD95/CD95L pathway.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:11 (abstract no. 11145)

Collette Y, Zauli G, Gibellini D, Secchiero P, Dutartre H, Olive D, Capitani S;;; University of Ferrara, Italy.

BACKGROUND: Many viruses have evolved genes encoding proteins which regulate cell death by apoptosis. The Nef protein from primate lentiviruses alters T cell development and signaling and provides a signal required for optimal viral replication and pathogenecity in vivo, possibly through interaction with cellular kinases.

METHODS: To analyse interference of Nef with cell survival, we used both regulated and constitutively expressed HIV-1 nef alleles in stably transfected T cell lines.

RESULTS: Upon Nef expression, cells displayed a marked retardation of cell growth and were sensitized to cell death by apoptosis which was counter-regulated by growth factors. Apoptosis induced by Nef was exacerbated by an anti-CD95 (Fas/Apo-1) IgM monoclonal antibody. Indeed, flow cytometric analysis showed that the surface expression of CD95 was upregulated in a Nef dependent manner, and that upon serum withdrawal, Nef also induced CD95L expression. Nef-mediated apoptosis could be suppressed by the addition in culture of an anti-CD95L Fab' mAb, which specifically blocks the binding of CD95L. Lastly, mutation of a proline motif in the core region of Nef, which disrupts its ability to interact with cellular kinases and reduces HIV-1 replication in vitro, completely abrogated the Nef-mediated induction of apoptosis as well as its ability to upregulate surface CD95 and to induce CD95L.

CONCLUSION: Together, our findings unequivocally demonstrate that HIV-1 Nef is cytotoxic for lymphold T cells via an upregulation of the CD95/CD95L pathway and provide molecular insights into the role of Nef in T cell depletion observed in vivo, particularly bystander non-infected cells such as HIV-specific cytotoxic CD8+ T cells.

Keywords: AEGIS, Gene Products, nef, Antigens, CD95, Antigens, CD4, HIV-1, T-Lymphocytes, Membrane Glycoproteins, Apoptosis, Up-Regulation, HIV Infections, Cell Line, Antigens, CD8, FasL protein, In Vitro, immunology, genetics, ICA12
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