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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1000-1010
Human Immunodeficiency Virus Type 1 Nef Protein Sensitizes
CD4+ T Lymphoid Cells to Apoptosis via Functional
Upregulation of the CD95/CD95 Ligand Pathway
Giorgio Zauli,
Davide Gibellini,
Paola Secchiero,
Hélène Dutartre,
Daniel Olive,
Silvano Capitani, and
Yves Collette
From the Human Anatomy Section, Department of Morphology and
Embryology, University of Ferrara, Ferrara; Institute of Microbiology,
University of Bologna, Bologna, Italy; Institute of Human Virology,
University of Maryland at Baltimore, Baltimore, MD; and Unité 119 Istitut National de la Santé et de la Recherche Medicale
(INSERM), Université dela Mediterrainée, Marseille, France.
Many viruses have evolved genes encoding proteins that regulate cell
death by apoptosis. The human immunodeficiency virus type 1 (HIV-1) Nef
protein alters T-cell development and signaling and is required for
optimal viral replication and pathogenicity in vivo. To analyze the
interference of Nef with cell survival, we used both regulated and
constitutively expressed nef alleles in stably transfected
T-cell lines. Nef-expressing cells were sensitized to cell death by
apoptosis, which was specifically exacerbated by an anti-CD95 IgM
monoclonal antibody (MoAb). Flow cytometric analysis showed that the
surface expression of both CD95 and CD95 ligand (CD95L) was upregulated
by endogenous Nef expression. Nef-mediated apoptosis was almost
completely suppressed by the addition in culture of an anti-CD95 Fab'
IgG MoAb, which specifically blocks CD95/CD95L interactions. Lastly,
mutation of a proline motif in the core region of the nef gene,
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 CD95L. These findings may provide molecular
insight into the role of endogenous Nef in the T-cell depletion
observed in vivo, particularly HIV-specific cytotoxic
CD8+ T cells.
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