Journal of Virology, October 2001, p. 9378-9392, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.9378-9392.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Laboratory of Molecular Biology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7,1 Departments of Medicine2 and Microbiology and Immunology,4 Université de Montréal, Montreal, Quebec H3C 3J7, and Division of Experimental Medicine, McGill University, Montreal, Quebec H3G 1A4,5 Canada, and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 941433
Received 27 December 2000/Accepted 23 June 2001
The human immunodeficiency virus type 1 (HIV-1) Nef protein is an
important determinant of AIDS pathogenesis. We have previously reported
that HIV-1 Nef is responsible for the induction of a severe AIDS-like
disease in CD4C/HIV transgenic (Tg) mice. To understand the molecular
mechanisms of this Nef-induced disease, we generated Tg mice expressing
a mutated Nef protein in which the SH3 ligand-binding domain
(P72XXP75XXP78) was mutated to
A72XXA75XXQ78. This mutation
completely abolished the pathogenic potential of Nef, although a
partial downregulation of the CD4 cell surface expression was still
observed in these Tg mice. We also studied whether Hck, one of the
effectors previously found to bind to this PXXP motif of Nef, was
involved in disease development. Breeding of Tg mice expressing
wild-type Nef on an hck
/
(knockout)
background did not abolish any of the pathological phenotypes. However,
the latency of disease development was prolonged. These data indicate
that an intact PXXP domain is essential for inducing an AIDS-like
disease in CD4C/HIV Tg mice and suggest that interaction of a cellular
effector(s) with this domain is required for the induction of this
multiorgan disease. Our findings indicate that Hck is an important, but
not an essential, effector of Nef and suggest that another
factor(s), yet to be identified, may be more critical for disease development.
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