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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.

The Pathogenicity of Human Immunodeficiency Virus (HIV) Type 1 Nef in CD4C/HIV Transgenic Mice Is Abolished by Mutation of Its SH3-Binding Domain, and Disease Development Is Delayed in the Absence of Hck

Zaher Hanna,1,2,* Xiaoduan Weng,1 Denis G. Kay,1 Johanne Poudrier,1 Clifford Lowell,3 and Paul Jolicoeur1,4,5,*

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.

* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Québec, Canada H2W 1R7. Phone for Zaher Hanna: (514) 987-5571. Fax for Zaher Hanna: (514) 987-5794. E-mail for Zaher Hanna: hannaz{at}ircm.qc.ca. Phone for Paul Jolicoeur: (514) 987-5569. Fax for Paul Jolicoeur: (514) 987-5794. E-mail for Paul Jolicoeur: jolicop{at}ircm.qc.ca.

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.


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