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

doi:10.1128/JVI.75.19.9378-9392.2001

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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 previouslyreported that HIV-1 Nef is responsible for the induction of asevere AIDS-like disease in CD4C/HIV transgenic (Tg) mice. Tounderstand the molecular mechanisms of this Nef-induced disease,we generated Tg mice expressing a mutated Nef protein in whichthe SH3 ligand-binding domain (P₇₂XXP₇₅XXP₇₈) was mutated to A₇₂XXA₇₅XXQ₇₈.This mutation completely abolished the pathogenic potential ofNef, although a partial downregulation of the CD4 cell surfaceexpression was still observed in these Tg mice. We also studiedwhether Hck, one of the effectors previously found to bind tothis PXXP motif of Nef, was involved in disease development. Breedingof Tg mice expressing wild-type Nef on an hck^/ (knockout) background did not abolish any of the pathologicalphenotypes. However, the latency of disease development was prolonged.These data indicate that an intact PXXP domain is essential forinducing an AIDS-like disease in CD4C/HIV Tg mice and suggestthat interaction of a cellular effector(s) with this domain isrequired for the induction of this multiorgan disease. Our findingsindicate that Hck is an important, but not an essential, effectorof Nef and suggest that another factor(s), yet to be identified,may be more critical for diseasedevelopment.

^* Corresponding author. Mailing address: Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Québec, CanadaH2W 1R7. Phone for Zaher Hanna: (514) 987-5571. Fax for ZaherHanna: (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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