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Journal of Virology, April 2002, p. 3981-3995, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3981-3995.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Expression of Simian Immunodeficiency Virus nef in Immune Cells of Transgenic Mice Leads to a Severe AIDS-Like Disease

Marie-Chantal Simard,1 Pavel Chrobak,1 Denis G. Kay,1 Zaher Hanna,1,2 Serge Jothy,3 and Paul Jolicoeur1,4,5*

Laboratory of Molecular Biology, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7,1 Departments of Medicine,2 Microbiology and Immunology, Université de Montréal, Montréal, Québec H3C 3J7,4 Division of Experimental Medicine, McGill University, Montréal, Québec,5 Department of Laboratory Medicine and Pathobiology, Sunnybrook and Women's College Health Science Centre, University of Toronto, Toronto, Ontario, Canada3

Received 11 July 2001/ Accepted 17 January 2002

In order to study the functions of simian immunodeficiency virus (SIV) Nef in vivo in a small-animal model, we constructed transgenic (Tg) mice expressing the SIVmac239 nef gene in the natural target cells of the virus under the control of the human CD4 gene promoter (CD4C). These CD4C/SHIV-nefSIV Tg mice develop a severe AIDS-like disease, with manifestations including premature death, failure to thrive or weight loss, wasting, thymic atrophy, an especially low number of peripheral CD8+ T cells as well as a low number of peripheral CD4+ T cells, diarrhea, splenomegaly, and kidney (interstitial nephritis, segmental glomerulosclerosis), lung (lymphocytic interstitial pneumonitis), and heart disease. In addition, these Tg mice fail to mount a class-switched antibody response after immunization with ovalbumin, they produce anti-DNA autoantibodies, and some of them develop Pneumocystis carinii lung infections. All these results suggest a generalized Nef-induced immunodeficiency. The low numbers of peripheral CD8+ and CD4+ T cells are likely to reflect a thymic defect and may be similar to the DiGeorge-like "thymic defect" immunophenotype described for a subgroup of human immunodeficiency virus type 1-infected children. Therefore, it appears that SIV Nef alone expressed in mice, in appropriate cell types and at sufficient levels, can elicit many of the phenotypes of simian and human AIDS. These Tg mice should be instrumental in studying the pathogenesis of SIV Nef-induced phenotypes.

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

Journal of Virology, April 2002, p. 3981-3995, Vol. 76, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.8.3981-3995.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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