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Journal of Virology, May 2005, p. 6377-6391, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6377-6391.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Nef-Mediated AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Increased Fas/FasL Expression on T Cells and T-Cell Death but Is Not Prevented in Fas-, FasL-, Tumor Necrosis Factor Receptor 1-, or Interleukin-1ß-Converting Enzyme-Deficient or Bcl2-Expressing Transgenic Mice

Elena Priceputu,1 Isabelle Rodrigue,1 Pavel Chrobak,1 Johanne Poudrier,1 Tak W. Mak,5 Zaher Hanna,1,3,4 Chunyan Hu,1 Denis G. Kay,1 and Paul Jolicoeur1,2,4*

Laboratory of Molecular Biology, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7,1 Department of Microbiology and Immunology,2 Department of Medicine, Université de Montréal, Montreal, Quebec H3C 3J7,3 Division of Experimental Medicine, McGill University, Montreal, Quebec H3G 1A4,4 Department of Medical Biophysics and Immunology, Ontario Cancer Institute, University of Toronto, 500 Sherbourne Street, Toronto, Ontario M4X 1K9, Canada5

Received 15 July 2004/ Accepted 10 January 2005

CD4+- and CD8+-T-cell death is a frequent immunological dysfunction associated with the development of human AIDS. We studied a murine model of AIDS, the CD4C/HIV transgenic (Tg) mouse model, to assess the importance of the apoptotic pathway in human immunodeficiency virus type 1 (HIV-1) pathogenesis. In these Tg mice, Nef is the major determinant of the disease and is expressed in immature and mature CD4+ T cells and in cells of the macrophage/myeloid lineage. We report here a novel AIDS-like phenotype: enhanced death, most likely by apoptosis (as assessed by 7-aminoactinomycin D and annexin V/propidium iodide staining), of Tg thymic and peripheral CD4+ and CD8+ T cells. The Tg CD4+ and CD8+ T cells were also more susceptible to cell death after activation in vitro in mixed lymph node (LN) cultures. However, activation-induced cell death was not higher in Tg than in non-Tg-purified CD4+ T cells. In addition, expression of Fas and FasL, assessed by flow cytometry, was increased in CD4+ and CD8+ T cells from Tg mice compared to that of non-Tg littermates. Despite the enhanced expression of Fas and FasL on Tg CD4+ and CD8+ T cells, Fas (lpr/lpr) and FasL (gld/gld) mutant CD4C/HIV Tg mice developed an AIDS-like disease indistinguishable from lpr/+ and gld/+ CD4C/HIV Tg mice, including loss of CD4+ T cells. Similarly, CD4C/HIV Tg mice homozygous for mutations of two other genes implicated in cell death (interleukin-1ß-converting enzyme [ICE], tumor necrosis factor receptor 1 [TNFR-1]) developed similar AIDS-like disease as their respective heterozygous controls. Moreover, the double-Tg mice from a cross between the Bcl2/Wehi25 and CD4C/HIV Tg mice showed no major protection against disease. These results represent genetic evidence for the dispensable role of Fas, FasL, ICE, and TNFR-1 on the development of both T-cell loss and organ disease of these Tg mice. They also provide compelling evidence on the lack of protection by Bcl2 against Tg CD4+-T-cell death. In view of the high resemblance between numerous phenotypes observed in the CD4C/HIV Tg mice and in human AIDS, our findings are likely to be relevant for the human disease.

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

Journal of Virology, May 2005, p. 6377-6391, Vol. 79, No. 10
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.10.6377-6391.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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