title: 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-1beta-converting enzyme-deficient or Bcl2-expressing transgenic mice.
abstract: 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-1beta-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.
authors.affiliation: Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec H2W 1R7, Canada. Paul.Jolicoeur@ircm.qc.ca.
authors.forename: Elena
authors.initials: E
authors.lastname: Priceputu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rodrigue
authors.forename: Pavel
authors.initials: P
authors.lastname: Chrobak
authors.forename: Johanne
authors.initials: J
authors.lastname: Poudrier
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Zaher
authors.initials: Z
authors.lastname: Hanna
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.forename: Denis G
authors.initials: DG
authors.lastname: Kay
authors.forename: Paul
authors.initials: P
authors.lastname: Jolicoeur
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004487:Edema / Q000473:pathology; D053222:Fas Ligand Protein; D015754:Genes, nef / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics*; D007668:Kidney / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D047990:TNF Receptor-Associated Factor 1 / Q000172:deficiency* / Q000235:genetics; D013950:Thymus Gland / Q000473:pathology; D015431:Weight Loss; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D047990:TNF Receptor-Associated Factor 1; D019014:fas Receptor; C052617:Bcl2 protein, mouse; D020170:Caspase 1