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

Abstract

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 SIV mac 239 nef gene in the natural target cells of the virus under the control of the human CD4 gene promoter (CD4C). These CD4C/SHIV-nef SIV 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 classswitched 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.

Reduction of Stat3 Activity Attenuates HIV-Induced Kidney Injury

“…Studies from Jolicoeur's laboratory showed that transgenic mice expressing Nef under the control of the human CD4 gene promoter develop a severe AIDS-like disease, with manifestations including premature death, failure to thrive, thymic atrophy, and an especially low number of peripheral CD8ϩ T cells as well as a low number of peripheral CD4ϩ T cells. 28,29 These phenotypes are quite similar to those observed in homozygous Tg26 mice but not in heterozygous mice. The observed difference in phenotype could also be caused by the level of transgene expression in CD4ϩ cells, although it has never been examined.…”

HIV-1 Nef upregulates CCL2/MCP-1 expression in astrocytes in a myristoylation- and calmodulin-dependent manner

“…Moreover, as shown in a transgenic mouse model, it is sufficient to express HIV-1 nef to trigger an AIDS-like disease (Hanna et al, 1998;Simard et al, 2002). The N-terminal region of Nef including the myristoylation site has been shown to be crucial for the development of an AIDSlike disease in mice (Hanna et al, 2004).…”

CD4+T Cells from CD4C/HIVNefTransgenic Mice Show Enhanced Activation In Vivo with Impaired Proliferation In Vitro but Are Dispensable for the Development of a Severe AIDS-Like Organ Disease

“…Only littermates were compared. All mice used for this work were kept under specificpathogen-free conditions as described previously (59), and all experiments were approved by the Institutional Animal Ethics Committee.…”