NEF-INDUCED HIV-ASSOCIATED NEPHROPATHY THROUGH HCK/LYN.

HIVAN is a severe complication of HIV-1 infection. To gain insight into the pathogenesis of kidney disease in the setting of HIV, we used a transgenic (Tg) mouse model (CD4C/HIV-Nef) in which HIV-1 nef expression is under control of regulatory sequences (CD4C) of the human CD4 gene, thus allowing expression in target cells of the virus. These Tg mice develop a collapsing focal segmental glomerulosclerosis (FSGS) associated with microcystic dilatation, similar to human HIVAN. Proliferation of tubular and glomerular Tg cells is enhanced. To identify kidney cells permissive to the CD4C promoter, CD4C/GFP reporter Tg mice were used. They showed preferential expression in glomeruli, mainly in mesangial cells. Breeding CD4C/HIV Tg mice on ten different mouse backgrounds showed that HIVAN was modulated by host genetic factors. Studies of gene-deficient Tg mice revealed that the presence of B and T cells and that of several genes was dispensable for the development of HIVAN: those involved in apoptosis (p53, TRAIL, TNF-α, TNF-R2, Bax), in immune cell recruitment (MIP-1α, MCP-1, CCR-2, CCR-5 and CX3CR-1), in NO formation (eNOS, iNOS) or in cell signaling (Fyn, Lck, Hck/Fgr). However, deletion of Src partially and that of Hck/Lyn largely abrogated its development. Our data suggest that Nef expression in mesangial cells through Hck/Lyn represents important cellular and molecular events for the development of HIVAN in these Tg mice.