Nef modulation of HIV type 1 gene expression and cytopathicity in tissues of HIV transgenic mice

Transgenic mice bearing HIV-1 proviral DNA deleted in the gag/pol region (H IVd1443 mice) model a chronic, nonproductive form of viral gene expression in various cell types including macrophages. They display a disease phenoty pe that includes HIV-associated nephropathy (HIVAN), congenital cataracts, papillomatosis, and growth failure. The role of HIV-1 Nef in viral gene reg ulation and the development of disease was explored in mice bearing an isog enic HIV transgene in which nef was mutated by frameshift mutation. Like it s Nef(+) counterpart, HIVd1443[Nef(-)] mice expressed HIV gene products in the skin, muscle, kidney, and peritoneal macrophages. While these mice did not develop cataracts, papillomatous skin lesions, or display any apparent growth defect, they did develop HIVAN. Nef expression was introduced to HIV d1443[Nef(-)] mice through breeding to mice bearing an HIV LTR-linked nef t ransgene. Nef-complemented HIVd1443[Nef(-)] mice had reduced levels of vira l gene products in the muscle and kidney. In contrast, HIV gene expression in the skin of these mice remained high and papillomatous lesions emerged t hat were more severe than those on wildtype HIVd1443 mice. Still, Nef had a negative effect on LPS-induced viral gene expression in visibly normal ski n. In comparisons of peritoneal macrophages, viral RNA expression was signi ficantly reduced in resident macrophages of Nef(+) mice. HIV inflammatory m acrophages expressed viral genes and displayed an altered FAGS profile. In particular, Nef+ populations were marked by an increased proportion of F4/8 0(med)/Mac-1(-) cells as well as fewer Mac-1 cells and reduced F4/80 staini ng. This HIV proviral transgenic model has demonstrated the capacity of HIV -1 Nef to contribute to HIV cytopathicity by altering cellular maturation a nd viral gene expression in vivo.