Podocyte proliferation and de-differentiation are the hallmarks of the collapsing glomerulopathy associated with HIV-associated nephropathy (HIVAN). Nef, an HIV-1 accessory protein, was recently found to cause podocyte proliferation and dedifferentiation by activating the STAT3/MAPK1,2 pathways. STAT3 activation requires tyrosine 705 phosphorylation; however serine 727 phosphorylation increases its transcriptional activity. A mouse strain that is wild-type/null (STAT3 +/-) and a strain with a S727A mutation at the serine phosphorylation site (STAT3 SA) allows for generation of mice with variable amounts of STATS transcriptional activity (wild type 100%; SA/+ 75%; SA/SA and +/- 50%; SA/- 25%). Using this mouse model, our plan is to study the role of STATS in causing the phenotypic changes of podocytes observed in HIVAN. Different mice strains are known to have variable degrees of susceptibility to renal disease in the setting of HIV-1 infection. HIV-transgenic mice (Tg26) are on the FBV background and develop more severe renal disease in response to HIV-1 infection than many other strains of mice. Since STAT3 knockout mice are on the C57/B6 background, our secondary goal is to determine if differences exist between the two strains in podocyte cell proliferation and activation of signaling pathways in response to HIV-1 infection.