Apolipoprotein E (apoE) has been demonstrated to play an important role in providing protection against mesangial cell injury. In the present study, we evaluated the role of apoE and its associated downstream effects in human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Control (n = 6) and age- and sex-matched HIV-1 transgenic mice (Tg26, n = 6) were evaluated for their renal cortical expression of apoE. Renal tissue from Tg26 mice not only showed decreased apoE expression but also displayed downregulation of perlecan mRNA expression. In in vitro studies, conditionally immortalized human podocytes (CIHPs) were transduced with either NL4-3HIV (an HIV-1 construct lacking gag and pol, used for the development of Tg26 mouse model; NL4-3/CIHP) or empty vector (EV/CIHP); NL4-3/CIHPs and EV/CIHPs were studied for apoE mRNA expression. NL4-3/CIHPs showed reduction in apoE expression compared with EV/CIHPs. To evaluate the role of HIV-1 genes in the modulation of apoE expression, conditionally immortalized mouse podocytes (CIMPs) were transduced with individual HIV-1 gene constructs. Only nef-transduced CIMPs showed a decrease in apoE expression. To confirm this effect of nef in CIHPs, microarray analysis was performed in stable colonies of nef/CIHPs and EV/CIHPs. nef/CIHPs showed a 60% decrease in apoE and a 90% reduction in heparan sulfate mRNA expression. Moreover, nef transgenic mice showed a decrease in renal tissue expression of both apoE and perlecan. Both Tg26 and nef transgenic mice also showed areas of mesangial cell proliferation. These findings suggest that HIV-1-induced reduction in podocyte apoE expression and associated downregulation of podocyte perlecan might be contributing to mesangial cell (MC) phenotype in HIVAN.