Host Factors in Pathogenesis of HIV Associated Nephropathy

HIVAN is a unique disease that results from the interplay of HIV, host responses to the virus, and a genetic predisposition to disease in individuals of African descent. This project focuses on the identification of host responses to HIV infection that are critical for HIVAN pathogenesis. We have previously demonstrated that podocytes expressing HIV genes have increased production of the adhesion molecule Sidekick-1 (Sdk-1) and the small leucine-rich repeat protein Podocan. These two responses appear to participate in the glomerulosclerosis typical of HIVAN. We have also shown that HIV infection of renal tubular epithelial cells induces a proinflammatory cascade that appears to be in response to activation of Toll-like receptors (TLRs). We now propose to explore in depth how these host responses produce disease. We will explore the role of sdk-1 in the focal segmental glomerulosclerosis (FSGS) of HIVAN using a novel podocyte-specific sdk-1 overexpression mouse that develops FSGS. We will determine whether podocyte-specific expression of sdk-1 in vivo in mice can recreate the FSGS typical of HIVAN. We will also explore the differences in gene expression patterns of glomeruli from the sdk-1 FSGS mice compared to Tg26 mice to determine whether the response pathways involve the same or distinct disease pathways. We will then determine which HIV gene stimulates sdk-1, and we will explore whether inhibition of sdk-1 ameliorates the glomerulosclerosis of HIVAN. We will also explore the role of podocan in HIVAN pathogenesis by crossing our HIV transgenic mice with podocan knockout mice. Using human biopsies, we will determine whether there is differential regulation of other members of the SLRP family including decorin and biglycan. We will also explore the role of podocan in proliferation, differentiation, and apoptosis of HIV-infected and uninfected renal epithelial cells. Finally, we will perform a thorough analysis of the subcellular expression of TLRs in human proximal tubular epithelial cells before and after infection with HIV. We will evaluate the immune responses downstream of the TLR signaling pathways triggered by HIV and will explore the pattern of TLR expression in kidney biopsies obtained from patients with HIVAN and other kidney diseases.