HIV associated neuropathy has emerged as a major epidemic in the end stge renal disease (ESRD) program in the United States. From an occasional oddity observed in the mid 1980s, HIVAN has become the third leading cause of ESRD in Blacks. Unfortunately, unlike many of the infectious complications of HIV that have declined dramatically with highly active antiretroviral therapy (HAART), HIVAN continues to increase in both incidence and prevalence. The explanation for the continued increase in HIVAN likely reflects the disproportionate impact that HIV-1 has had on the Black urban community. With the disproportionate increase in new cases of HIV-1 in Blacks and with the decline in mortality from HAART, there has been an astounding increase in the pool of patients at risk for the development of HIVAN to almost 50% of those patients living with AIDS. Continued advances in our understanding of HIVAN pathogenesis are required to address this epidemic, but much has been learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and learned already. HIV-1 is the primary etiologic agent responsible for HIVAN and the renal glomerular and tubular epithelium appears to be the targeted cell type. Recent studies have now revealed that HIV-1 can be detected in renal epithelial cells of HIVAN patients. Furthermore, we have identified a series of epithelial surrogate markers for disease. The purpose of this proposal is to explore the viral-host interactions that lead to pathogenesis.
The specific aims are first to develop molecular markers in vitro than accurately reflect pathogenesis in vivo using representation difference analysis (RDA). These markers, along with those already identified, will serve as the readout for mapping which HIV-1 genes are responsible for producing HIVAN.
The second aim i s to identify the HIV-1 gene product(s) responsible for HIVAN pathogenesis by in vitro minimal combinatorial HIV-1 gene expression necessary for the development of HIVAN pathology in vivo using studies should lead us to the initial pathways of renal pathogenesis as well as identify the downstream effectors of disease. Results will define mechanisms of HIVAN pathogenesis, provide potential targets for therapy, and perhaps most importantly, provide insights into the predisposition of Blacks for renal disease of all causes.
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