HIV-associated nephropathy (HIVAN), the most common cause of end-stage renal disease in HIV-1 seropositive individuals, is a unique tissue of manifestation of infection found predominantly in Blacks and is associated with poor prognosis even in the area of highly active antiretroviral therapy. Without completely understanding the role of the virus in HIVAN, it is difficult to predict what effects the widespread use of potent antiretroviral might eventually have on the incidence of natural history of HIVAN. Epidemiologic data supports the direct involvement of HIV-1 infection in the pathogenesis of HIVAN and animal studies suggest that expression of viral proteins in the kidney is required to produce the disease. Nevertheless, direct infection of human renal tissue with HIV-1 has been difficult most likely due to both technical difficulties in processing tissues as well as the lack of available primary viral isolates and primary renal cells to properly pursue this issue. The first two specific aims of this proposal will utilize tissue derived from a well characterized clinical cohort identified through the Renal Complications of AIDS Consortium (RCAC) to define the replication capacity of HIV-1 in primary renal tissue. RNA in situ hybridization on carefully characterized renal biopsy material as well as quantitative PCR on isolated renal tubules will precisely identify cell types infected as well as expressing HIV-1 RNA. Primary renal epithelial cells derived from donors of different genetic backgrounds will be challenged with viral isolates obtained simultaneously from biopsy material and peripheral blood to provide evidence for viral strains tropism and/or genetic determinants of infection. The demonstration that a number of chemokine and related 7 membrane spanning G-proteins can act as HIV-1 co-receptors and play a major role in determining cellular tropism may have important implications for understanding the pathogenesis and genetics of HIVAN.
Specific aim 3 will explore this possibility by characterizing co-receptor expression on biopsy material and on primary renal epithelial cells in culture and additional comparison and analysis of the derived envelope sequences will explore whether there are selective factors that influence infection and/or replciation of HIV in the kidney making it a unique reservoir for HIV. These studies should completely define the replication capacity of HIV-1 in renal cells and identify the role of virus tropism and co-receptor utilization in this process.
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