Viral Pathogenesis of HIV Associated Nephropathy

We have previously shown that HIV plays a broad role in the pathogenesis of HIVAN, and suggested that the kidney may be a long-term reservoir for HIV infection. We will utilize human kidney biopsies, in vitro human renal tubular epithelial cell (RTEC) cultures, and murine modeling to further define the dynamics of HIV infection in the kidney. Preliminary data suggest efficient transfer of viral particles from infected T cells to RTEC via a viral synapse, and we will further define the efficiency and consequences of cell-free and cell-associated infection of RTEC. To determine if continual exchange of virus occurs in vivo between these two cell types, we will analyze envelope sequences extracted from interstitial T cells and RTEC isolated by laser capture microdissection. We have previously shown that HIV Vpr causes polyploidy, hypertrophy, and apoptosis of RTEC, all aspects of HIVAN pathology. The mechanism for this phenotype appears to be distinct from Vpr-induced G2 arrest of lymphocytes. We will define the mechanisms by which Vpr and other viral genes induce pathologic changes characteristic of HIVAN, using in vitro studies, transgenic mice, and kidney biopsies from patients with HIVAN. Our previous work has established the kidney as a compartment with distinct HIV evolution compared to peripheral blood mononuclear cells (PBMC); however, it is not known whether the kidney serves as a reservoir for eventual recrudescence. Preliminary data suggest that viral sequences derived from urine are distinct from PBMC sequences, and simultaneously derived sequences from urine and laser captured RTEC will be analyzed to determine if they represent the same compartment. To further support the urinary tract as a separate compartment, we will define the rate of evolution of viral sequences over time compared to PBMC in a cohort of patients with acute HIV infection enrolled in CHAVI. If the analyses support the urinary compartment as unique and reflective of the kidney, this will allow sequential sampling to determine whether the kidney serves as a true long-term reservoir for HIV.