PATHOPHYSIOLOGY

HIVAN is caused by direct infection of renal epithelial cells by the HIV-1 virus, leading to viral gene expression. RNA in situ hybridization and DNA in situ polymerase chain reaction amplification of specific HIV-1 genes from human renal biopsies have detected HIV-1 virus in the podocytes (glomerular visceral epithelial cells), the parietal epithelial cells lining Bowman’s capsule, and tubular epithelial cells. Individual patients are noted to have different HIV-1 quasispecies in their renal epithelium compared with their peripheral blood leukocytes, indicating the ability of the virus to replicate and undergo mutation within the renal epithelium. This process of error-prone viral replication allows the virus to change its coat and evade the host immune system. How the virus enters renal epithelial cells is uncertain because there is no evidence of renal epithelial expression of CD4 (the major HIV receptor in T helper cells) or the HIV-1 coreceptors, CXCR4 and CCR5. It is possible that HIV-1 infects renal epithelium via transcytosis from infiltrating lymphocytes.

Once the HIV-1 virus enters renal epithelium, it expresses viral genes that can cause cellular injury by inducing dysregulation of host genes. The HIV-1 genome contains a total of nine genes, including genes that encode structural proteins (gag, pol, env), regulatory proteins (tat and rev), and accessory proteins (vif, vpr, vpu, nef). The use of genetically engineered mice has identified several genes as particularly important in HIVAN pathogenesis, namely nef (which augments viral replication and infectivity) and vpr (which transports the HIV-1 preintegration complex into the nucleus and induces cell cycle arrest). In the podocyte, expression of nef activates signaling cascades that disrupt the actin cytoskeleton, causing foot process effacement and failure to maintain the normal filtration barrier. Heavy glomerular proteinuria and nephroti syndrome ensue. The infected podocytes revert to more immature phenotype resembling that seen in pro liferating podocytes during glomerular development The inability of the podocyte to maintain its norma mature phenotype leads to cellular dedifferentiation proliferation, and glomerular tuft collapse. The dysregulation of tubular epithelial cells by viral infection compounded by the tubular injury caused by sever proteinuria, leads to tubular microcyst formation, inter stitial fibrosis, and progressive renal failure. Tubula expression of vpr causes G2 cell cycle arrest and impair cytokinesis of tubular epithelial cells, leading t increased chromosomal copy number. As a result infected tubular epithelial cells appear hypertrophie with atypical enlarged nuclei.