HIV-1 entry into renal epithelia.

Presence of HIV-1 nucleic acid in both glomerular and tubular cells indicates that the kidney may serve as a reservoir for HIV-1.1,2 Moreover, HIV-1 genes express in tubular epithelial cells in the absence of detectable viral load in HIV-associated nephropathy (HIVAN).3 Although these studies offered strong evidence for renal epithelial cell infection, the mechanism of HIV-1 entry is not clear. Recently, several investigators attempted to identify the route of HIV entry into renal epithelia.4 – 6 DEC-205, an endocytic receptor abundantly present on dendritic cell surfaces, is present in renal tubular epithelial cells and may facilitate HIV-1 entry.4 Upon co-culture with T cells, a small fraction of internalized virus is also rescued by T cells, raising a possibility of productive infection within tubular epithelia.4 Another cell surface molecule, globotriaosyl ceramide (Gb3), which acts as a receptor for Shiga or Vero toxins, is also present on glomerular and tubular epithelial cells.6 The Gb3 interaction with gp120 promotes a CD4-, CXCR4-, and/or CCR5-dependent fusion process; however, the exact role played by Gb3 in HIV-1 entry into tubular cells is not clear. Recent studies strongly suggested that cell-to-cell transmission is much more efficient than cell-free transmission.7,8 Cell-to-cell transmission is described mostly between infected T cells or virus-laden antigen-presenting cells and uninfected T cells. This interaction at the site of cell-to-cell contact is called a virologic synapse with polarized T cells forming a protrusion called uropod, which mediates contact with the other cell.9,10 Chen et al.,11 in this issue of JASN, describe similar interactions between infected T cells and renal tubular epithelia. These investigators in their in vitro experimental model found viral transmission from infected T cells to renal tubular epithelial cells through cell-to-cell interaction, which they argue occurs through the formation of a virologic synapse.11 They used replication competent green fluorescence protein (GFP)-tagged HIV to infect primary CD4 T cells or a T cell line. During co-culture, T cells efficiently transmitted this laboratory-manipulated virus to renal tubular cells. Transmission was not limited to renal tubular epithelial cells alone but also took place in other epithelia, suggesting that transmission specificity may depend on epithelial cell type. Furthermore, efficient transfer happened only with viral particles contained within T cells, whereas transmission of cell-free virus was minimal. The viral transmission was CD4 independent and did not require envelope protein (Env). Rather, heparan sulfate proteoglycans (HSPGs), specifically syndecan 1 and agrin, seemed important in this transmission, although their functional role without the engagement of Env was not clarified. HIV-1 entry into epithelial cells, independent of CD4, has been reported by several investigators.4,12,13 Renal epithelial cell expression of conventional receptors such as CD4, CXCR4, and CCR5, which are commonly used by HIV-1 for entry into T cells, remained controversial.4,12,13 Interestingly, tubular cell expression of other transmembrane family receptors such as STL33, GPR1, and APJ along with low levels of viral expression has been reported in isolated cases13–15; however, confirmation of their presence and studies pertaining to their functional role are still awaited. Besides conventional receptors and co-receptors used by HIV-1, several other cell surface molecules may be used by HIV-1 to enter the cell.16 –19 The most studied among them have been dendritic cell-specific ICAM-3– grabbing nonintegrin (DC-SIGN), but macrophage mannose receptor, galactosylceramide, and HSPGs may also facilitate viral entry. These nonconventional pathways of HIV-1 entry may facilitate viral compartmentalization in various organs, and, thus, the repertoire of HIV-1 reservoirs may be much more varied than previously thought. Role of HSPGs in HIV-1 transmission from T cells to intestinal epithelial cells (HT29) is known20 and suggests nonconventional cell surface HIV-1 entry through a virologic synapse.20,21 In the studies carried out by Chen et al.,11 the punctate expression of GFP in renal tubular cells is indicative of viral transfer because the GFP is part of Gag moiety. In addition, further confirmation of viral transfer to renal tubular cells was shown by quantification of unspliced forms of viral RNA; however, the efficiency of virus replication was not evaluated. Glomerular visceral epithelial cells (podocytes) are also infected by HIV-1 in patients with HIVAN.1 Dysregulated podocyte growth displayed in HIVAN is attributed to HIV-1 gene expression. Although direct evidence demonstrating HIV-1 transmission into podocytes has never been shown, recent in vitro studies suggested the possibility of nonproducPublished online ahead of print. Publication date available at www.jasn.org.