Taking a hard look at the pathogenesis of childhood HIV-associated nephropathy

Abstract

Childhood human immunodeficiency virus-associated nephropathy (HIVAN) is defined by the presence of proteinuria associated with mesangial hyperplasia and/or global-focal segmental glomerulosclerosis, in combination with the microcystic transformation of renal tubules. This review discusses the pathogenesis of childhood HIVAN and explores how the current pathological paradigm for HIVAN in adults can be applied to children. The Human Immunodeficiency Virus-1 (HIV-1) induces renal epithelial injury in African American children with a genetic susceptibility to develop HIVAN. The mechanism is not well understood, since renal epithelial cells harvested from children with HIVAN do not appear to be productively infected. Children with HIVAN show a renal up-regulation of heparan sulphate proteoglycans and a recruitment of circulating heparin-binding growth factors, chemokines, and mononuclear cells. Macrophages appear to establish a renal HIV-reservoir and transfer viral particles to renal epithelial cells. All of these changes seem to trigger an aberrant and persistent renal epithelial proliferative response. The paradigm that viral products produced by infected renal epithelial cells per se induce the proliferation of these cells is not supported by data available in children with HIVAN. More research is needed to elucidate how HIV-1 induces renal epithelial injury and proliferation in HIV-infected children.

Fig. 1

Representative hematoxylin and eosin staining of a renal biopsy from a child with human immunodeficiency virus-associated nephropathy (HIVAN). Original magnification ×150

Fig. 2

Structure and viral cycle of HIV-1 in productively infected cells. a Diagram of the HIV-1 virus. The viral proteins (p) are designated with a number corresponding to the protein size (×1000). b Electron micrograph picture of mature viral particles (×100,000). c Representative diagram of the viral cycle in productively infected cells. MA Matrix protein, CA capside, NC nucleocapside, RT reverse transcriptase, PR protease, IN integrase, CD4 HIV-1 receptor, CXCR-4, CCR-5 HIV-1 co- receptors, HSPG heparan sulfate proteoglycans

Fig. 3

Function of HIV-1 viral proteins. This picture was reproduced with modifications from Ray et al. [36] (used with permission)

Fig. 4

Electron micrographs showing the transfer of viral particles from HIV-infected macrophages (M) to cultured primary renal tubular epithelial cells (RTEc) harvested from a child with HIVAN. a Viral particles released into the interstitial space between cells and trapped inside RTEc (black and open arrows, respectively). b, c Higher magnification view of the viral particles show in a. Magnification: a ×10,000, b 50,000, c ×70,000. These pictures were reproduced with modifications from Ray et al. [53] (used with permission)

Fig. 5

¹²⁵I-fibroblast growth factor-2 (FGF-2) binding to representative renal sections harvested from normal wild-type mice (a) and HIV-Tg₂₆ mice with renal disease (b). Renal sections were exposed to ¹²⁵I-FGF-2 in the presence of heparin (30 μg/ml) as described previously [58]. HIV-Tg₂₆ mice with renal disease show increased binding of ¹²⁵I-FGF-2 to the renal cortex and medulla [58]. Original magnification × 20