HIV-1 Vpr inhibits cytokinesis in human proximal tubule cells

Abstract

HIV associated nephropathy (HIVAN) afflicts an estimated 1–3 million people worldwide and is a major cause of morbidity and mortality. Murine transgenic models have demonstrated that expression of HIV-1 genes in kidney cells results in characteristic HIVAN pathology: collapsing FSGS and microcystic tubular disease. While we have gained significant understanding of the podocyte disease, less is known about the tubular epithelial responses to infection. HIV-1 vpr plays an important role in the FSGS of HIVAN particularly in association with nef expression in podocytes. In addition, Vpr is reported to exacerbate tubular pathology. Therefore, we explored the effect of vpr expression on renal tubular epithelial cell function. Proximal tubule epithelial cells (PTEC) were transduced in vitro using a pseudotyped lentivirus vector carrying HIV-1 vpr and control genes. HIV-1 vpr expression in cultured PTECs impaired cytokinesis causing cell enlargement and multinucleation. Because the in vitro phenotype was so profound, we re-examined the HIVAN murine model and human HIVAN biopsies to see if similar changes could be seen in vivo. Surprisingly, both the transgenic murine HIVAN model and human HIVAN biopsies showed abundant hypertrophic tubule cells consistent with the in vitro findings. The extent of the tubular cell hypertrophy was particularly impressive and represents a previously unappreciated aspect of the disease. Additionally, multinucleated tubular cells were identified in the murine HIVAN model and increased chromosome number was detected in tubular cells in HIVAN biopsies. This study provides evidence of a new clinical phenotype in HIVAN that may result from Vpr’s ability to impair cytokinesis.

Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells

“…Previous work using pseudotyped lentiviral particles expressing single---gene constructs, pHR---Vpr, pHR---Tat, or pHR---Vif, confirm that the G2 arrest phenotype is Vpr---specific in RTEC model systems [60]. …”

“…Vpr---mediated arrest in the G2 phase of the cell cycle is well established in both immortalized and primary renal tubule epithelial cells [60,138,139]. Previous work using pseudotyped lentiviral particles expressing single---gene constructs, pHR---Vpr, pHR---Tat, or pHR---Vif, confirm that the G2 arrest phenotype is Vpr---specific in RTEC model systems [60].…”

“…Additionally, tubule epithelial cells exhibit hypertrophy with enlarged hyperchromatic nuclei, and focal apoptosis [24,60]. Tubules in HIVAN biopsies also exhibit high levels of DNA damage marker γH2AX, indicating activation of the DNA damage response in these cells [61].…”

“…Proximal tubule epithelial cells were transduced using a pseudotyped lentivirus vector expressing HIV---1 vpr and control genes [60]. …”

In-Depth Review of Human Immunodeficiency Virus-Associated Nephropathy

“…Its expression in tubular epithelial cells is associated with G2 cell cycle arrest, impaired cytokinesis and finally apoptosis (Zhong et al, 2005;Rosenstiel et al, 2008;2009b;Snyder et al, 2010;Vashistha et al, 2008). A synergistic effect of nef and vpr was observed in a study which showed that mice with both nef and vpr expression developed more severe nephropathy (Zuo et al, 2006).…”