Critical role for Nef in HIV-1-induced podocyte dedifferentiation.
The notable glomerular feature of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is the collapse of the capillary tuft with marked glomerular epithelial cell hyperplasia. These data suggest a loss of normal podocyte function, which is associated with a loss of the podocyte differentiation markers, Wilm's tumor (WT-1), synaptopodin, podocalyxin, and common acute lymphoblastic leukemia antigen (CALLA). We have previously shown that HIV-1 expression can induce these changes in HIV-1 transgenic mice. To identify which HIV-1 gene product(s) are responsible for the phenotypic changes in podocytes, we created multiple mutated HIV-1 constructs and then pseudotyped them with vesticular stomatitis virus glycoprotein (VSVG) envelope to enhance the tropism of these mutant viruses. In addition to gag/pol, the mutant viruses lacked one of the following, env, nef, rev, vif, vpr, or vpu. In addition, we generated single gene expressing pseudotyped viruses to complement the scanning mutation approach of our viral parental construct. Murine podocytes were then infected with one of the viral constructs either lacking or expressing the various HIV-1 genes. We found that HIV-1 nef was necessary and sufficient for proliferation of podocytes and down-regulation of synaptopodin and CALLA. These data suggest that Nef induces many of the changes we observe in HIV transgenic model and, as a result, this now defines the pathway for exploration of host responses to HIV-1 infection.
Sunamoto
Masaaki
M
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Husain
Mohammad
M
He
John Cijiang
JC
Schwartz
Elissa J
EJ
Klotman
Paul E
PE
D016263:AIDS-Associated Nephropathy / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation; D002478:Cells, Cultured; D002874:Chromosome Mapping; D015693:Gene Products, nef / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D015260:Neprilysin / Q000235:genetics; D010641:Phenotype; D012795:Sialoglycoproteins / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics; D054311:nef Gene Products, Human Immunodeficiency Virus
D015415:Biomarkers; D015693:Gene Products, nef; D008840:Microfilament Proteins; C503967:SYNPO protein, human; D012795:Sialoglycoproteins; C503968:Synpo protein, mouse; D025721:WT1 Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; C001643:podocalyxin; D015260:Neprilysin