Transmembrane TNF-αFacilitates HIV-1 Infection of Podocytes Cultured from Children with HIV-Associated Nephropathy.
Studies have shown that podocytes and renal tubular epithelial cells from patients with HIV-associated nephropathy (HIVAN) express HIV-1 transcripts, suggesting that productive infection of renal epithelial cells precipitates development of HIVAN. However, podocytes and renal tubular epithelial cells do not express CD4 receptors, and it is unclear how these cells become productively infectedin vivoWe investigated the mechanisms underlying the infection by HIV-1 of podocytes cultured from the urine of children with HIVAN. We observed low-level productive infection on exposure of these cells to primary cell-free HIV-1 supernatants. However, envelope-defective recombinant HIV-1 did not infect the renal epithelial cell lines. Moreover, treatment of podocytes to inhibit endocytic transport or dynamin activity or remove cell surface heparan sulfate proteoglycans reduced infection efficiency. Transfection of CD4- 293T cells with a cDNA expression library developed from a podocyte cell line derived from a child with HIVAN led to the identification of TNF-αas a possible mediator of HIV-1 infection. Overexpression of transmembrane TNF-αin cultured CD4- renal tubular epithelial cells, 293T cells, and HeLa cells enabled the infection of these cells; exposure to soluble TNF-αdid not. Immunohistochemistry showed TNF-αexpression in podocytes of renal sections from children with HIVAN. Furthermore, we found that TNF-αenhanced NF-κB activation and integration of HIV-1 into the podocyte DNA. Finally, inhibition of dynamin activity blocked TNF-α-mediated infection. These data establish a role for transmembrane TNF-αin facilitating the viral entry and integration of HIV-1 into the DNA of renal epithelial cells.
Centers for *Genetic Medicine Research and.|Department of Pediatrics, and.
Jinliang
J
Li
Centers for *Genetic Medicine Research and.|Department of Pediatrics, and.
Jharna R
JR
Das
Centers for *Genetic Medicine Research and.|Department of Pediatrics, and.
Pingtao
P
Tang
Department of Pediatrics, and.|Cancer and Immunology.
Zhe
Z
Han
Centers for *Genetic Medicine Research and.|Department of Pediatrics, and.
Jyoti K
JK
Jaiswal
Centers for *Genetic Medicine Research and Pray@cnmc.org.|Department of Pediatrics, and.|Division of Nephrology, Children's National Health System, The George Washington University School of Medicine, Washington, DC.
Patricio E
PE
Ray
D016263:AIDS-Associated Nephropathy / Q000821:virology*; D002478:Cells, Cultured; D002648:Child; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D050199:Podocytes / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha
HIV nephropathy; children; cytokines; pediatric nephrology; podocyte; renal tubular epithelial cells