Podocyte damage induced by HIV-1 is critical to the pathogenesis of HIV-1 associated nephropathy (HIVAN) and is believed to result from productive replication of the virus. Here we demonstrate that HIV-1 readily enters human podocytes by a dynamin-mediated endocytosis but does not establish productive infection. We provide evidence suggesting that viral nucleic acids and proteins detected in podocytes are delivered by viral particles internalized by the cells. Endocytosed HIV-1 is only transiently harbored by podocytes and is subsequently released to the extracellular milieu as fully infectious virus. Similarly, primary podocytes established from normal human urine do not support productive infection by HIV-1 but sustain replication of VSV-G pseudotyped virus that bypasses HIV-1 entry receptors. Moreover, transfected podocytes expressing CD4 and CXCR4 receptors support productive replication of HIV-1. This further confirms that lack of HIV-1 entry receptors is the major barrier preventing productive infection of podocytes in vitro.
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