Viral-immune interaction in glomerular kidney disease

HIV infection is a major contributor to the global burden of infectious diseases. Chronic kidney disease (CKD) is prevalent especially in people living with HIV (PWH). Viral exposure can alter host immunity in subtle ways, leaving an indelible footprint on the immune system. Among remarkable research obstacles, lacking a convenient and relevant animal model for virus-host dynamics study can be the most alarming one. We have recently established a novel mouse model whereby HIV envelope protein gp120 drives kidney glomerular disease in concert with a unique host immune molecule, soluble urokinase receptor (suPAR). Clinically, suPAR is associated with kidney function loss in patients with HIV infection. Mechanistically, host suPAR interacts with CD4 protein on T cells, which is essential for HIV-1 attachment via binding its viral protein gp120. Based on these intriguing new insights, we hypothesize that viral-host suPAR interplay induces renal integrin activation and plays an important role in HIV-associated kidney disease. We propose to test this hypothesis by comprehensively evaluating the implication of viral protein-suPAR-integrin triad in both mouse models (Aim 1) and virus-associated human glomerular diseases (Aim 2), utilizing state of the art tools, and unique combinations of top-down and bottom-up approaches. Additionally, we will test therapeutic modalities targeting the vicious viral protein-suPAR-integrin cycle with relevant small molecule inhibitors and antibodies (Aim 3).