HIV-1 Nef synergizes with APOL1-G1 to induce nephrocyte cell death in HIV-related kidney diseases

People carrying two APOL1 risk alleles (RA) - G1 or G2 - are at greater risk of developing human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). However, it remains unclear whether the encoded protein(s) (APOL1-RA) and HIV-1 Nef interact to induce podocyte cell death. Here, we generated transgenic flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. We found that HIV-1 Nef acts in synergy with APOL1-G1, resulting in nephrocyte structural and functional defects, and that Nef exacerbates the organelle acidification defects and autophagy reduction induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating endoplasmic reticulum (ER) stress, triggering nephrocyte dysfunction and, ultimately, cell death. Thus, we identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high similarity between Drosophila nephrocytes and human podocytes, our findings suggest ER stress as a new therapeutic target for HIV-1- and APOL1-associated nephropathies.