biostudies-literatureZhu JYNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesSchool of Medicine, University of Marylanddmm052178https://www.ebi.ac.uk/biostudies/studies/S-EPMC12352291biostudies-literatureUnknown18(7)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 Disease models & mechanismsHIV-1 Nef synergizes with APOL1-G1 to induce nephrocyte cell death in HIV-related kidney diseases.PMC12352291R01 DK103564R01-DK120908R01 DK098410R01-DK103564R01 DK115968R01 DK120908R01-DK098410R01-DK115968Ray PELi JFu YZhu JYHan ZYu Jvan de Leemput JfalseHIV-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 2025-01-01T00:00:00Z2025 Jul2026-05-01T18:45:12.348Z2026-04-07T17:09:49.085ZS-EPMC123522914074777310.1242/dmm.052178