EYA1 as a novel regulator of HIV-induced end stage kidney disease - SUMMARY Chronic kidney disease (CKD) is significantly more prevalent among persons with HIV (PWH). HIV infection increases the likelihood of progression from CKD to end-stage kidney disease (ESKD), and HIV-associated nephropathy (HIVAN) continues to be a major cause of ESKD in PWH. Despite the widespread implementation of antiretroviral therapy, PWH remain at significantly higher risk of ESKD compared to the general population. While carriage of the apolipoprotein-L1 (APOL1) haplotype has emerged as the strongest genetic contributor to the elevated ESKD risk in PWH, this alone does not fully explain the risk, warranting further investigation into ESKD pathogenesis. In the largest genome-wide association study of ESKD in HIV to date, we identified a new locus in the EYA1 gene with the top signal conferring nearly a 5-fold increased risk of developing ESKD independent of clinical comorbidities and APOL1 haplotype. While this association was validated in two independent HIV cohorts, inconsistent results were observed in two non-HIV populations. EYA1 is a tyrosine phosphatase and transcriptional co-factor that plays a key role in kidney development and is a critical regulator of nephron progenitor cell differentiation, as evidenced by Eya1-deficient mice lacking kidneys. Our team demonstrated that Eya1 gene expression is increased in the adult podocytes of HIV-1 transgenic mice (Tg26), an experimental model for HIVAN, compared to wild type. Moreover, higher EYA1 protein expression was detected in human kidney biopsy samples from patients with HIVAN than in nephrectomy controls. Yet, how EYA1 functionally contributes to the pathogenesis of HIVAN remains unknown. Therefore, our objective is to characterize the regulatory landscape of the EYA1 locus in PWH with ESKD and conduct mechanistic studies to determine whether EYA1 directly causes glomerular damage or facilitates damage caused by HIV. We hypothesize that a) EYA1 risk locus regulates the expression of EYA1 and/or other target genes responsible for renal injury; and b) HIV infection serves as a second hit in EYA1 risk variant carriers, leading to podocyte dysfunction and HIVAN. In this proposal, we plan to 1) Investigate the genetic origins and fine map the novel EYA1 risk locus to identify causal drivers. We will also compare EYA1 contribution to ESKD risk in PWH versus general population; 2) Characterize kidney histology, podocyte function, and EYA1 expression in archived formalin fixed paraffin imbedded human kidney biopsies from EYA1 carriers vs non-carriers with or without HIVAN, and 3) Characterize novel mouse models of HIVAN with podocyte-inducible Eya1 expression and determine whether Eya1 induction in podocytes affects kidney disease in the presence of HIV versus no HIV. This proposal leverages strong preliminary data, transdisciplinary expertise, and access to large well-characterized cohorts to explore EYA1 as a potential risk factor and therapeutic target for HIVAN and beyond.
