The RCMI Program in Health Disparities Research at Meharry Medical College

Meharry Medical College, Nashville TN

Investigators

Linked publications & trials

Abstract

Project Summary/Abstract The kidney podocytes are highly vulnerable to damage by HIV infection. This damage can be exacerbated in podocytes that express variants of the APOL1 gene, G1 and G2, which are unique to the African population and found in about 13% of African Americans (AAs). Notably, expression of APOL1 variants has been linked to a higher risk of non-diabetic chronic kidney disease (CKD), faster progression to end-stage kidney disease (ESKD), and HIV-associated nephropathy (HIVAN). The risk of developing ESKD in HIV-infected AAs is 50 times higher than in whites, and more than 70% of AAs with HIVAN have two APOL1 gene risk variants. While antiretroviral therapy (ART) has reduced the incidence and mortality of HIVAN, certain drugs are nephrotoxic and poorly target latent HIV reservoirs. HIV infection in the kidney cells occurs in a low-oxygen environment (hypoxia), which stabilizes oxygen- sensitive hypoxia inducible factor HIF-1α. HIF-1α binds to the hypoxia response element (HRE) DNA motif in gene promoters to induce transcription of a wide range of genes. However, most studies of HIV replication were conducted under normoxic conditions, where HIF-1α is degraded. There is evidence that hypoxia inhibits HIV-1 replication and promotes latency by reducing HIV-1 promoter activity by epigenetic modifications, such as promoter methylation. In this regard, the HRE elements have been identified in HIV-1 promoter sequences. We have shown that hypoxia stimulates the expression of APOL1 RVs in urine-derived podocytes from AAs by recruiting HIF-1α to HREs in the APOL1 promoter. This suggests that APOL1 RVs may affect the methylation status of the HIV-1 promoter and stimulate virus replication in hypoxia. However, the molecular mechanisms underlying this epigenetic modification of the HIV-1 promoter in the context of APOL1 RVs expression have not been investigated. We hypothesize that the expression of APOL1 RVs in hypoxic podocytes contributes to increased HIV-1 replication by promoting demethylation of HRE in the HIV-1 promoter. We will test our hypothesis in two specific aims: 1) Establish the methylation status of the HRE in the HIV-1 promoter in hypoxia in podocytes without and with APOL1 RVs and 2) Identify the mechanism(s) by which APOL1 RVs promote HIV HRE demethylation in hypoxia. At the completion of the proposed research, we expect to define the mechanisms by which APOL1 RVs in podocytes of AA origin promote HRE demethylation and stimulate HIV-1 replication in hypoxia. These results may provide a link between the expression of APOL1 RVs in hypoxia and the development of HIV-associated nephropathy and present new therapeutic targets to combat HIV replication in AAs with APOL1 RVs.