APOL1 Renal Risk Variants: Fertile Soil for HIV-Associated Nephropathy

Abstract

Apolipoprotein L1 (APOL1) genetic variants are potent risk factors for glomerular disease, but one or more additional factors are required for expression of glomerular disease. Uncontrolled or poorly controlled HIV infection is the most potent susceptibility factor for APOL1 nephropathy that has been identified to date. APOL1 variants are associated with HIV-associated nephropathy (HIVAN), a podocyte disease, but not with HIV-immune complex disease, primarily a disease of the mesangium. The mechanism by which HIV brings out the latent glomerular disease risk remains to be defined. There are at least two classes of candidate mechanisms to explain the potent interaction between HIV-1 and APOL1. First, APOL1 variant proteins and HIV accessory proteins implicated in HIVAN may target the same or related intracellular pathways in podocytes. Recent data suggests roles for interleukin 1b and transcription factor EB (TFEB). Second, features of uncontrolled HIV-infection, including elevated circulating factors such as interferon, may drive APOL1 gene transcription or act upon podocytes in other ways. Deeper probing of APOL1-HIV interactions may yield insights that will aid understanding HIVAN, APOL1 nephropathy, and podocyte biology.

APOL 1 and kidney disease

“…Additionally, it was found that these patients had a diagnosis 2 to 5 years earlier than the other population without risk variant associated with APOL1. The deterioration of renal function was after 10 years of diagnosis of hypertension in these patients, which is why a possible effect on blood pressure has been suggested rather than with the development of CKD [19].…”

“…In patients with HIV, the role of interferon has been studied extensively, finding that the type of interferon gamma is the one that has the most power to boost the expression of the APOL1 gene, this is achieved by activating STAT 3, occupying the promoter sites of APOL1 [19]. Once this second HIT occurs, the processes of autophagy and alteration of mitochondrial function in podocytes and the development of collapsing glomerulopathy take place [17].…”

“…As previously mentioned, patients with a high-risk genotype are 17 to 19 times more likely to develop FSGS and 89 times more likely to develop HIVAN in patients with HIV. In a study conducted in the USA of patients with FSGS without HIV, it was found that 72% of patients had high-risk genotypes compared to 13% of patients in the general African-American population, however this probability varies depending on the study that reports them, with some biases given given the small sample size of most studies [19].…”

APOL1 polymorphism modulates sphingolipid profile of human podocytes

“…The online version of this article (https://doi.org/10.1007/s10719-020-09944-w) contains supplementary material, which is available to authorized users. [7,8]. The pathogenesis of HIVAN is likely due to direct HIV infection of podocytes, the end-stage differentiated kidney epithelial cells critical for the glomerular filtration barrier [9,10].…”

Apolipoprotein L1 nephropathies

“…In all, 91 papers appeared in 2017 with the key word "APOL1", of which 74 also had the key word "kidney" and only a fraction can be reviewed here. A number of useful reviews have appeared this year, some of which are referenced below and others review the evolution of the APOL1 gene [1], APOL1 role in HIV-associated nephropathy [2], role of APOL1 genetic testing in clinical medicine [3], effects on APOL1 on transmembrane ion flux [4] and possible therapeutic avenues [5].…”