APOL1 risk variants and the development of HIV-associated nephropathy

Abstract

HIV-associated nephropathy (HIVAN) remains a concern among untreated HIV patients, notably of African descent, as patients can reach end-stage renal disease within 3 years. Two variants (G1 and G2) of the APOL1 gene, common in African populations to protect against African sleeping sickness, have been associated with an increased risk of several glomerular disorders including HIVAN, hypertension-attributed chronic kidney disease, and idiopathic focal segmental glomerulosclerosis and are accordingly named renal risk variants (RRVs). This review examines the mechanisms by which APOL1 RRVs drive glomerular injury in the setting of HIV infection and their potential application to patient management. Innate antiviral mechanisms activated by chronic HIV infection, especially those involving type 1 interferons, are of particular interest as they have been shown to upregulate APOL1 expression. Additionally, the downregulation of miRNA 193a (a repressor of APOL1) is also associated with the upregulation of APOL1. Interestingly, glomerular damage affected by APOL1 RRVs is caused by both loss- and gain-of-function changes in the protein, explicitly characterizing these effects. Their intracellular localization offers a further understanding of the nuances of APOL1 variant effects in promoting renal disease. Finally, although APOL1 variants have been recognized as a critical genetic player in mediating kidney disease, there are significant gaps in their application to patient management for screening, diagnosis, and treatment.

Keywords: Apolipoprotein (Apo)L1; HIVAN; collapsing FSGS; parietal epithelial cells; podocytes.

Figure 1.

cGMP-AMP synthase (cGAS), interferon-inducible protein 16 (IFI16), and RIG-I are sensors of HIV infection. cGAS and IFI16 activate STING, which upregulates interferon (IFN)-β; the latter acts in an autocrine/paracrine manner to upregulate APOL1 and IFI16, which then further enhance STING upregulation. Retinoic acid-inducible gene (RIG)-I also mediates transcriptional activation of type 1 interferons, which upregulate APOL1.

Figure 2.

The APOL1 G0 variant has been shown to preferentially localize to intracellular lipid droplets, whereas RRVs (G1 used as an example) preferentially localize to membrane-bound organelles such as the endoplasmic reticulum and mitochondrion. Interestingly, the G0 allele has been described to exert a protective effect by causing RRVs to also localize to intracellular lipid droplets. M, Mitochondria; E, endoplasmic reticulum; N, nucleus

Figure 3.

A. The APOL1-G0 allele down-regulates miR193a, which enhances autophagy and podocyte molecular markers sustaining podocytes in differentiated state. B. APOL1-G1 and G2 cause increased miR193a, which induces podocyte de-differentiation via autophagy blockade and favoring adherens complex destabilization.