The Innate Immune Factor Apolipoprotein L1 Restricts HIV-1 Infection

Abstract

b Apolipoprotein L1 (APOL1) is a major component of the human innate immune response against African trypanosomes. Although the mechanism of the trypanolytic activity of circulating APOL1 has been recently clarified, the intracellular function(s) of APOL1 in human cells remains poorly defined. Like that of many genes linked to host immunity, APOL1 expression is induced by proinflammatory cytokines gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣). Additionally, IFN-␥-polarized macrophages that potently restrict HIV-1 replication express APOL1, which suggests that APOL1 may contribute to HIV-1 suppression. Here, we report that APOL1 inhibits HIV-1 replication by multiple mechanisms. We found that APOL1 protein targeted HIV-1 Gag for degradation by the endolysosomal pathway. Interestingly, we found that APOL1 stimulated both endocytosis and lysosomal biogenesis by promoting nuclear localization of transcription factor EB (TFEB) and expression of TFEB target genes. Moreover, we demonstrated that APOL1 depletes cellular viral accessory protein Vif, which counteracts the host restriction factor APOBEC3G, via a pathway involving degradation of Vif in lysosomes and by secretion of Vif in microvesicles. As a result of Vif depletion by APOL1, APOBEC3G was not degraded and reduced infectivity of progeny virions. In support of this model, we also showed that endogenous expression of APOL1 in differentiated U937 monocytic cells stimulated with IFN-␥ resulted in a reduced production of virus particles. This finding supports the hypothesis that induction of APOL1 contributes to HIV-1 suppression in differentiated monocytes. Deciphering the precise mechanism of APOL1-mediated HIV-1 restriction may facilitate the design of unique therapeutics to target HIV-1 replication.

Plasma Levels of Risk-Variant APOL1 Do Not Associate with Renal Disease in a Population-Based Cohort

“…These lines of evidence include transplant data suggesting that allograft survival tracks with donor rather than recipient genotype [29][30][31] ; evidence from studies in human cells and biopsy data demonstrating that APOL1 is expressed in the podocyte and may have detrimental effects in that cell type 7,12,20,32,33 and cell biologic and epidemiologic studies demonstrating that APOL1 is induced by innate immune effectors in podocytes, which may account for the variable penetrance of the RRG seen in different forms of renal disease. 7,34,35 Although it is difficult to rule out the potential effects of transient changes in circulating APOL1 levels (i.e., due to infection) or a threshold effect (the damage occurs at levels above or below those monitored), the lack of an association between plasma APOL1 and prevalent renal disease in the DHS is in line with these previous observations.…”

Genetic Analysis of the Localization of APOBEC3F to Human Immunodeficiency Virus Type 1 Virion Cores

“…No A3F immunoreactivity was detectable in the centrifuged supernatants, despite abundant cellular expression of each A3F and GAPDH (data not shown). This is consistent with a lack of microvesicle secretion from HEK293T cells, as previously reported by others (34). Sucrose density gradient centrifugation.…”

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…Either viral infection or genetic risk alone fails to equate to kidney disease; it is the gene-by-environment interaction that is of cardinal pathogenic importance. Biologic studies have since delineated pathways for the interaction of APOL1 and its allelic gene products as well as other APOL gene family members with viral response mediators (e.g., class II interferons) in circulating immune cells as well as the key kidney target cell, the podocyte, which is responsible for structural integrity of the glomerulus or filtering unit of the kidney (58).…”