title: The innate immune factor apolipoprotein L1 restricts HIV-1 infection.
abstract: 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-γ) and tumor necrosis factor alpha (TNF-α). Additionally, IFN-γ-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-γ 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.
authors.affiliation: Meharry Medical College, Center for AIDS Health Disparities Research, Nashville, Tennessee, USA.
authors.forename: Harry E
authors.initials: HE
authors.lastname: Taylor
authors.forename: Atanu K
authors.initials: AK
authors.lastname: Khatua
authors.forename: Waldemar
authors.initials: W
authors.lastname: Popik
mesh_terms: D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D004705:Endocytosis; D005434:Flow Cytometry; D015683:Gene Products, gag / Q000276:immunology; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000302:isolation & purification* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000276:immunology; D008075:Lipoproteins, HDL / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D014779:Virus Replication
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D015683:Gene Products, gag; D008075:Lipoproteins, HDL; D007372:Interferons