Interferon-α Subtypes in an Ex Vivo Model of Acute HIV-1 Infection: Expression, Potency and Effector Mechanisms

HIV-1 is transmitted primarily across mucosal surfaces and rapidly spreads within the intestinal mucosa during acute infection. The type I interferons (IFNs) likely serve as a first line of defense, but the relative expression and antiviral properties of the 12 IFN alpha subtypes against HIV-1 infection of mucosal tissues remain unknown. Here, we evaluated the expression of all IFN alpha subtypes in HIV-1-exposed plasmacytoid dendritic cells by next-generation sequencing. We then determined the relative antiviral potency of each IFN alpha subtype ex vivo using the human intestinal Lamina Propria Aggregate Culture model. IFN alpha subtype transcripts from the centromeric half of the IFNA gene complex were highly expressed in pDCs following HIV-1 exposure. There was an inverse relationship between IFNA subtype expression and potency. IFN alpha 8, IFN alpha 6 and IFN alpha 14 were the most potent in restricting HIV-1 infection. IFN alpha 2, the clinically-approved subtype, and IFN alpha 1 were both highly expressed but exhibited relatively weak antiviral activity. The relative potencies correlated with binding affinity to the type I IFN receptor and the induction levels of HIV-1 restriction factors Mx2 and Tetherin/ BST-2 but not APOBEC3G, F and D. However, despite the lack of APOBEC3 transcriptional induction, the higher relative potency of IFN alpha 8 and IFN alpha 14 correlated with stronger inhibition of virion infectivity, which is linked to deaminase-independent APOBEC3 restriction activity. By contrast, both potent (IFN alpha 8) and weak (IFN alpha 1) subtypes significantly induced HIV-1 GG-to-AG hypermutation. The results unravel non-redundant functions of the IFN alpha subtypes against HIV-1 infection, with strong implications for HIV-1 mucosal immunity, viral evolution and IFN alpha-based functional cure strategies.