Interferon epsilon protects primary human macrophages against HIV-1 infection by blocking early stages of the viral life cycle (VIR9P.1152)

Abstract

Abstract Interferon epsilon (IFNε), a type-I IFN, is hormonally regulated and plays a protective role against several viral and bacterial pathogens. In this study, we examined the effect of IFNε on HIV infection and its underlying mechanism. IFNε at 10ng/mL inhibited HIV infection of human monocyte derived macrophages (MDMs) but not activated CD4+ T cells. Pretreatment of MDMs with IFNε protected MDMs against infection by replication competent X4, R5, and X4R5 dual-tropic viruses and HIV transmitted/founder viruses. We further delineated the underlying mechanism of the anti-HIV activity of IFNε and found IFNε down-regulated cell surface expression of the co-receptor CCR5 but not CD4 or the co-receptor CXCR4. Although IFNε treatment affected HIV entry, it also blocked infection by HIV reporter virus pseudotyped with VSV envelope, which enters cells independently of CD4 and HIV co-receptors, indicating that IFNε treatment inhibited HIV infection after viral entry. Quantitative PCR analysis of HIV reverse transcribed (RT) DNA products revealed IFNε blocked the step of early RT. IFNε induced expression of the HIV host restriction factor APOBEC3A in MDMs, however siRNA knockdown of A3A determined it may not play a significant role in IFNε mediated HIV inhibition. Taken together, IFNε protects MDMs against HIV infection through multiple mechanisms by down-regulation of CCR5 expression and by inhibiting the synthesis of HIV reverse transcribed products.