IFN-ε protects primary macrophages against HIV infection

IFN-epsilon is a unique type I IFN that is not induced by pattern recognition response elements. IFN-epsilon is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-epsilon was thought to be weak compared with IFN-alpha, IFN-epsilon controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFN-epsilon induces an antiviral state in human macrophages that blocks HIV-1 replication. IFN-epsilon had little or no protective effect in activated CD4(+) T cells or transformed cell lines unless activated CD4(+) T cells were infected with replication-competent HIV-1 at a low MOI. The block to HIV infection of macrophages was maximal after 24 hours of treatment and was reversible. IFN-epsilon acted on early stages of the HIV life cycle, including viral entry, reverse transcription, and nuclear import. The protection did not appear to operate through known type I IFN-induced HIV host restriction factors, such as APOBEC3A and SAMHD1. IFN-epsilon-stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFN-alpha in macrophages. IFN-epsilon induced significant phagocytosis and ROS, which contributed to the block to HIV replication. These findings indicate that IFN-epsilon induces an antiviral state in macrophages that is mediated by different factors than those induced by IFN-alpha. Understanding the mechanism of IFN-epsilon-mediated HIV inhibition through immune modulation has implications for prevention.