IFN-ε protects primary macrophages against HIV infection
Carley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, Theresa L. Chang
Carley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, Theresa L. Chang
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Research Article AIDS/HIV Immunology

IFN-ε protects primary macrophages against HIV infection

Abstract

IFN-ε is a unique type I IFN that is not induced by pattern recognition response elements. IFN-ε is constitutively expressed in mucosal tissues, including the female genital mucosa. Although the direct antiviral activity of IFN-ε was thought to be weak compared with IFN-α, IFN-ε controls Chlamydia muridarum and herpes simplex virus 2 in mice, possibly through modulation of immune response. We show here that IFN-ε induces an antiviral state in human macrophages that blocks HIV-1 replication. IFN-ε 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-ε 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-ε–stimulated immune mediators and pathways had the signature of type I IFNs but were distinct from IFN-α in macrophages. IFN-ε induced significant phagocytosis and ROS, which contributed to the block to HIV replication. These findings indicate that IFN-ε induces an antiviral state in macrophages that is mediated by different factors than those induced by IFN-α. Understanding the mechanism of IFN-ε–mediated HIV inhibition through immune modulation has implications for prevention.

Authors

Carley Tasker, Selvakumar Subbian, Pan Gao, Jennifer Couret, Carly Levine, Saleena Ghanny, Patricia Soteropoulos, Xilin Zhao, Nathaniel Landau, Wuyuan Lu, Theresa L. Chang

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Figure 5

Differential profiles of immune mediators in response to IFN-ε and IFN-α.

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Differential profiles of immune mediators in response to IFN-ε and IFN-α...
(A) Induction of immune mediators by IFN-ε or IFN-α. MDMs were treated with IFN-ε or IFN-α (both 10 ng/ml) for 6 hours. Levels of cytokines/chemokines in the media were determined by a multiplex assay. Triangles of different colors designate differential regulation between IFN-ε and IFN-α: red triangles denote immune mediators that are induced by IFN-ε but not IFN-α; blue triangles denote immune mediators that are upregulated by IFN-ε to a greater extent than IFN-α; black triangles denote immune mediators that are induced by IFN-α to a greater extent than to IFN-ε; and white triangles denote immune mediators that are similarly responsive to IFN-ε and IFN-α. Mann-Whitney U test was used for the statistical analysis. (B) Induction of IFN, IL-6, and TNF-α signaling networks by IFN-ε and IFN-α. Intensity maps for expression patterns of genes associated with type I IFN, IL-6, and TNF-α networks in IFN-α– or IFN-ε–stimulated MDMs from 4 donors at 6 or 24 hours. Red color denotes upregulation, blue color denotes downregulation, and yellow color indicates no significant change or absence of expression; color intensity correlates with expression level. The scale bar ranges from +3 (red) to –3 (blue). The complete list of genes in these networks and their expression levels are shown in Supplemental Table 1. (C) Effect of IL-6 and TNF-α on HIV infection. MDMs were treated with IL-6 or TNF-α for 24 hours and then infected with HIV-luc (JR-FL). Cytokines were not present during the infection. *P < 0.05, #P > 0.05, treated vs. untreated controls by independent-samples t test. Dots in A represent data from individual donors (median, IQR). Data in C are mean ± SD of triplicate samples.