IFN-ε protects primary macrophages against HIV infection
Carley Tasker, … , Wuyuan Lu, Theresa L. Chang
Carley Tasker, … , Wuyuan Lu, Theresa L. Chang
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e88255. https://doi.org/10.1172/jci.insight.88255.
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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 1

IFN-ε protects primary macrophages from HIV infection.

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IFN-ε protects primary macrophages from HIV infection. (A) IFN-ε inhibit...
(A) IFN-ε inhibits HIV replication. MDMs were treated with IFN-ε for 24 hours and then exposed to HIV-1 primary isolates. The cells were cultured without IFN-ε, during which time the supernatants were collected for HIV p24 measurement. The tropisms of the virus isolates are indicated, and viral genotypes are shown in parentheses. (B) IFN-ε inhibits single-cycle HIV-luciferase reporter virus. MDMs were treated with IFN-ε (10 ng/ml) for 24 hours and then exposed to pseudotyped HIV-luc (JR-FL). Luciferase activity (RLUs) was normalized to untreated controls. (C) HIV inhibition by IFN-ε (10 ng/ml) from different sources. MDMs were pretreated with IFN-ε from yeast, Expi293F cells, and E. coli for 24 hours and then infected with HIV-luc (JR-FL). Reduced and alkylated bacteria-expressed IFN-ε was included for comparison. (D) Effect of IFN-ε on HIV infection of CD4+ T cells. PHA-activated CD4+ T cells were treated with different amounts of IFN-ε for 24 hours and then infected with HIV-luc (JR-FL) or HIV-1BaL at different MOIs. IFN-α was included as a comparison. (E) Effect of IFN-ε on PMA-differentiated THP-1 cells. PMA-differentiated THP-1 cells were treated with different amounts of IFN-ε or IFN-α for 24 hours and then infected with pseudotyped HIV-luc (VSV-G) in a single-cycle infection assay. (F) Effect of IFN-ε on SAMHD1 knockdown THP-1 cells. Cell lines with or without SAMHD1 knockdown were treated with IFN-ε or IFN-α for 24 hours and then infected with pseudotyped HIV-luc (VSV-G). Data in A, E, and F are mean ± SD of triplicate samples and are representative of 3 independent experiments. Actual data points are shown. Dots in B (median, IQR), C (mean ± SD), and D (mean ± SD) represent data from individual donors of 3–12 experiments. *P < 0.05, IFN-ε–treated cells vs. untreated controls by independent-samples t test.