IFN- ε protects primary macrophages against HIV infection

JCI Insight. 2016 Dec 8;1(20):e88255. doi: 10.1172/jci.insight.88255.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / virology
  • Cells, Cultured
  • Cytidine Deaminase / metabolism
  • HIV Infections / drug therapy*
  • HIV Infections / immunology
  • HIV-1
  • Humans
  • Interferons / pharmacology*
  • Macrophages / drug effects*
  • Macrophages / virology*
  • Proteins / metabolism
  • SAM Domain and HD Domain-Containing Protein 1 / metabolism
  • Virus Replication


  • Proteins
  • interferon-epsilon, human
  • Interferons
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • APOBEC3A protein, human
  • Cytidine Deaminase