Human Cervical Epithelial Cells Release Antiviral Factors and Inhibit HIV Replication in Macrophages

J Innate Immun. 2019;11(1):29-40. doi: 10.1159/000490586. Epub 2018 Jul 20.

Abstract

The female reproductive tract is a major site of HIV sexual transmission. We here examined whether human cervical epithelial cells (HCEs) can be immunologically activated and produce antiviral factors against HIV. We demonstrated that HCEs (End1/E6E7 cells) possess the functional toll-like receptor (TLR)3 signaling system, which could be activated by Poly I:C and induce multiple cellular HIV restriction factors. The treatment of primary human macrophages with supernatant (SN) from TLR3-activated End1/E6E7 cell cultures resulted in HIV inhibition. This SN-mediated HIV inhibition was mainly through the induction of interferons (IFN)-β and IFN-λs, as the antibodies to IFN-β or IFN-λs receptor could effectively block the SN-mediated anti-HIV effect. Further studies showed that the incubation of macrophages with SN from the activated cervical epithelial cell cultures induced the expression of a number of IFN-stimulated genes (ISGs), including IFN-stimulated gene (ISG15), ISG56, 2', 5'-oligoadenylate synthetase 1 (OAS 1), OAS 2, Myxovirus Resistance A (MxA), MxB, and Guanylate-binding protein 5 (GBP5). In addition, TLR3-activated cells produced the CC chemokines [regulated on activation, normal T cell expressed and secreted (RANTES), Human macrophage inflammatory protein 1 alpha (MIP-1α), MIP-1β] the ligands of HIV entry co-receptor CCR5. These observations support further studies on HCEs as potentially crucial and alternative targets for immunological intervention to control and prevent HIV sexual transmission.

Keywords: HIV; Human cervical epithelial cells; Interferon-stimulated genes; Macrophages; Toll-like receptor 3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents / metabolism
  • Antiviral Agents / pharmacology
  • Cells, Cultured
  • Cervix Uteri / cytology
  • Cervix Uteri / immunology*
  • Cervix Uteri / metabolism*
  • Chemokine CCL3 / immunology
  • Chemokine CCL3 / metabolism
  • Chemokines, CC / immunology
  • Chemokines, CC / metabolism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Female
  • HIV-1 / physiology*
  • Humans
  • Immunity, Innate
  • Interferons / metabolism
  • Macrophages / immunology
  • Macrophages / virology*
  • RNA-Binding Proteins
  • Toll-Like Receptor 3 / immunology
  • Toll-Like Receptor 3 / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / immunology
  • Virus Replication / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • Chemokine CCL3
  • Chemokines, CC
  • IFIT1 protein, human
  • RNA-Binding Proteins
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Transcription Factors
  • Interferons