Δ20 IFITM2 differentially restricts X4 and R5 HIV-1

Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7112-7117. doi: 10.1073/pnas.1619640114. Epub 2017 Jun 19.

Abstract

CCR5 (R5)-tropic, but not CXCR4 (X4)-tropic, HIV-1 is associated with primary HIV-1 infection and transmission. Recent studies have shown that IFN-induced transmembrane (IFITM) proteins, including IFITM1, IFITM2, and IFITM3, restrict a broad range of viruses. Here, we demonstrate that an IFITM2 isoform (Δ20 IFITM2) lacking 20 amino acids at the N terminus differentially restricts X4 and R5 HIV-1. Δ20 IFITM2 suppresses replication of X4 HIV-1 strains by inhibiting their entry. High levels of Δ20 IFITM2 expression could be detected in CD4+ T cells and in monocytes. Infection of X4 viruses in monocyte-derived macrophages and dendritic cells is enhanced upon depletion of IFITM2 isoforms. Furthermore, we also show that coreceptor use is the determining factor for differential HIV-1 restriction of Δ20 IFITM2. When we replace the C terminus of CCR5 with the C terminus of CXCR4, R5 viruses become more susceptible to Δ20 IFITM2-mediated restriction. In contrast to previous studies, our research reveals that neither X4 nor R5 HIV-1 is suppressed by IFITM2 and IFITM3. The multifactor gatekeeping model has been proposed to explain restriction of X4 viruses in the early stage of HIV-1 diseases. Our findings indicate that Δ20 IFITM2 may serve as a major contributor to this gatekeeping mechanism.

Keywords: HIV; gatekeeping; interferon-inducible transmembrane protein; viral entry; Δ20 IFITM2.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Alleles
  • Cell Membrane / metabolism
  • Epitopes / immunology
  • Gene Frequency
  • HEK293 Cells
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / classification*
  • Humans
  • Immunity, Innate
  • Jurkat Cells
  • Membrane Proteins / metabolism*
  • Protein Isoforms
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / metabolism
  • Signal Transduction
  • Virion

Substances

  • CCR5 protein, human
  • CXCR4 protein, human
  • Epitopes
  • IFITM2 protein, human
  • Membrane Proteins
  • Protein Isoforms
  • Receptors, CCR5
  • Receptors, CXCR4