The interferon‐induced transmembrane (IFITM) proteins protect host cells from diverse virus infections. IFITM proteins also incorporate into HIV‐1 virions and inhibit virus fusion and cell‐to‐cell spread, with IFITM3 showing the greatest potency. Here, we report that amino‐terminal mutants of IFITM3 preventing ubiquitination and endocytosis are more abundantly incorporated into virions and exhibit enhanced inhibition of HIV‐1 fusion. An analysis of primate genomes revealed that IFITM3 is the most ancient antiviral family member of the IFITM locus and has undergone a repeated duplication in independent host lineages. Some IFITM3 genes in nonhuman primates, including those that arose following gene duplication, carry amino‐terminal mutations that modify protein localization and function. This suggests that “runaway” IFITM3 variants could be selected for altered antiviral activity. Furthermore, we show that adaptations in IFITM3 result in a trade‐off in antiviral specificity, as variants exhibiting enhanced activity against HIV‐1 poorly restrict influenza A virus. Overall, we provide the first experimental evidence that diversification of IFITM3 genes may boost the antiviral coverage of host cells and provide selective functional advantages.
By analyzing synthetic and naturally occurring mutations of interferon‐induced transmembrane 3 (IFITM3), this study provides novel insight into the antiviral mechanisms at play during HIV‐1 infection. The authors further show that the diversification of IFITM3 genes during evolution may boost the antiviral coverage of host cells and provides selective functional advantages.
Amino‐terminal mutations of IFITM3 result in an enhanced incorporation into HIV‐1 virions and promote the inhibition of virus–cell fusion.
Two adjacent regulatory motifs that control ubiquitination and endocytosis of IFITM3 regulate its potency and antiviral specificity.
IFITM3 shows recurrent gene duplication and divergence during primate evolution.
EMBO Reports (2016) 17: 1657–1671
- Received May 24, 2016.
- Revision received August 3, 2016.
- Accepted August 3, 2016.
- © 2016 The Authors