Natural mutations in IFITM3 modulate post‐translational regulation and toggle antiviral specificity

Abstract

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.

SNP-mediated disruption of CTCF binding at the IFITM3 promoter is associated with risk of severe influenza in humans

“…The minor allele of rs12252 has been associated with HIV progression in a Chinese cohort 35 . However, the predicted truncation mutant mediated by rs12252 8 , which has not been observed in published studies, was able to restrict HIV replication 36 , so this association may indicate a role for other effects of this locus.…”

IFITM 3 requires an amphipathic helix for antiviral activity

“…The differential susceptibility of viruses to IFITM3‐mediated restriction has revealed that IFITM3 inhibits infections by viruses that enter cells through endocytosis . Indeed, IFITM3 primarily localizes to endosomes and lysosomes , and IFITM3 mutants that alternatively localize to the plasma membrane possess a diminished ability to inhibit influenza virus infection . Taken together, these findings indicate that IFITM3 acts within the endolysosomal pathway.…”

Human Genetic Determinants of Viral Diseases

“…This 1F1TM3 polymorphism is predicted to cause alternative splicing of the transcript, resulting in truncation and altered localization of IFITM3, though the existence of a shortened form of IFITM3 remains to be conclusively demonstrated (39). Recent work in vitro suggests that although this alteration of IFITM3 decreases antiviral activity against influenza virus, its activity against retroviruses is increased (29), thus revealing a potential selective advantage for the SNP that may explain its high prevalence in certain human populations (177). Additionally, given that IFITM3 antiviral activity is highly regulated by at least four posttranslational modifications, polymorphisms in factors that install or remove these modifications and impact influenza virus susceptibility may be uncovered in the future (22–24, 117, 172).…”