Gene duplication and retrotransposition expand antiviral IFITM protein diversity in macaques
Researchers characterized an expanded repertoire of IFITM antiviral proteins in macaques, including duplicated and retrotransposed variants, finding that these variants have distinct antiviral activities against multiple viruses. IFITM proteins are broad-spectrum restriction factors that inhibit viral entry, and their lineage-specific diversification has been observed across primates but remained functionally uncharacterized. Understanding how evolutionary gene duplication and retrotransposition enhance innate antiviral defenses could inform research on primate immune evolution and viral restriction mechanisms.
A bioRxiv preprint describes a comprehensive functional characterization of macaque IFITM proteins, an expanded antiviral repertoire consisting of canonical IFITM1 and IFITM3, a duplicated IFITM3 paralog (IFITM3A), and two retrotransposed IFITM3-derived genes (IFITM3-R1 and IFITM3-R2). The researchers tested these variants against vesicular stomatitis virus (VSV), influenza A virus (IAV), Sendai virus, and HIV-1, finding that IFITM3A exhibited enhanced antiviral activity compared to IFITM3, particularly against VSV and HIV-1. The retrocopy IFITM3-R1 showed markedly reduced expression due to protein degradation mechanisms, but altering specific amino acid determinants increased its expression and selectively enhanced restriction of VSV and IAV. Notably, while several macaque IFITMs reduced HIV-1 infectivity in producer cells, none significantly inhibited infection in target cells, and differential incorporation into virions did not correlate with antiviral activity. The findings demonstrate that evolutionary diversification through gene duplication and retrotransposition generates functional diversity in innate antiviral defenses.
What's missing
The study's own limitations and open questions include: whether the enhanced antiviral activities observed in cell culture translate to in vivo protection in macaques; the evolutionary pressures that drove the expansion and maintenance of this IFITM repertoire; and the mechanisms by which IFITM3A achieves enhanced antiviral activity, which the authors identify through mutational analysis but do not fully mechanistically explain. Additionally, the study does not address whether similar retrotransposed IFITM variants exist in other primate species or whether the HIV-1 restriction patterns observed differ from those in human IFITM proteins.
What different sources said
- bioRxivCenter
Gene duplication and retrotransposition diversify the antiviral repertoire of macaque IFITM proteins
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