Interferon-induced transmembrane (IFITM) proteins are broad-spectrum antiviral restriction factors that inhibit viral entry of diverse enveloped viruses. Comparative genomic studies have revealed extensive lineage-specific diversification of IFITM genes, yet the functional consequences of this diversification remain poorly understood. We previously identified an expanded IFITM repertoire in macaques consisting of the canonical IFITM proteins, IFITM1 and IFITM3, a duplicated IFITM3 paralog (IFITM3A), and two retrotransposed IFITM3-derived genes (IFITM3-R1 and IFITM3-R2). Here, we thoroughly characterized the antiviral activities, intracellular localization, and mechanisms of regulation of canonical and non-canonical macaque IFITMs against vesicular stomatitis virus (VSV), influenza A virus (IAV), Sendai virus, and HIV-1. IFITM3A exhibited enhanced antiviral activity relative to IFITM3, particularly against VSV and HIV-1. Comparative mutational analyses identified amino acid substitutions in IFITM3 that contribute to the enhanced antiviral phenotype of IFITM3A. In contrast, the retrocopy IFITM3-R1 exhibited markedly reduced expression due to lysosome-dependent protein turnover mediated by a PPxY motif and a unique lysine residue (K51). Alteration of these determinants increased IFITM3-R1 expression and selectively enhanced restriction of VSV and IAV. Although several macaque IFITMs reduced HIV-1 infectivity when expressed in producer cells, none significantly inhibited HIV-1 infection in target cells. Furthermore, differential incorporation of IFITMs into HIV-1 virions did not consistently correlate with antiviral activity, indicating that virion incorporation alone is insufficient to explain HIV-1 restriction. Together, these findings demonstrate that gene duplication and retrotransposition have generated a functionally diverse IFITM repertoire in macaques and provide insight into how evolutionary diversification expands innate antiviral defenses in primates.
Kappala, D., Sauer, A., Atwood, E., Zhang, Y., Pimplapure, A., Bektas-Jolly, N., Gujjari, L., Chandra, K., Saini, Y., Yount, J., Suryawanshi, A., Li, J., Sharma, A.
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