The Role of Interferon-Inducible Transmembrane Proteins in Virus Infection

Several studies have demonstrated that overexpression of IFITMs could inhibit virus entry and infection of a variety of virus families (including orthomyxoviridae and flaviviruses) in cell culture systems [2,3]. Over-expression of IFITM1, IFITM2 or IFITM3 restricted early viral replication. On the contrary, knock-down of IFITM3 stimulated influenza A virus replication [4]. Researchers reported that IFITM3 is required for IFNα-induced anti-viral defense and restricts influenza A virus infection at viral entry and early-stage of virus life cycle. Knockdown of IFITM3 dampen 40%-70% of IFN's anti-viral effect. Thus, IFITM proteins are critical for the innate immunity to influenza A virus mediated by IFNs [5]. IFITMs have been demonstrated to suppress the replication of several flaviviruses including West Nile virus, dengue virus, hepatitis C virus and Zika virus [4]. IFITM1 and IFITM3 inhibit ZIKV infection at early stage of the viral life cycle. In addition, IFITM3 could inhibit ZIKV-induced cell death [6]. Another IFITMs superfamily member TMEM2 has been found to inhibit HBV infection by activating the Jak/STAT signaling pathway [7]. Notably, these restricted viruses were all encapsulated, containing the ssRNA genome, and were reported to enter cells by membrane fusion after endocytosis. However, some retroviruses, such as HIV-1 and Moloney leukaemia virus and Bunyaviridae, Crimean–Congo haemorrhagic fever virus, are obviously not affected by IFITMs. In the past studies, IFITMs were not shown to inhibit HIV-1 infection [4]. However, recent studies have reported that IFITM2 and IFITM3 could interact with HIV-1 Env protein in viral producer cells, leading to impaired Env processing and virion incorporation [8]. Meanwhile, some evidence showed that IFITM3 could also limit Non-enveloped Reoviridae, reovirus replication, suggesting that IFITMs affected a variety of viruses, not limited to viruses with envelopes [9].