More than meets the I: the diverse antiviral and cellular functions of interferon-induced transmembrane proteins

Abstract

The first responders of human antiviral immunity are components of the intrinsic immune response that reside within each and every one of our cells. This cell-autonomous arsenal consists of nucleic acid sensors and antiviral effectors strategically placed by evolution to detect and restrict invading viruses. While some factors are present at baseline to allow for constant surveillance of the cell interior, others are upregulated by cytokines (such as interferons) that signal a viral infection underway in neighboring cells. In this review, we highlight the multiple roles played by the interferon-induced transmembrane (IFITM) proteins during viral infection, with focuses on IFITM3 and HIV-1. Moreover, we discuss the cellular pathways in which IFITM proteins are intertwined and the various functions they have been ascribed outside the context of infection. While appreciated as broadly-acting, potent restriction factors that prevent virus infection and pathogenesis in cell culture and in vivo, questions remain regarding their precise mode of action and importance in certain viral contexts. Continued efforts to study IFITM protein function will further cement their status as critical host determinants of virus susceptibility and prioritize them in the development of new antiviral therapies.

Functional Mapping of Regions Involved in the Negative Imprinting of Virion Particle Infectivity and in Target Cell Protection by Interferon-Induced Transmembrane Protein 3 against HIV-1

“…The expression of WT IFITM3 had been previously associated with the loss of mature Env incorporation in HIV (37). However, this finding remains controversial, as other studies have not observed such changes in the HIV-1 glycoprotein (16,23,41,42) or for other viral glycoproteins (36), so at present, the reasons for this discrepancy remain unclear. Given that under the experimental conditions used here, no major changes were observed in the amounts of mature Env incorporated into HIV-1 virions upon the expression of the WT or of most IFITM3 mutants, we believe that 85-90 most likely represents a gain-of-function mutant.…”

“…Over the years, several studies raised the possibility that IFITM3 could act by either modulating the intracellular content of cholesterol (during target cell protection) (39) or commandeering a decrease in the amount of mature envelope glycoproteins incorporated into HIV-1 virions (37). However, both of these findings remain debated, as further studies failed to obtain evidence of changes in either intracellular cholesterol levels (31,40) or glycoprotein incorporation upon IFITM expression (16,23,36,41,42).…”

A Virus-Packageable CRISPR Screen Identifies Host Factors Mediating Interferon Inhibition of HIV

“…Viral entry is a key target of potent IFN-mediated restriction, specifically by ISGs such as IFITMs, 214 a family of 5 membrane-resident antiviral genes in humans with broad antiviral effects (Shi, Schwartz, & 215 Compton, 2017). IFITMs restrict viruses that enter cells by fusion at the plasma membrane or in the 216 endosome.…”

Construction, expression and antiviral activity analysis of recombinant adenovirus expressing human IFITM3 in vitro

“…Furthermore, there is almost no species specificity in antiviral activity of IFITMs [22,23]. For example, primate-derived IFITMs are effective inhibitors of simian immunodeficiency virus (SIV), and primate IFITM3 alleles also exhibit superior anti-HIV activity compared to human IFITM3 [22,24,25]. Amino-terminal mutants of primate IFITM3 are more easily incorporated into HIV virions, resulting in enhanced inhibition of HIV-1 fusion [25].…”