Fuse me IFITM can!

Abstract

Two independent papers show that IFITMs proteins are incorporated into HIV-1 particles and restrict infection at an early stage Five members of the interferon inducible transmembrane (IFITM) gene family are found in humans: IFITM1, 2, 3, 5 and 10. Typically, IFITMs 1, 2 and 3 are induced by both type I and type II interferon [1,2] although they are also constitutively expressed in cells of the upper airway and visceral pleura. IFITM 5 is not interferon-inducible and is involved in bone mineralization, and IFITM10 function is unknown. IFITM1, 2 and 3 are likely to have arisen from lineage and species-specific gene duplications. Indeed they are highly similar and highly conserved genes throughout evolution, with at least one member present in jawless fish (lampreys). The rapid expansion of the IFITM gene family during mammalian evolution was accompanied by positive selection, suggesting a broad role as antivirals. Conversely, IFITM5 and 10, which are not interferon-inducible, show no sign of gene duplications and positive selection [3,4]. IFITMs, as the name suggests, are located at membranes; IFITM1 is found mainly at the plasma membrane, IFITM2 and 3 are found mainly in intracellular compartments and endosomal membranes, although stimulation with interferon can change their distribution [5,6]. IFITMs have been shown to restrict influenza A virus (IAV) infection, in vitro and in a Ifitm3 mouse model [7-9]. IFITM3 restricts IAV infection more potently than IFITM1 and 2, acting at the early stages of the viral replicative cycle, most likely fusion [7]. Furthermore, Caucasian and Han Chinese individuals bearing the synonymous single nucleotide polymorphism (SNP) rs12252 in the IFITM3 gene were significantly more likely to suffer from severe IAV infection and be hospitalized [8]. This SNP resulted in a truncated IFITM3 protein that is found mainly at the cell membrane instead of endosomal membranes [8]. IAV fusion and release into the cytoplasm occurs in the late endosomal compartment following acidification. Therefore it is likely that IFITM3 needs to be in the right intracellular compartment to exert its anti-IAV activity.