Nonhuman Primate IFITM Proteins Are Potent Inhibitors of HIV and SIV

Wilkins, Jordan; Zheng, Yi-Min; Yu, Jingyou; Liang, Chen; Liu, Shan-Lu

In humans, five IFITM isoforms have been discovered thus far [20] . IFITM5 is found in osteoblasts and functions in bone mineralization while IFITM10 has an unknown function [21, 22] . The remaining three members (IFITM1, 2, and 3) have been characterized with antiviral activity [20, 23] . The IFITM proteins are localized to both the plasma membrane and the endosomal membranes where they are thought to restrict viral entry by directly modulating cell membranes or antagonizing components of the viral structure [19, [24] [25] [26] [27] [28] [29] . While the exact topology of IFITMs remains unclear, studies have suggested that the IFITMs have full or partial membrane-spanning regions, with the N-terminus and a conserved central region on the cytosolic side and the C-terminus being extracellular [26, 30, 31] . The N-terminus of human IFITM2 and IFITM3 contain an additional 20 or 21 amino acids, respectively, compared to IFITM1. This extended N-terminal region contains a tyrosine residue (Y20) that is important for IFITM localization and their antiviral activity [32] [33] [34] . Recently, the PPxY motif of IFITM3 was discovered to interact with the NEDD4 E3 ligase that causes IFITM3 ubiquitination [35] . Cysteine residues C71, C72, and C105 in IFITM3, which are also conserved in IFITM1 and IFITM2, are palmitoylated and contribute to its antiviral function [24, 31] . Two phenylalanine residues (F75 and F78) in IFITM3 mediate interaction amongst the IFITMs, increasing IFITM3 antiviral properties [36] . Interestingly, IFITM proteins have also been shown to promote infection or replication of some viruses, although the underlying mechanisms remain to be defined [37, 38] .