IFITM Proteins Restrict HIV-1 Infection by Antagonizing the Envelope Glycoprotein

The interferon-induced transmembrane (IFITM) proteins have been recently shown to restrict HIV-1 and other viruses. Here, we provide evidence that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interact with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions does not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes leads to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appears to be virus-strain dependent. Overall, our study uncovers a mechanism by which IFITM proteins specifically antagonize HIV-1 Env to restrict HIV-1 infection and provides insight into the specialized role of IFITMs in HIV infection. [Display omitted] •IFITMs inhibit HIV-1 cell-to-cell infection and impair viral infectivity•IFITMs specifically interact with HIV-1 Env and inhibit Env processing•IFITM incorporation into HIV-1 virions does not correlate with inhibition•IFITM inhibition of primate lentiviruses is virus-strain specific Yu et al. show that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 Env glycoprotein to inhibit infection. IFITM proteins interact with HIV-1 Env and impair its processing and incorporation into virions. The effects of IFITMs on HIV-1, HIV-2, and SIVs are virus-strain dependent.