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

Abstract

SUMMARY 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.

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

“…As expected, IFNAR1 mAb treatment blocked the expression of ISGs, including those with anti-HIV-1 function such as Mx2 (28,29) and IFITM3 (30,31), in PBMCs of infected hu-mice ( Figure 3A and Supplemental Figure 2, A and B). We found that HIV-1 replication increased 8-fold within 1 week after IFNAR1 blockade and was sustained at higher levels than in control mice from 7 to 10 wpi ( Figure 3B).…”

Cytokines Elevated in HIV Elite Controllers Reduce HIV ReplicationIn Vitroand Modulate HIV Restriction Factor Expression

“…IFITM2, but not IFITM1, impedes HIV entry into cells, and neither protein affects cell proliferation or CD4 cell surface expression though the intracellular moiety of IFITM1 is required for anti-HIV activity (60). More recently it has been shown that IFITMs, particularly IFITM2 and IFITM3, colocalize with Env and Gag proteins and can be incorporated into nascent virions, which can impair fusion to target cells (61,62). IFITMs have relatively modest HIV-suppressive activity, and it is hypothesized that these proteins act in part by interfering with viral protein production (63).…”

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