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

Jingyou Yu,Shan-Lu Liu,Minghua Li,Jordan Wilkins,Benjamin K Chen,Anthony M Esposito,Chen Liang,Eric O Freed,Shilei Ding,Yi-Min Zheng,Talia H Swartz

doi:10.1016/j.celrep.2015.08.055

Abstract

SummaryThe 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.

Highlights

Interferons are cytokines that inhibit viral infection by inducing expression of hundreds of the interferon-stimulated genes (ISGs) (Sadler and Williams, 2008)
Most previous studies are based on cellfree HIV type 1 (HIV-1) infection, in which interferon-induced transmembrane (IFITM) are expressed in target cells
We first established Jurkat cell lines stably expressing IFITM1, IFITM2, or IFITM3 using Jurkat/intron-Gaussia luciferase (inGLuc) previously engineered to express inGLuc HIV-1 vector (Agosto et al, 2014), and we infected these cells with wild-type (WT) HIV-1NL43 bearing vesicular stomatitis virus (VSV)-G so that the majority of donor cells would be HIV-1 infected

Summary

Introduction

Interferons are cytokines that inhibit viral infection by inducing expression of hundreds of the interferon-stimulated genes (ISGs) (Sadler and Williams, 2008). The underlying mechanism by which IFITMs broadly inhibit viral infection is currently not well understood. We reported that IFITMs inhibit cell-cell fusion mediated by all three classes of viral fusion proteins, acting at the level of hemifusion initiation (Li et al, 2013). IFITM3 is known to interact with vesicle-membrane-protein-associated protein A (VAPA) and disrupt intracellular cholesterol homeostasis (Amini-Bavil-Olyaee et al, 2013), but the exact role of cholesterol in IFITM-mediated inhibition of the viral membrane remains elusive

Results

Discussion

Conclusion