Resistance of Transmitted Founder HIV-1 to IFITM-Mediated Restriction

Interferon-induced transmembrane proteins (IFITMs) restrict the entry of diverse enveloped viruses through incompletely understood mechanisms. While IFITMs are reported to inhibit HIV-1, their in vivo relevance is unclear. We show that IFITM sensitivity of HIV-1 strains is determined by the co-receptor usage of the viral envelope glycoproteins as well as IFITM subcellular localization within the target cell. Importantly, we find that transmitted founder HIV-1, which establishes de novo infections, is uniquely resistant to the antiviral activity of IFITMs. However, viral sensitivity to IFITMs, particularly IFITM2 and IFITM3, increases over the first 6 months of infection, primarily as a result of neutralizing antibody escape mutations. Additionally, the ability to evade IFITM restriction contributes to the different interferon sensitivities of transmitted founder and chronic viruses. Together, these data indicate that IFITMs constitute an important barrier to HIV-1 transmission and that escape from adaptive immune responses exposes the virus to antiviral restriction. [Display omitted] •IFITM restriction of HIV-1 depends on virus co-receptor use and IFITM localization•Transmitted founder viruses are resistant to IFITM restriction•Escape from early neutralizing antibodies confers IFITM sensitivity•IFITM restriction contributes to the increased IFN sensitivity of chronic viruses IFITMs are interferon-induced proteins with broad antiviral activity. Foster et al. demonstrate that HIV-1 sensitivity to IFITMs depends on the viral entry route into target cells. Strikingly, transmitted HIV-1 strains are IFITM resistant, but viral envelope mutations that escape neutralizing antibody responses after infection lead to IFITM and interferon sensitivity.