IFITMs mediate viral evasion in acute and chronic hepatitis C virus infection

While adaptive immune responses against hepatitis C virus (HCV) infection have been studied in great detail, the role of innate immunity in protection against HCV infection and immune evasion is only partially understood. Interferon?induced transmembrane proteins (IFITMs) are innate effector proteins restricting host cell entry of many enveloped viruses, including HCV. However, the clinical impact of IFITMs on HCV immune escape remains to be determined. Here, we show that IFITMs promote viral escape from the neutralizing antibody response in clinical cohorts of HCV?infected patients. Using pseudoparticles bearing HCV envelope proteins from acutely infected patients, we show that HCV variants isolated pre?seroconversion are more sensitive to the antiviral activity of IFITMs than variants from patients isolated during chronic infection post?seroconversion. Furthermore, HCV variants escaping neutralizing antibody responses during liver transplantation exhibited a significantly higher resistance to IFITMs than variants that were eliminated post?transplantation. Gain?of?function and mechanistic studies revealed that IFITMs markedly enhance the antiviral activity of neutralizing antibodies and suggest a cooperative effect of human monoclonal antibodies and IFITMs for antibody?mediated neutralization driving the selection pressure in viral evasion. Perturbation studies with the IFITM antagonist amphotericin B revealed that modulation of membrane properties by IFITM proteins is responsible for the IFITM?mediated blockade of viral entry and enhancement of antibody?mediated neutralization.