HCV NS5A inhibitors disrupt replication factory formation: A novel mechanism of antiviral action

In recent years, progress in the development of effective antivirals to treat chronic hepatitis C virus (HCV) infection has accelerated enormously. For more than a decade the standard of care therapy for HCV was a combination of pegylated interferon-α and ribavirin (pegIFN-α/RBV) for 24-48 weeks. Unfortunately this treatment regimen is associated with only moderate efficacy (50%-80% sustained virologic response rates) and severe side effects. However, as a result of the efforts of academic and industry research groups and advances in our understanding of the HCV life cycle, made possible by reliable cell culture systems, numerous promising direct-acting antivirals are in advanced stages of clinical development or have already been approved. The addition of first-generation NS3/4A protease inhibitors, telaprevir and boceprevir, to pegIFN-α/RBV therapy significantly improved sustained virologic response rates for genotype 1 infections.1, 2 Likewise, the recent approvals of the second-wave NS3/4A protease inhibitor simeprevir,3 and the highly effective nucleotide analog inhibitor of the viral NS5B polymerase, sofosbuvir,4 brings closer the goal of a safe, effective, all-oral, and IFN-free direct-acting antiviral combination therapy in the near future. Along with molecules that target NS3/4A and NS5B, potent inhibitors of the viral NS5A phosphoprotein will likely be important components of future direct-acting antiviral combination therapies. Indeed, the first-in-class NS5A inhibitor daclatasvir (DCV) and structurally related NS5A inhibitors ledipasvir and ombitasvir are in the final stages of clinical development for use in various combinations, and a number of second-generation NS5A inhibitors with higher genetic barriers to resistance (eg, ACH-3102, MK-5172, and GS-5816) are in earlier stages of clinical development. NS5A has no known enzymatic activity and to date the exact mechanism(s) of action of these inhibitors and indeed the exact functions of NS5A remain unclear. In this issue of Gastroenterology, Berger et al5 report that NS5A inhibitors interact with NS5A and block formation of the “membranous web” (MW) that houses HCV RNA replication, independent of effects on HCV RNA replication. Furthermore, the authors present evidence that DCV derivatives interact with NS5A dimers and moderately impair functional interaction of NS5A with phosphatidylinositol-4 kinase IIIα (PI4KIIIα) that stimulates local accumulation of PI4-phosphate (PI4P) at sites of HCV RNA replication. Together this study sheds new light on the mechanisms of action of this unique and extraordinarily potent class of antivirals.