In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

clinicaltrials.gov Identifier: NCT01939197.

No abstract

The internal ribosome entry site (IRES), a highly conserved structured element of the hepatitis C virus genomic RNA, is an attractive target for antiviral drugs. Here we show that benzimidazole inhibitors of the HCV replicon act by conformational induction of a widened interhelical angle in the IRES subdomain IIa which facilitates the undocking of subdomain IIb from the ribosome and ultimately leads to inhibition of IRES-driven translation in HCV-infected cells.

No abstract

These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.

The internal ribosome entry site (IRES) in the hepatitis C virus (HCV) RNA genome is essential for the initiation of viral protein synthesis. IRES domains adopt well-defined folds that are potential targets for antiviral translation inhibitors. We have determined the three-dimensional structure of the IRES subdomain IIa in complex with a benzimidazole translation inhibitor at 2.2 Å resolution.Comparison to the structure of the unbound RNA in conjunction with studies of inhibitor binding to the target in solution demonstrate that the RNA undergoes a dramatic ligand-induced conformational adaptation to form a deep pocket that resembles the substrate binding sites in riboswitches. The presence of a well-defined ligand-binding pocket within the highly conserved IRES subdomain IIa holds promise for the development of unique anti-HCV drugs with a high barrier to resistance.crystallography | hepatitis C virus inhibitor | RNA structure I nfection with hepatitis C virus (HCV), which affects over 170 million individuals worldwide, is a leading cause of liver failure and hepatocellular carcinoma (1). Until earlier this year, when two protease inhibitors were approved as the first direct antiviral drugs for the treatment of HCV infection (2), the standard anti-HCV therapy consisted of an immunostimulatory regimen of pegylated interferon-α and the nucleoside analog ribavirin, which suffered from low efficacy as well as serious side effects (3). The prevalence of preexisting drug-resistance mutations in HCV quasispecies due to the low fidelity of the viral RNA-dependent RNA polymerase (NS5B) creates an urgent need for combination therapy with unique antiviral agents directed at distinct HCV targets (4).Among the potential targets for HCV inhibitors, the 5′ untranslated region (UTR) of the viral RNA genome stands out for its high sequence conservation within virus clinical isolates (5), which exceeds the conservation of the HCV protein reading frames. The HCV 5′ UTR harbors an internal ribosome entry site (IRES) which recruits host cell 40S ribosomal subunits and ultimately initiates translation of virus proteins via a 5′ cap-independent mechanism (6, 7). The function of the IRES relies on a structured RNA element, which contains several independently folding domains (Fig. 1A) (8, 9). The three-dimensional structure of the subdomain IIa target was previously determined in our laboratory revealing an overall bent architecture around an RNA internal loop (Fig. 1B) (10), in agreement with NMR analyses of the full domain II (11) and cryoelectron microscopy studies of 13). The L-shaped conformation of subdomain IIa directs the apical hairpin loop IIb toward the ribosomal E site in proximity of the active site. Ribosomal association of domain II induces a conformational change in the 40S head and closes the mRNA binding cleft. Both, the correct positioning of the viral mRNA initiation codon as well as the joining of the ribosomal subunits to form functional 80S units depend critically on the L-shaped architecture of the domain II (7...