How NS5A inhibitors block hepatitis C virus replication impacts treatment outcomes.
Although the development of antivirals has changed the treatment landscape of hepatitis C virus (HCV), there is still a small proportion of individuals who do not respond to treatment, largely due to drug resistance.
In a study published in PLOS Pathogens, the investigators identified how NS5A inhibitors interact with HCV. Their findings pointed to the difference between strains of the virus.
“When HCV infects a liver cell, it establishes replication complexes (RCs) within the cell,” said lead author David McGivern, PhD. “These may be thought of as factories that replicate the virus genetic material. We wanted to understand how long these factories persist in an infected cell after treatment with an NS5A inhibitor.”
In prior studies, the investigators showed that NS5A inhibitors blocked the formation of new RCs, but had no effect on existing ones. Without new RC formation, the existing RCs turn over and are eventually lost from the cell, according to the authors.
For the current study, investigators sought to estimate the half-life of functional RC of HCV using NS5A inhibitors.
They compared different cell culture-infectious strains of HCV that may be grouped based on sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistance (LPOR) viruses and more slowly replicating lipid, peroxidation sensitive (LPOS) viruses.
Study findings showed a difference in the rate of decline depending on the strain of HCV. In luciferase assays, LPOS declined with much slower kinetics under NS5A inhibitor treatment compared with LPOR HCV strains.
“This difference in rate of decline was not observed for inhibitors of the NS5B RNA-dependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability,” the authors wrote.
Upon further analysis, the investigators compared 2 isoclonal HCV variants that only differed by 12 amino acids. The differences in decline rates following the addition of NS5A inhibitors were due to a combination of amino acid differences in the non-structural proteins that make up the RC, rather than due to amino acid sequences in NS5A.
“The majority of people who undergo antiviral treatment clear their HCV infection,” McGivern said. “But about 5% of people experience treatment failure, often associated with drug resistance. Our findings have potentially important implications for this group of people. Did the treatment fail because replication complexes turned over more slowly? Do some strains of HCV need longer treatment? A better understanding of these issues may lead to more effective therapies active against broader range of viruses.”