Differential effect of p7 inhibitors on hepatitis C virus cell-to-cell transmission

• Published in: Antiviral research Vol. 100; no. 3; pp. 636 - 639
• Main Authors: Meredith, L.W., Zitzmann, N., McKeating, J.A.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01-12-2013; Elsevier
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - pharmacology; Assembly; Biological and medical sciences; Cell Communication - drug effects; Cell Line; Cell-to-cell; Coculture Techniques; Genotype; Guanidines - pharmacology; Hepacivirus - drug effects; Hepacivirus - genetics; Hepacivirus - physiology; Hepatitis C; Hepatitis C virus; Human viral diseases; Humans; Infectious diseases; Inhibitors; Medical sciences; Pharmacology. Drug treatments; Pyrazoles - pharmacology; Reassortant Viruses - drug effects; Reassortant Viruses - genetics; Reassortant Viruses - physiology; Rimantadine - pharmacology; Short Communication; Viral diseases; Viral hepatitis; Viral Proteins - antagonists & inhibitors; Virus Assembly - genetics; Virus Attachment; Virus Cultivation; Inhibitors; Cell-to-cell; Hepatitis C; Assembly; p7; Transmission; Hepatic disease; In vitro; Infection; Virus; Viral disease; Digestive diseases; Inhibitor; Flaviviridae; Hepatitis C virus; Hepacivirus; Cell; Viral hepatitis C
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2013.10.006

•p7 Inhibitors were tested for their ability to block HCV cell-free and cell-to-cell transmission.•p7 Inhibitor BIT225 reduced the infectivity of diverse HCV extracellular virus.•p7 Inhibitors had minimal effect on HCV cell-to-cell transmission.•Important to consider HCV transmission route when assessing assembly inhibitors.
Inhibitors targeting the hepatitis C virus (HCV) encoded viroporin, p7 prevent virus release in vitro. HCV can transmit by cell-free particle infection of new target cells and via cell-to-cell dependent contact with limited exposure to the extracellular environment. The role of assembly inhibitors in preventing HCV transmission via these pathways has not been studied. We compared the efficacy of three published p7 inhibitors to inhibit cell-free and cell-to-cell transmission of two chimeric HCV strains encoding genotype 2 (GT2) or 5 (GT5) p7 using a recently developed single cycle co-culture assay. The inhibitors reduced the infectivity of extracellular GT2 and GT5 virus by 80–90% and GT2 virus cell-to-cell transmission by 50%. However, all of the p7 inhibitors had minimal effect on GT5 cell contact dependent transmission. Screening a wider panel of diverse viral genotypes demonstrated that p7 viroporin inhibitors were significantly more effective at blocking cell-free virus than cell-to-cell transmission. These results suggest an altered assembly or trafficking of cell-to-cell transmitted compared to secreted virus. These observations have important implications for the validation, therapeutic design and testing of HCV assembly inhibitors.