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Response of hepatitis C virus to long-term passage in the presence of alpha interferon: Multiple mutations and a common phenotype

AuthorsPerales, Celia ; Beach, Nathan M. ; Gallego, Isabel ; Quer, Josep; Esteban, Juan Ignacio; Domingo, Esteban ; Sheldon, Julie ; Soria, María Eugenia; Rice, Charles
Issue Date2013
PublisherAmerican Society for Microbiology
CitationJournal of Virology 87: 7593- 7607 (2013)
AbstractCell culture-produced hepatitis C virus (HCV) has been subjected to up to 100 serial passages in human hepatoma cells in the absence or presence of different doses of alpha interferon (IFN-α). Virus survival, genetic changes, fitness levels, and phenotypic traits have been examined. While high initial IFN-α doses (increasing from 1 to 4 IU/ml) did not allow HCV survival beyond passage 40, a gradual exposure (from 0.25 to 10 IU/ml) allowed the virus to survive for at least 100 passages. The virus passaged in the presence of IFN-α acquired IFN-α resistance as evidenced by enhanced progeny production and viral protein expression in an IFN-α environment. A partial IFN-α resistance was also noted in populations passaged in the absence of IFN-α. All lineages acquired adaptative mutations, and multiple, nonsynonymous mutations scattered throughout the genome were present in IFN-α-selected populations. Comparison of consensus sequences indicates a dominance of synonymous versus nonsynonymous substitutions. IFN-α-resistant populations displayed decreased sensitivity to a combination of IFN-α and ribavirin. A phenotypic trait common to all assayed viral populations is the ability to increase shutoff host cell protein synthesis, accentuated in infections with IFN-α-selected populations carried out in the presence of IFN-α. The trait was associated with enhanced phosphorylation of protein kinase R (PKR) and eIF2α, although other contributing factors are likely. The results suggest that multiple, independent mutational pathways can confer IFN-α resistance to HCV and might explain why no unified picture has been obtained regarding IFN-α resistance in vivo © 2013 American Society for Microbiology.
Identifiersdoi: 10.1128/JVI.02824-12
issn: 0022-538X
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