A laboratory-adapted HCV JFH-1 strain is sensitive to neutralization and can gradually escape under the selection pressure of neutralizing human plasma

Hongshuo Song, Furong Ren, Jin Li, Shuang Shi, Ling Yan, Feng Gao, Kui Li, Hui Zhuang

Research output: Contribution to journalArticle

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Abstract

Viral replication and neutralization of hepatitis C viruses (HCV) have been studied using the infectious molecular clone JFH-1. By passaging JFH-1 in hepatoma cells in the absence or presence of HCV neutralizing antibodies (nAbs), we investigated the molecular mechanisms of cell-culture adaptation and sensitivity to nAbs. The cell culture-adapted JFH-1 virus (JFH-1-CA) became more sensitive to nAbs than its parental virus. Sequence analysis revealed that the predominant viruses in the JFH-1-CA population carried two mutations in their envelopes (I414T and V293A). Plasma that could neutralize JFH-1-CA was found in 2 of 7 HCV-infected individuals who have cleared the virus in blood. Plasma 226233 with a higher 50% neutralization titer was used for in vitro selection of neutralization resistant viruses. Under the increasing selection pressure of plasma 226233, the neutralizing sensitivity of JFH-1-CA decreased gradually. Two mutations (T414I and P500S) in envelope were found in all but one sequenced clones in the viral population after eight rounds of selection. Interestingly, the cell-culture adapted mutation I414T reverted back to the wild-type residue (I414) under the selection pressure. By introducing mutations at positions 414 and 500 into the JFH-1 clone, we confirmed that the T414I mutation alone can confer neutralization resistance. The results of this current study suggest that nAbs are present in a subset of HCV-infected individuals who have cleared the virus in blood. Our data also provide the first evidence that, the E2 residue P500, located within a previously identified highly conserved polyclonal epitope, may be a target for neutralizing antibodies present in individual who have spontaneously resolved the HCV infection.

Original languageEnglish (US)
Pages (from-to)154-161
Number of pages8
JournalVirus Research
Volume169
Issue number1
DOIs
StatePublished - Oct 1 2012

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Hepacivirus
Neutralizing Antibodies
Viruses
Pressure
Mutation
Clone Cells
Cell Culture Techniques
Hepatitis C Antibodies
Virus Diseases
Population
Sequence Analysis
Epitopes
Hepatocellular Carcinoma

All Science Journal Classification (ASJC) codes

  • Virology
  • Infectious Diseases
  • Cancer Research

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A laboratory-adapted HCV JFH-1 strain is sensitive to neutralization and can gradually escape under the selection pressure of neutralizing human plasma. / Song, Hongshuo; Ren, Furong; Li, Jin; Shi, Shuang; Yan, Ling; Gao, Feng; Li, Kui; Zhuang, Hui.

In: Virus Research, Vol. 169, No. 1, 01.10.2012, p. 154-161.

Research output: Contribution to journalArticle

Song, Hongshuo ; Ren, Furong ; Li, Jin ; Shi, Shuang ; Yan, Ling ; Gao, Feng ; Li, Kui ; Zhuang, Hui. / A laboratory-adapted HCV JFH-1 strain is sensitive to neutralization and can gradually escape under the selection pressure of neutralizing human plasma. In: Virus Research. 2012 ; Vol. 169, No. 1. pp. 154-161.
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