Transmitted/founder viruses rapidly escape from CD8+ T cell responses in acute hepatitis C virus infection

R.A. Bull, P. Leung, Silvana Gaudieri, Pooja Deshpande, B.A. Cameron, M. Walker, A. Chopra, A.R. Lloyd, F. Luciani, K.A. Dolan, P.S.W. Haber, W.D. Rawlinson, C.J. Treloar, G.J. Doré, L.S. Maher

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    21 Citations (Scopus)

    Abstract

    The interaction between hepatitis C virus (HCV) and cellular immune responses during very early infection is critical for disease outcome. To date, the impact of antigen-specific cellular immune responses on the evolution of the viral population establishing infection and on potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine. Three subjects who were followed longitudinally from the detection of viremia preseroconversion until disease outcome were analyzed. The evolution of transmitted/founder (T/F) viruses was undertaken using deep sequencing. CD8+ T cell responses were measured via enzyme-linked immunosorbent spot (ELISpot) assay using HLA class I-restricted T/F epitopes. T/F viruses were rapidly extinguished in all subjects associated with either viral clearance (n = 1) or replacement with viral variants leading to establishment of chronic infection (n = 2). CD8+ T cell responses against 11 T/F epitopes were detectable by 33 to 44 days postinfection, and 5 of these epitopes had not previously been reported. These responses declined rapidly in those who became chronically infected and were maintained in the subject who cleared infection. Higher-magnitude CD8+ T cell responses were associated with rapid development of immune escape variants at a rate of up to 0.1 per day. Rapid escape from CD8+ T cell responses has been quantified for the first time in the early phase of primaryHCVinfection. These rapid escape dynamics were associated with higher-magnitude CD8+ T cell responses. These findings raise questions regarding optimal selection of immunogens forHCVvaccine development and suggest that detailed analysis of individual epitopes may be required. © 2015, American Society for Microbiology.
    Original languageEnglish
    Pages (from-to)5478-5490
    JournalJournal of Virology
    Volume89
    Issue number10
    Early online date4 Mar 2015
    DOIs
    Publication statusPublished - May 2015

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