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

Bull, R.A., Leung, P., Gaudieri, S., Deshpande, P., Cameron, B., Walker, M., Chopra, A., Lloyd, A.R. and Luciani, F. (2015) Transmitted/founder viruses rapidly escape from CD8+T cell responses in acute hepatitis C virus infection. Journal of Virology, 89 (10). pp. 5478-5490.

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Background 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 potential escape has not been studied. Understanding these early host-virus dynamics is important for the development of a preventative vaccine.

Methods Three subjects followed longitudinally from viremia identified pre-seroconversion 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 ELISpot using HLA class I restricted T/F epitopes.

Results T/F viruses were rapidly extinguished in all subjects associated either with 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 33-44 days post-infection, of which five 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 up to 0.1 mutations/day.

Conclusion Rapid escape from CD8+ T cell responses has been quantified for the first time in the early phase of primary HCV infection. These rapid escape dynamics were associated with higher magnitude CD8+ T cell responses. These findings raise questions regarding optimal selection of immunogens for HCV vaccine development and suggest detailed analysis of individual epitopes may be required.

Importance A major limitation in our detailed understanding of the role of immune response in HCV clearance has been the lack of data on very early primary infection, when the transmitted viral variants successfully establish the acute infection. This study was made possible through the availability of specimens from a unique cohort of asymptomatic primary infection cases, in who the first available viremic sample were collected approximately three weeks post-infection, and at regular intervals thereafter. The study included detailed examination of both the evolution of the viral population and host cellular immune responses against the T/F viruses. The findings here provide the first evidence of host cellular responses targeting T/F variants and imposing a strong selective force towards viral escape. The results of this study provide useful insight on how virus escape the host response, and consequently on future analysis of vaccine-induced immunity.

Item Type: Journal Article
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Publisher: American Society for Microbiology
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