Role of HVR1 sequence similarity in the cross-genotypic neutralization of HCV
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SHORT REPORT
Role of HVR1 sequence similarity in the cross‑genotypic neutralization of HCV Alexander I. Mosa1* , Mounir G. AbouHaidar1, Richard A. Urbanowicz2,3, John E. Tavis4, Jonathan K. Ball2,3 and Jordan J. Feld5
Abstract Despite available treatments, a prophylactic HCV vaccine is needed to achieve elimination targets. HCV vaccine development has faltered largely because the extreme diversity of the virus limits the protective breadth of vaccine elicited antibodies. It is believed that the principle neutralizing epitope in natural infection, HVR1, which is the most variable epitope in HCV, mediates humoral immune escape. So far, efforts to circumvent HVR1 interference in the induction and function of conserved targeting Ab have failed. Efforts to understand factors contributing to cross-neutralization of HVR1 variants have also been limited. Here, following mouse immunizations with two patient-derived HVR1 peptides, we observe cross-genotype neutralization of variants differing at 15/21 positions. Surprisingly, sequence similarity was not associated with cross-neutralization. It appeared neutralization sensitivity was an intrinsic feature of each variant, rather than emergent from the immunogen specific Ab response. These findings provide novel insight into HVR1-mediated immune evasion, with important implications for HCV vaccine design. Keywords: Hypervariable epitope, Cross-reactivity, HCV, Antigenic convergence Introduction Chronic infection with hepatitis C virus (HCV) is a leading cause of liver disease, cirrhosis, and hepatocellular carcinoma, resulting in 475,000 deaths annually [1]. Estimates of prevalence based on seropositivity range between 1.3 and 2.1%, or between 92 and 149 million individuals globally [2]. Though direct-acting antiviral (DAA) therapy is largely curative, only a minority of chronic infections (~ 20%) have been diagnosed, with even fewer treated (~ 3%) [1]. Persistent challenges in screening, diagnosis, access to affordable DAA, and the risk for re-infection in vulnerable populations aggravates elimination efforts [2]. A prophylactic vaccine for HCV is therefore still urgently needed. The extreme diversity of the virus, with billions of related but distinct variants circulating in each infected *Correspondence: [email protected] 1 Department of Cell and Systems Biology, University of Toronto, Toronto, Canada Full list of author information is available at the end of the article
person, has been a major barrier to vaccine development [3]. Early candidate vaccines using mammalian expressed E2 glycoprotein (E2), a meditator of viral entry expressed on the surface of mature virions, were successful in inducing protective immunity in chimpanzee against homologous challenge [4]. However, progression to chronic infection was observed following heterologous challenge, with escape mutations subsequently mapped to the highly variable N-terminus of E2, termed HVR1 [4, 5]. Since then, cohort and in vitro analysis has consistently identified HVR1 as the principle
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