Evolutionary modeling reveals enhanced mutational flexibility of HCV subtype 1b compared with 1a

Hepatitis C virus (HCV) is a leading cause of liver-associated disease and liver cancer. Of the major HCV subtypes, patients infected with subtype 1b have been associated with having a higher risk of developing chronic infection and hepatocellular carcinoma. However, underlying reasons for this increased disease severity remain unknown. Here, we provide an evolutionary rationale, based on a comparative study of fitness landscape and in-host evolutionary models of the E2 glycoprotein of HCV subtypes 1a and 1b. Our analysis demonstrates that a higher chronicity rate of 1b may be attributed to lower fitness constraints, enabling 1b viruses to more easily escape antibody responses. More generally, our results suggest that differences in evolutionary constraints between HCV subtypes may be an important factor in mediating distinct disease outcomes. Our analysis also identifies antibodies that appear escape-resistant against both subtypes 1a and 1b, providing directions for designing HCV vaccines having cross-subtype protection

SARS-CoV-2 T Cell Responses Elicited by COVID-19 Vaccines or Infection Are Expected to Remain Robust against Omicron

Omicron, the most recent SARS-CoV-2 variant of concern (VOC), harbours multiple mutations in the spike protein that were not observed in previous VOCs. Initial studies suggest Omicron to substantially reduce the neutralizing capability of antibodies induced from vaccines and previous infection. However, its effect on T cell responses remains to be determined. Here, we assess the effect of Omicron mutations on known T cell epitopes and report data suggesting T cell responses to remain broadly robust against this new variant

Landscape of epitopes targeted by T cells in 852 individuals recovered from COVID-19: Meta-analysis, immunoprevalence, and web platform

Knowledge of the epitopes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targeted by T cells in recovered (convalescent) individuals is important for understanding T cell immunity against coronavirus disease 2019 (COVID-19). This information can aid development and assessment of COVID-19 vaccines and inform novel diagnostic technologies. Here, we provide a unified description and meta-analysis of SARS-CoV-2 T cell epitopes compiled from 18 studies of cohorts of individuals recovered from COVID-19 (852 individuals in total). Our analysis demonstrates the broad diversity of T cell epitopes that have been recorded for SARS-CoV-2. A large majority are seemingly unaffected by current variants of concern. We identify a set of 20 immunoprevalent epitopes that induced T cell responses in multiple cohorts and in a large fraction of tested individuals. The landscape of SARS-CoV-2 T cell epitopes we describe can help guide immunological studies, including those related to vaccines and diagnostics. A web-based platform has been developed to help complement these efforts

Direct-acting antiviral resistance of Hepatitis C virus is promoted by epistasis

Direct-acting antiviral agents (DAAs) provide efficacious therapeutic treatments for chronic Hepatitis C virus (HCV) infection. However, emergence of drug resistance mutations (DRMs) can greatly affect treatment outcomes and impede virological cure. While multiple DRMs have been observed for all currently used DAAs, the evolutionary determinants of such mutations are not currently well understood. Here, by considering DAAs targeting the nonstructural 3 (NS3) protein of HCV, we present results suggesting that epistasis plays an important role in the evolution of DRMs. Employing a sequence-based fitness landscape model whose predictions correlate highly with experimental data, we identify specific DRMs that are associated with strong epistatic interactions, and these are found to be enriched in multiple NS3-specific DAAs. Evolutionary modelling further supports that the identified DRMs involve compensatory mutational interactions that facilitate relatively easy escape from drug-induced selection pressures. Our results indicate that accounting for epistasis is important for designing future HCV NS3-targeting DAAs

Identifying immunologically-vulnerable regions of the HCV E2 glycoprotein and broadly neutralizing antibodies that target them

Isolation of broadly neutralizing human monoclonal antibodies (HmAbs) targeting the E2 glycoprotein of Hepatitis C virus (HCV) has sparked hope for effective vaccine development. Nonetheless, escape mutations have been reported. Ideally, a potent vaccine should elicit HmAbs that target regions of E2 that are most difficult to escape. Here, aimed at addressing this challenge, we develop a predictive in-silico evolutionary model for E2 that identifies one such region, a specific antigenic domain, making it an attractive target for a robust antibody response. Specific broadly neutralizing HmAbs that appear difficult to escape from are also identified. By providing a framework for identifying vulnerable regions of E2 and for assessing the potency of specific antibodies, our results can aid the rational design of an effective prophylactic HCV vaccine

Cross-Reactivity Assessment of Vaccine-Derived SARS-CoV-2 T Cell Responses against BA.2.86 and JN.1

The SARS-CoV-2 Omicron sub-variants BA.2.86 and JN.1 contain multiple mutations in the spike protein that were not present in previous variants of concern and Omicron sub-variants. Preliminary research suggests that these variants reduce the neutralizing capability of antibodies induced by vaccines, which is particularly significant for JN.1. This raises concern as many widely deployed COVID-19 vaccines are based on the spike protein of the ancestral Wuhan strain of SARS-CoV-2. While T cell responses have been shown to be robust against previous SARS-CoV-2 variants, less is known about the impact of mutations in BA.2.86 and JN.1 on T cell responses. We evaluate the effect of mutations specific to BA.2.86 and JN.1 on experimentally determined T cell epitopes derived from the spike protein of the ancestral Wuhan strain and the spike protein of the XBB.1.5 strain that has been recommended as a booster vaccine. Our data suggest that BA.2.86 and JN.1 affect numerous T cell epitopes in spike compared to previous variants; however, the widespread loss of T cell recognition against these variants is unlikely

Identification of Potential SARS-CoV-2 CD8<SUP>+</SUP> T Cell Escape Mutants

Memory SARS-CoV-2-specific CD8+ T cell responses induced upon infection or COVID-19 vaccination have been important for protecting against severe COVID-19 disease while being largely robust against variants of concern (VOCs) observed so far. However, T cell immunity may be weakened by genetic mutations in future SARS-CoV-2 variants that lead to widespread T cell escape. The capacity for SARS-CoV-2 mutations to escape memory T cell responses requires comprehensive experimental investigation, though this is prohibited by the large number of SARS-CoV-2 mutations that have been observed. To guide targeted experimental studies, here we provide a screened list of potential SARS-CoV-2 T cell escape mutants. These mutants are identified as candidates for T cell escape as they lie within CD8+ T cell epitopes that are commonly targeted in individuals and are predicted to abrogate HLA-peptide binding

HCV E1 influences the fitness landscape of E2 and may enhance escape from E2-specific antibodies

The Hepatitis C virus (HCV) envelope glycoprotein E1 forms a non-covalent heterodimer with E2, the main target of neutralizing antibodies. How E1-E2 interactions influence viral fitness and contribute to resistance to E2-specific antibodies remain largely unknown. We investigate this problem using a combination of fitness landscape and evolutionary modeling. Our analysis indicates that E1 and E2 proteins collectively mediate viral fitness and suggests that fitness-compensating E1 mutations may accelerate escape from E2-targeting antibodies. Our analysis also identifies a set of E2-specific human monoclonal antibodies that are predicted to be especially resilient to escape via genetic variation in both E1 and E2, providing directions for robust HCV vaccine development