glycoprotein-e2--hepatitis-c-virus and Remission--Spontaneous

Hepatitis C virus (HCV) is a major public health concern, with over 70 million people infected worldwide, who are at risk for developing life-threatening liver disease. No vaccine is available, and immunity against the virus is not well-understood. Following the acute stage, HCV usually causes chronic infections. However, ~30% of infected individuals spontaneously clear the virus. Therefore, using HCV as a model for comparing immune responses between spontaneous clearer (SC) and chronically infected (CI) individuals may empower the identification of mechanisms governing viral infection outcomes. Here, we provide the first in-depth analysis of adaptive immune receptor repertoires in individuals with current or past HCV infection. We demonstrate that SC individuals, in contrast to CI patients, develop clusters of antibodies with distinct properties. These antibodies' characteristics were used in a machine learning framework to accurately predict infection outcome. Using combinatorial antibody phage display library technology, we identified HCV-specific antibody sequences. By integrating these data with the repertoire analysis, we constructed two antibodies characterized by high neutralization breadth, which are associated with clearance. This study provides insight into the nature of effective immune response against HCV and demonstrates an innovative approach for constructing antibodies correlating with successful infection clearance. It may have clinical implications for prognosis of the future status of infection, and the design of effective immunotherapies and a vaccine for HCV.

Topics: Antibodies, Neutralizing; Cell Line, Tumor; Computational Biology; Datasets as Topic; Hepacivirus; Hepatitis C Antibodies; Hepatitis C, Chronic; High-Throughput Nucleotide Sequencing; Humans; Machine Learning; Peptide Library; Prognosis; Remission, Spontaneous; Viral Envelope Proteins

CD8(+) cytotoxic T lymphocytes (CTL) are thought to control hepatitis C virus (HCV) replication and so we investigated why this response fails in persistently infected individuals. The HCV quasispecies in three persistently infected chimpanzees acquired mutations in multiple epitopes that impaired class I MHC binding and/or CTL recognition. Most escape mutations appeared during acute infection and remained fixed in the quasispecies for years without further diversification. A statistically significant increase in the amino acid replacement rate was observed in epitopes versus adjacent regions of HCV proteins. In contrast, most epitopes were intact when hepatitis C resolved spontaneously. We conclude that CTL exert positive selection pressure against the HCV quasispecies and the outcome of infection is predicted by mutations in class I MHC restricted epitopes.

Topics: Acute Disease; Amino Acid Sequence; Animals; Antigenic Variation; Cell Line; Epitopes; Follow-Up Studies; Hepacivirus; Hepatitis C; Hepatitis C Antigens; Hepatitis C, Chronic; Histocompatibility Antigens Class I; Molecular Sequence Data; Mutation; Pan troglodytes; Remission, Spontaneous; RNA, Viral; Sequence Alignment; Sequence Homology, Amino Acid; T-Lymphocytes, Cytotoxic; Viral Envelope Proteins; Viral Nonstructural Proteins