Abstract
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.
Highlights
Hepatitis C virus (HCV) infection can lead to hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC); it is the leading cause of liver transplantation [1]
Our overall approach is summarized in Figure 1; it included a collection of blood samples from chronically infected (CI) and spontaneous clearer (SC) HCV infections in addition to healthy controls, and a screen to identify samples containing high levels of HCV-neutralizing antibodies (nAbs)
To validate the presence of nAbs in sera from CI and SC HCV infections, we first screened these sera by ELISA for antibodies able to bind a recombinant HCV envelope protein E2 that we have produced
Summary
HCV infection can lead to hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC); it is the leading cause of liver transplantation [1]. Its prevalence in the US and Western Europe is increasing [1]. No vaccine is currently available for HCV, and immunity against the virus is not well-understood. Cure rates are expected to increase with the recent approval of Antibody Repertoire Analysis of HCV. Despite this progress, many challenges remain, such as limited implementation, efficacy, and protection from reinfection [2]. Global eradication of HCV by implementing DAAs is currently not a feasible goal [3,4,5,6]. Critical gaps in understanding the correlates of protective HCV immunity have hindered the design of anti-HCV vaccines and novel immunotherapeutics [3,4,5,6]
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