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.
|Journal||Frontiers in Immunology|
|State||Published - 21 Dec 2018|
Bibliographical noteFunding Information:
We thank Barak Shalom for help with the visualization of the phylogenetic trees in Figure 5. We Thank Dr. Itai Benhar (Tel-Aviv University, Tel-Aviv, Israel) for providing the pMAZ-IgH and pMAZ-IgL vectors and for helpful discussions, and Dr. Steven Foung (Stanford Univ., Stanford, California) for providing HCV-neutralizing mAbs. This research was supported by grant number 832/16 from the ISF to GY, OS, PP, and RH, by the Helmsley Charitable Trust Fund (grant number 2012PG-ISL013) to MG-T and by the BIU-RABIN collaborative grant to MG-T and MB.
© Copyright © 2018 Eliyahu, Sharabi, Elmedvi, Timor, Davidovich, Vigneault, Clouser, Hope, Nimer, Braun, Weiss, Polak, Yaari and Gal-Tanamy.
- antibody repertoire
- hepatitis C virus
- immune signature
- infectious disease
- neutralizing antibodies