@article{1f6e9c393d7749aaa6616ef5f536d649,
title = "Early T follicular helper cell activity accelerates hepatitis C virus-specific B cell expansion",
abstract = "Early appearance of neutralizing antibodies during acute hepatitis C virus (HCV) infection is associated with spontaneous viral clearance. However, the longitudinal changes in antigen-specific memory B cell (MBCs) associated with divergent HCV infection outcomes remain undefined. We characterized longitudinal changes in E2 glycoprotein-specific MBCs from subjects who either spontaneously resolved acute HCV infection or progressed to chronic infection, using single-cell RNA-seq and functional assays. HCV-specific antibodies in plasma from chronically infected subjects recognized multiple E2 genotypes, while those from spontaneous resolvers exhibited variable cross-reactivity to heterotypic E2. E2-specific MBCs from spontaneous resolvers peaked early after infection (4-6 months), following expansion of activated circulating T follicular helper cells (cTfh) expressing interleukin 21. In contrast, E2-specific MBCs from chronically infected subjects, enriched in VH1-69, expanded during persistent infection (> 1 year), in the absence of significantly activated cTfh expansion. Early E2-specific MBCs from spontaneous resolvers produced monoclonal antibodies (mAbs) with fewer somatic hypermutations and lower E2 binding but similar neutralization as mAbs from late E2-specific MBCs of chronically infected subjects. These findings indicate that early cTfh activity accelerates expansion of E2-specific MBCs during acute infection, which might contribute to spontaneous clearance of HCV.",
author = "Eduardo Salinas and Maude Boisvert and Upadhyay, {Amit A.} and Nathalie B{\'e}dard and Nelson, {Sydney A.} and Julie Bruneau and Derdeyn, {Cynthia A.} and Joseph Marcotrigiano and Evans, {Matthew J.} and Bosinger, {Steven E.} and Shoukry, {Naglaa H.} and Arash Grakoui",
note = "Funding Information: This study was funded by NIH grants R01AI136533, R01AI124680, R01AI096882, and R01AI126890 (to AG); Office of Research Infrastructure Programs/Office of the Director P51OD011132 (formerly National Center for Research Resources P51RR000165) to the Yerkes National Primate Research Center; 5U01AI131313 from NIH (to NHS); the Canadian Institutes of Health Research (CIHR) (PJT-173467; to NHS and JB); Alberta Innovates-Health Solutions (to NHS and JB); Fonds de recherche du Qu{\'e}bec – Sant{\'e} (FRQS) AIDS and Infectious Disease Network (R{\'e}seau SIDA-MI) (to NHS and JB); and the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases (to JM). MB received postdoctoral fellowships from the FRQS, the American Liver Foundation, and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the CIHR (NHC142832) and the Public Health Agency of Canada. JB is the Canada Research Chair in Addiction Medicine. This work was facilitated by the Immunology and Flow Cytometry Core of the Center for AIDS Research at Emory University (P30AI050409). Funding Information: We would like to thank the Yerkes and the Research Center of Montreal University Hospital flow cytometry cores for their assistance in cell sorting and the Yerkes Non-human Primate Genomics Core laboratory for processing samples for single-cell RNA-seq. We thank Dennis Jang and Carson “Elliot” Anderson at Emory University for their assistance in cloning IgG plasmids for expression of mAbs. This study was funded by NIH grants R01AI136533, R01AI124680, R01AI096882, and R01AI126890 (to AG); Office of Research Infrastructure Programs/Office of the Director P51OD011132 (formerly National Center for Research Resources P51RR000165) to the Yerkes National Primate Research Center; 5U01AI131313 from NIH (to NHS); the Canadian Institutes of Health Research (CIHR) (PJT-173467; to NHS and JB); Alberta Innovates-Health Solutions (to NHS and JB); Fonds de recherche du Qu{\'e}bec - Sant{\'e} (FRQS) AIDS and Infectious Disease Network (R{\'e}seau SIDA-MI) (to NHS and JB); and the Intramural Research Programs of the National Institute of Allergy and Infectious Diseases (to JM). MB received postdoctoral fellowships from the FRQS, the American Liver Foundation, and the Canadian Network on Hepatitis C (CanHepC). CanHepC is funded by a joint initiative of the CIHR (NHC142832) and the Public Health Agency of Canada. JB is the Canada Research Chair in Addiction Medicine. This work was facilitated by the Immunology and Flow Cytometry Core of the Center for AIDS Research at Emory University (P30AI050409). Publisher Copyright: Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = jan,
day = "19",
doi = "10.1172/JCI140590",
language = "English",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",
}