Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

Bénédict Fallet,Yi Hao,Marianna Florova,Karen Cornille,Alba Verge De Los Aires,Giulia Girelli Zubani,Yusuf I Ertuna,Victor Greiff,Ulrike Menzel,Karim Hammad,Doron Merkler,Sai T Reddy,Jean-Claude Weill,Claude-Agnès Reynaud,Daniel D Pinschewer

doi:10.1016/j.celrep.2019.12.023

Abstract

SummaryPersistent viral infections subvert key elements of adaptive immunity. To compare germinal center (GC) B cell responses in chronic and acute lymphocytic choriomeningitis virus infection, we exploit activation-induced deaminase (AID) fate-reporter mice and perform adoptive B cell transfer experiments. Chronic infection yields GC B cell responses of higher cellularity than acute infections do, higher memory B cell and antibody secreting cell output for longer periods of time, a better representation of the late B cell repertoire in serum immunoglobulin, and higher titers of protective neutralizing antibodies. GC B cells of chronically infected mice are similarly hypermutated as those emerging from acute infection. They efficiently adapt to viral escape variants and even in hypermutation-impaired AID mutant mice, chronic infection selects for GC B cells with hypermutated B cell receptors (BCRs) and neutralizing antibody formation. These findings demonstrate that, unlike for CD8+ T cells, chronic viral infection drives a functional, productive, and protective GC B cell response.

Highlights

Persistent viral diseases, such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infection, represent major global health challenges and affect several hundred million people worldwide (WHO, 2018a, 2018b, 2018c)
HBV-specific B cells of chronically infected patients fail to differentiate into antibody-secreting cells (ASCs) upon in vitro re-stimulation and produce inadequate amounts of immunoglobulin, both of which can be partially restored by PD-1 blockade (Burton et al, 2018; Salimzadeh et al, 2018)
We report that the neutralizing capacity of the murine lymphocytic choriomeningitis virus (LCMV)-envelope-specific antibodies, as generated during chronic infection, requires their mutational maturation, analogous to human HIV and HCV neutralizing antibodies (Bailey et al, 2017; Georgiev et al, 2014; Jardine et al, 2016; Simonich et al, 2016; Wiehe et al, 2018; Xiao et al, 2009)

Summary

Introduction

Persistent viral diseases, such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infection, represent major global health challenges and affect several hundred million people worldwide (WHO, 2018a, 2018b, 2018c). Broadly neutralizing antibody (bnAb) responses to HIV itself are most commonly found in patients with long-term uncontrolled viremia (Rusert et al, 2016) These findings raised the possibility that, unlike for CD8 T cell responses, high levels of persisting viral antigen may result in an efficient antiviral germinal center (GC) B cell response. In line with this hypothesis, the spontaneous resolution of HBV infection is associated with the formation of protective anti-HBs antibodies (Guidotti et al, 2015), and evidence is accumulating that

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