Multiple roads lead to Rome: B cell imprinting in distinct sequential flavivirus infections reveals different pathways to acquiring virus-neutralizing antibodies 4434

Abstract Description People experience multiple infections of the 4 related dengue virus serotypes (DENV1-4) and Zika (ZIKV) before acquiring protection, which is thought to be due to broadly neutralizing antibodies. Oddly, a primary ZIKV infection is a greater risk for subsequent severe dengue than primary DENV. To study underlying immune mechanisms, we conducted single cell sequencing on peripheral blood mononuclear cells from acute DENV2 cases in our cohort study in Nicaragua with no prior exposure (n = 1), prior DENV1 (n = 2), or prior ZIKV (n = 3), and analyzed ∼1,380 B cells/child. We found fewer acute antibody-secreting B cells (ASCs) in the ZIKV-DENV2 than the DENV1-DENV2 group, suggesting fewer precursors. ASCs of the ZIKV-DENV2 group revealed a transcriptional program of T-independent B cell responses, while DENV1-DENV2 ASCs showed use of memory and T-dependent regulation. Surprisingly, a single clone (18_VH3-23_V?1-39) dominated the ASC repertoire (33-50%) in all 3 ZIKV-DENV2 cases. Within this clone, we found a trajectory of evolution where the major constituent mAbs neutralized only ZIKV, but a minor constituent neutralized the infecting DENV2 virus. ASCs from DENV1-DENV2 showed clonal diversity and broader neutralization of DENV than the ZIKV-DENV2 clone. Thus, prior DENV1 infection led to diverse clones, whereas prior ZIKV led to selection and hypermutation of a single clone to achieve new specificity. This shows how populations may acquire immunity differently based on prior exposures. Funding Sources • HHMI Hanna H. Gray Fellowship to TS • U01 DHIPC 0255-C147-4609 to E.H. and S.W • P01 AI106695 and U01AI153416 to E.H. Topic Categories Viral Immunology (VIR)