B Cell Responses during Secondary Dengue Virus Infection Are Dominated by Highly Cross-Reactive, Memory-Derived Plasmablasts

• Type of Material: Article
• Authors: Lalita Priyamvada, Emory University; Alice Cho, Emory University; Nattawat Onlamoon, Mahidol University; Nai-Ying Zheng, University of Chicago; Min Huang, University of Chicago; Yevgeniy Kovalenkov, Emory University; Kulkanya Chokephaibulkit, Mahidol University; Nasikarn Angkasekwinai, Mahidol University; Kovit Pattanapanyasat, Mahidol University; Rafi Ahmed, Emory University; Patrick C. Wilson, University of Chicago; Jens Wrammert, Emory University
• Language: English
• Date: 2016-06-15
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.03203-15
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 12
• Start Page: 5574
• End Page: 5585
• Grant/Funding Information: Mahidol University; HHS; Mahidol University Chalermphrakiat Grant; National Institutes of Health (NIH)
• Keywords: NEUTRALIZING ANTIBODIES; DISEASE SEVERITY; IMMUNITY; Life Sciences & Biomedicine; HEMORRHAGIC-FEVER; RISK-FACTORS; Virology; Science & Technology; SHOCK SYNDROME; ORIGINAL ANTIGENIC SIN; ANTIBODY-DEPENDENT ENHANCEMENT; IN-DEPTH ANALYSIS; HUMAN MONOCLONAL-ANTIBODIES
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Dengue virus (DENV) infection results in the production of both type-specific and cross-neutralizing antibodies. While immunity to the infecting serotype is long-lived, heterotypic immunity wanes a few months after infection. Epidemiological studies link secondary heterotypic infections with more severe symptoms, and cross-reactive, poorly neutralizing antibodies have been implicated in this increased disease severity. To understand the cellular and functional properties of the acute dengue virus B cell response and its role in protection and immunopathology, we characterized the plasmablast response in four secondary DENV type 2 (DENV2) patients. Dengue plasmablasts had high degrees of somatic hypermutation, with a clear preference for replacement mutations. Clonal expansions were also present in each donor, strongly supporting a memory origin for these acutely induced cells. We generated 53 monoclonal antibodies (MAbs) from sorted patient plasmablasts and found that DENV-reactive MAbs were largely envelope specific and cross neutralizing. Many more MAbs neutralized DENV than reacted to envelope protein, emphasizing the significance of virion-dependent B cell epitopes and the limitations of envelope protein-based antibody screening. A majority of DENV-reactive MAbs, irrespective of neutralization potency, enhanced infection by antibody-dependent enhancement (ADE). Interestingly, even though DENV2 was the infecting serotype in all four patients, several MAbs from two patients neutralized DENV1 more potently than DENV2. Further, half of all type-specific neutralizing MAbs were also DENV1 biased in binding. Taken together, these findings are reminiscent of original antigenic sin (OAS), given that the patients had prior dengue virus exposures. These data describe the ongoing B cell response in secondary patients and may further our understanding of the impact of antibodies in dengue virus pathogenesis.