Targeting HIV Env immunogens to B cell follicles in nonhuman primates through immune complex or protein nanoparticle formulations

• Type of Material: Article
• Authors: Jacob T. Martin, MIT; Christopher A. Cottrell, Scripps Research Institute; Aleksandar Antanasijevic, Scripps Research Institute; Diane G. Carnathan, Scripps Research Institute; Benjamin J. Cossette, MIT; Chiamaka A. Enemuo, Emory University; Etse H. Gebru, Emory University; Yury Choe, Emory University; Federico Viviano, Emory University; Stephanie Fischinger, Massachusetts General Hospital; Talar Tokatlian, MIT; Kimberly M. Cirelli, Scripps Research Institute; George Ueda, University of Washington; Jeffrey Copps, Scripps Research Institute; Torben Schiffner, Scripps Research Institute; Sergey Menis, Scripps Research Institute; Galit Alter, Massachusetts General Hospital; William R. Schief, Scripps Research Institute; Shane Crotty, Scripps Research Institute; Neil P. King, University of Washington; David Baker, University of Washington; Guido Silvestri, Emory University; Andrew B. Ward, Scripps Research Institute; Darrell J. Irvine, MIT
• Language: English
• Date: 2020-08-05
• Publisher: NATURE RESEARCH
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41541-020-00223-1
• Title of Journal or Parent Work: NPJ VACCINES
• Volume: 5
• Issue: 1
• Start Page: 72
• End Page: 72
• Grant/Funding Information: This work was supported in part by the NIH (awards UM1AI100663 and UM1AI144462 to D.J.I., S.C., W.R.S., G.S., and A.B.W., AI125068 to D.J.I., S.C., and G.S., and P01AI048240 to D.J.I., and NINDS P30 Core Center Grant #NS072030), the Bill & Melinda Gates Foundation (OPP1156262 to D.B. and N.P.K.), the Ragon Institute for MGH, MIT, and Harvard, and the Samana Cay MGH Research Scholars 2017–2022 program (G.A.). C.A.C. is supported by the NIH F31 Ruth L. Kirschstein Predoctoral Award Al131873 and by the Achievement Rewards for College Scientists Foundation.
• Keywords: PARTICULATE; Life Sciences & Biomedicine; Science & Technology; ANTIGEN; SUBCAPSULAR SINUS; CRYO-EM STRUCTURE; ENVELOPE TRIMERS; NEUTRALIZING ANTIBODY-RESPONSES; INNATE; HIGH-THROUGHPUT; Medicine, Research & Experimental; Immunology; VACCINE; ELICITATION; Research & Experimental Medicine
• Research Categories: Biology, Virology; Health Sciences, Immunology; Biology, Cell

Abstract

Following immunization, high-affinity antibody responses develop within germinal centers (GCs), specialized sites within follicles of the lymph node (LN) where B cells proliferate and undergo somatic hypermutation. Antigen availability within GCs is important, as B cells must acquire and present antigen to follicular helper T cells to drive this process. However, recombinant protein immunogens such as soluble human immunodeficiency virus (HIV) envelope (Env) trimers do not efficiently accumulate in follicles following traditional immunization. Here, we demonstrate two strategies to concentrate HIV Env immunogens in follicles, via the formation of immune complexes (ICs) or by employing self-assembling protein nanoparticles for multivalent display of Env antigens. Using rhesus macaques, we show that within a few days following immunization, free trimers were present in a diffuse pattern in draining LNs, while trimer ICs and Env nanoparticles accumulated in B cell follicles. Whole LN imaging strikingly revealed that ICs and trimer nanoparticles concentrated in as many as 500 follicles in a single LN within two days after immunization. Imaging of LNs collected seven days postimmunization showed that Env nanoparticles persisted on follicular dendritic cells in the light zone of nascent GCs. These findings suggest that the form of antigen administered in vaccination can dramatically impact localization in lymphoid tissues and provides a new rationale for the enhanced immune responses observed following immunization with ICs or nanoparticles.