Immune checkpoint modulation enhances HIV-1 antibody induction.

Abstract

Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

Department

Description

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Citation

Published Version (Please cite this version)

10.1038/s41467-020-14670-w

Publication Info

Bradley, Todd, Masayuki Kuraoka, Chen-Hao Yeh, Ming Tian, Huan Chen, Derek W Cain, Xuejun Chen, Cheng Cheng, et al. (2020). Immune checkpoint modulation enhances HIV-1 antibody induction. Nature communications, 11(1). p. 948. 10.1038/s41467-020-14670-w Retrieved from https://hdl.handle.net/10161/21940.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Yeh

Chen-Hao Yeh

Assistant Professor in Medicine

Dr. Yeh completed his undergraduate and Master of Science degree at the National Taiwan University in Taipei. He then pursued his Ph.D. at the University of Tokyo in Japan. He moved to Durham in 2015 for postdoctoral training in Dr. Garnett Kelsoe’s laboratory at the Duke Department of Immunology.

Dr. Yeh holds a broad academic background in biochemistry and immunology, with specific training and expertise in lymphocyte development and differentiation. His research has focused on: 1) germinal center (GC) B cell selection, differentiation and antibody affinity maturation and 2) T follicular helper (Tfh) cell differentiation and TCR repertoire analysis. 

Over the years, Dr. Yeh has demonstrated that B-cell selection based on surface pMHCII density is stringent in the establishment of GCs, but relatively relaxed during GC responses; this observation has led to fundamental revisions in the standard models for affinity-driven selection. With multiple genetic models to identify GC-resident Tfh cells in the mouse, Dr. Yeh also showed that the standard phenotypic definition of “GCTfh” included a majority of T cells that do not enter GCs. The more abundant Tfh-like cells have distinct developmental requirements, TCR repertoires and transcriptomic profiles compared to the rarer GC-resident Tfh cells, implying distinct physiologies and function. In addition, Dr. Yeh has categorized the phenotype of memory and GC B cell populations in Rhesus macaque (RM) as a step forward in understanding humoral responses in RMs and to enable isolation of live GC B cells for in vitro culture.

Cain

Derek Wilson Cain

Associate Professor in Medicine

My research focuses on the interactions of T cells and B cells during infection or following vaccination. I am particularly interested in the inter- and intracellular events that take place within germinal centers, the anatomic site of antibody evolution during an immune response.


Wiehe

Kevin J Wiehe

Norman L. Letvin Associate Professor in Medicine

Dr. Kevin Wiehe is the associate director of research, director of computational biology and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute (DHVI). He has over 20 years of experience in the field of computational biology and has expertise in computational structural biology, computational genomics, and computational immunology.

For the past decade, he has applied his unique background to developing computational approaches for studying the B cell response in both the infection and vaccination settings. He has utilized his expertise in computational structural biology to structurally model and characterize HIV and influenza antibody recognition. Dr. Wiehe has utilized his expertise in computational genomics and computational immunology to develop software to analyze large scale next generation sequencing data of antibody repertoires as well as develop computational programs for estimating antibody mutation probabilities. Dr. Wiehe has shown that low probability antibody mutations can act as rate-limiting steps in the development of broadly neutralizing antibodies in HIV.

Through his PhD, postdoc work, and now his roles at DHVI, Dr. Wiehe always approaches the analysis and the scientific discovery process from a structural biology perspective. Supporting the Duke Center for HIV Structural Biology (DCHSB), Dr. Wiehe will conduct antibody sequence analysis for antibodies used in computational and molecular modeling analyses conducted.

Montefiori

David Charles Montefiori

Professor in Surgery

Dr. Montefiori is Professor and Director of the Laboratory for HIV and COVID-19 Vaccine Research & Development in the Department of Surgery, Division of Surgical Sciences at Duke University Medical Center. His major research interests are viral immunology and HIV and COVID-19 vaccine development, with a special emphasis on neutralizing antibodies.

Multiple aspects of HIV-1 neutralizing antibodies are studied in his laboratory, including mechanisms of neutralization and escape, epitope diversity among the different genetic subtypes and geographic distributions of the virus, neutralizing epitopes, requirements to elicit protective neutralizing antibodies by vaccination, optimal combinations of neutralizing antibodies for immunoprophylaxis, and novel vaccine designs for HIV-1. Dr. Montefiori also directs large vaccine immune monitoring programs funded by the NIH and the Bill & Melinda Gates Foundation that operate in compliance with Good Clinical Laboratory Practices and has served as a national and international resource for standardized assessments of neutralizing antibody responses in preclinical and clinical trials of candidate HIV vaccines since 1988.

At the onset of the COVID-19 pandemic he turned his attention to SARS-CoV-2, with a special interest in emerging variants and how they might impact transmission, vaccines and immunotherapeutics. His rapid response to emerging SARS-CoV-2 variants of concern provided some of the earliest evidence of the potential risk the variants pose to vaccines. In May 2020, his laboratory was recruited by the US Government to lead the national neutralizing antibody laboratory program for COVID-19 vaccines.

His laboratory utilizes FDA approved validated assay criteria to facilitate regulatory approvals of COVID-19 vaccines. He has published over 750 original research papers that have helped shape the scientific rationale for antibody-based vaccines.


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