Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations.

Abstract

A strategy for HIV-1 vaccine development is to define envelope (Env) evolution of broadly neutralizing antibodies (bnAbs) in infection and to recreate those events by vaccination. Here, we report host tolerance mechanisms that limit the development of CD4-binding site (CD4bs), HCDR3-binder bnAbs via sequential HIV-1 Env vaccination. Vaccine-induced macaque CD4bs antibodies neutralize 7% of HIV-1 strains, recognize open Env trimers, and accumulate relatively modest somatic mutations. In naive CD4bs, unmutated common ancestor knock-in mice Env+B cell clones develop anergy and partial deletion at the transitional to mature B cell stage, but become Env- upon receptor editing. In comparison with repetitive Env immunizations, sequential Env administration rescue anergic Env+ (non-edited) precursor B cells. Thus, stepwise immunization initiates CD4bs-bnAb responses, but immune tolerance mechanisms restrict their development, suggesting that sequential immunogen-based vaccine regimens will likely need to incorporate strategies to expand bnAb precursor pools.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1038/s41467-017-01336-3

Publication Info

Williams, Wilton B, Jinsong Zhang, Chuancang Jiang, Nathan I Nicely, Daniela Fera, Kan Luo, M Anthony Moody, Hua-Xin Liao, et al. (2017). Initiation of HIV neutralizing B cell lineages with sequential envelope immunizations. Nature communications, 8(1). p. 1732. 10.1038/s41467-017-01336-3 Retrieved from https://hdl.handle.net/10161/17302.

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Scholars@Duke

Williams

Wilton Bryan Williams

Associate Professor in Surgery

Dr. Williams completed a PhD in Biomedical Sciences (Immunology and Microbiology) from the University of Florida and did his postdoctoral work in the laboratory of Dr. Barton Haynes at the Duke Human Vaccine Institute (DHVI).

The key goals of HIV vaccine development are to define the host-virus events during natural HIV infection that lead to the induction of broadly neutralizing antibodies, and to recreate those events with a vaccine. As a junior faculty member in the DHVI, Dr. Williams is further characterizing SHIV non-human primate models for HIV infection, and evaluates B cell responses to HIV-1 vaccination in humans and non-human primates.

Nicely

Nathan I. Nicely

Assistant Professor in Medicine

Nathan Nicely, Ph.D., is an Assistant Professor of Medicine with the Duke Human Vaccine Institute and Director of the Duke University X-ray Crystallography shared resource. His major research interests lie in the structural biology of anti-HIV antibodies and HIV virion coat proteins. Dr. Nicely received his Ph.D. in Structural and Molecular Biochemistry from NC State University in 2005 with Dr. Carla Mattos. He then completed a postdoctoral fellowship with Dr. Al Claiborne in the Center for Structural Biology at Wake Forest University. After a brief stint working in computational biology and bioinformatics with the Renaissance Computing Institute at the University of North Carolina, Dr. Nicely came to the Duke Human Vaccine Institute in early 2008 to complete the construction of the X-ray crystallography facility and to undertake the DHVI's structural biology program.

The X-ray Crystallography Shared Resource aims to provide the full range of services necessary to determine macromolecular structures. The facility was constructed in mid-2008 and officially opened its doors to the structural biology community in late 2009. The overall goal of the crystallography lab is to centralize all the necessary instrumentation as well as experienced expertise requisite to produce validated, high impact crystal structures for the Duke Human Vaccine Institute’s structural aims as well as any other investigator on campus with similar goals.  The core lab offers everything from protein production to structure determination and publishing. The Shared Resource supports entry points for labs that are interested in expanding their research projects to include structural biology aims from basic methodological advice to full collaboration. A full description of the lab and its publications can be found at its website. Dr. Nicely enjoys engaging in the day-to-day operations of the crystallography facility, including user training and assistance as well as maintenance of the hardware and software that support the science.

Moody

Michael Anthony Moody

Professor of Pediatrics

Tony Moody, MD is a Professor in the Department of Pediatrics, Division of Infectious Diseases and Professor in the Department of Integrative Immunobiology at Duke University Medical Center. Research in the Moody lab is focused on understanding the B cell responses during infection, vaccination, and disease. The lab has become a resource for human phenotyping, flow characterization, staining and analysis at the Duke Human Vaccine Institute (DHVI). The Moody lab is currently funded to study influenza, syphilis, HIV-1, and emerging infectious diseases.

Dr. Moody is the director of the Duke CIVICs Vaccine Center (DCVC) at (DHVI) and co-director of the Centers for Research of Emerging Infectious Disease Coordinating Center (CREID-CC). Dr. Moody is co-PI of a U19 program to develop a syphilis vaccine; this program is led by Dr. Justin Radolf at the University of Connecticut. Dr. Moody is also the director of the DHVI Accessioning Unit, a biorepository that provides support for work occurring at DHVI and with its many collaborators around the world by providing processing, shipping, and inventory support for a wide array of projects.

Dr. Moody and his team are involved in many networks studying vaccine response including the Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the COVID-19 Prevention Network (CoVPN).


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