Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization.

Abstract

HIV-1-infected infants develop broadly neutralizing antibodies (bnAbs) more rapidly than adults, suggesting differences in the neonatal versus adult responses to the HIV-1 envelope (Env). Here, trimeric forms of HIV-1 Env immunogens elicit increased gp120- and gp41-specific antibodies more rapidly in neonatal macaques than adult macaques. Transcriptome analyses of neonatal versus adult immune cells after Env vaccination reveal that neonatal macaques have higher levels of the apoptosis regulator BCL2 in T cells and lower levels of the immunosuppressive interleukin-10 (IL-10) receptor alpha (IL10RA) mRNA transcripts in T cells, B cells, natural killer (NK) cells, and monocytes. In addition, immunized neonatal macaques exhibit increased frequencies of activated blood T follicular helper-like (Tfh) cells compared to adults. Thus, neonatal macaques have transcriptome signatures of decreased immunosuppression and apoptosis compared with adult macaques, providing an immune landscape conducive to early-life immunization prior to sexual debut.

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Citation

Published Version (Please cite this version)

10.1016/j.celrep.2019.12.091

Publication Info

Han, Qifeng, Todd Bradley, Wilton B Williams, Derek W Cain, David C Montefiori, Kevin O Saunders, Robert J Parks, Regina W Edwards, et al. (2020). Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization. Cell reports, 30(5). pp. 1553–1569.e6. 10.1016/j.celrep.2019.12.091 Retrieved from https://hdl.handle.net/10161/20297.

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

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.

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.


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.

Saunders

Kevin O'Neil Saunders

Professor in Surgery

Dr. Kevin O. Saunders graduated from Davidson College in 2005 with a bachelor of science in biology. At Davidson College, he trained in the laboratory of Dr. Karen Hales identifying the genetic basis of infertility. Dr. Saunders completed his doctoral research on CD8+ T cell immunity against HIV-1 infection with Dr. Georgia Tomaras at Duke University in 2010. He subsequently trained as a postdoctoral fellow in the laboratories of Drs. Gary Nabel and John Mascola at the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center.

In 2014, Dr. Saunders joined the faculty at the Duke Human Vaccine Institute as a medical instructor. In this role, he analyzed antibody responses in vaccinated macaques, which led to the identification of glycan-dependent HIV antibodies induced by vaccination. Dr. Saunders was appointed as a non-tenure track Assistant Professor of Surgery and the Director of the Laboratory of Protein Expression in the Duke Human Vaccine Institute in 2015. He successfully transitioned to a tenure-track appointment in 2018 and was later promoted to the rank of Associate Professor in Surgery in 2020. Dr. Saunders previously served as DHVI's director or research and currently serves as the associate director for DHVI.

Dr. Saunders has given invited lectures at international conferences such as HIVR4P and the Keystone Symposia for HIV Vaccines. He has authored book chapters and numerous journal articles and holds patents on vaccine design concepts and antiviral antibodies. As a faculty member at Duke, Dr. Saunders has received the Duke Human Vaccine Institute Outstanding Leadership Award and the Norman Letvin Center For HIV/AIDS Vaccine Immunology and Immunogen Discovery Outstanding Investigator Award. His current research interests include vaccine and antibody development to combat HIV-1 and coronavirus infections.

About the Saunders Laboratory
The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. Our research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. Using this technique we identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). We have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. We discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we have termed “glycan learning.” This approach modifies the glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. We have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, we use these Env antigens in vitro to investigate the biology of B cell receptor engagement. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.


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