Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum.
Date
2012
Editors
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
BACKGROUND: Generation of potent anti-HIV antibody responses in mucosal compartments is a potential requirement of a transmission-blocking HIV vaccine. HIV-specific, functional antibody responses are present in breast milk, and these mucosal antibody responses may play a role in protection of the majority of HIV-exposed, breastfeeding infants. Therefore, characterization of HIV-specific antibodies produced by B cells in milk could guide the development of vaccines that elicit protective mucosal antibody responses. METHODS: We isolated B cells from colostrum of an HIV-infected lactating woman with a detectable neutralization response in milk and recombinantly produced and characterized the resulting HIV-1 Envelope (Env)-specific monoclonal antibodies (mAbs). RESULTS: The identified HIV-1 Env-specific colostrum mAbs, CH07 and CH08, represent two of the first mucosally-derived anti-HIV antibodies yet to be reported. Colostrum mAb CH07 is a highly-autoreactive, weakly-neutralizing gp140-specific mAb that binds to linear epitopes in the gp120 C5 region and gp41 fusion domain. In contrast, colostrum mAb CH08 is a nonpolyreactive CD4-inducible (CD4i) gp120-specific mAb with moderate breadth of neutralization. CONCLUSIONS: These novel HIV-neutralizing mAbs isolated from a mucosal compartment provide insight into the ability of mucosal B cell populations to produce functional anti-HIV antibodies that may contribute to protection against virus acquisition at mucosal surfaces.
Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Friedman, James, S Munir Alam, Xiaoying Shen, Shi-Mao Xia, Shelley Stewart, Kara Anasti, Justin Pollara, Genevieve G Fouda, et al. (2012). Isolation of HIV-1-neutralizing mucosal monoclonal antibodies from human colostrum. PLoS One, 7(5). p. e37648. 10.1371/journal.pone.0037648 Retrieved from https://hdl.handle.net/10161/10587.
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.
Collections
Scholars@Duke
S. Munir Alam
Research Interests.
The Alam laboratory’s primary research is focused on understanding the biophysical properties of antigen-antibody binding and the molecular events of early B cell activation using the HIV-1 broadly neutralizing antibody (bnAb) lineage models. We are studying how HIV-1 Envelope proteins of varying affinities are sensed by B cells expressing HIV-1 bnAbs or their germline antigen receptors and initiate early signaling events for their activation. In the long-term these studies will facilitate design and pre-selection of immunogens for testing in animal models and accelerate HIV-1 vaccine development.
Current research include the following NIAID-funded projects
Antigen recognition and activation of B cell antigen receptors with the specificity of HIV-1 broadly neutralizing antibodies. This project involves elucidating the early events on the B cell surface following antigen (Ag) engagement of the B cell antigen receptor (BCR) and to provide an assessment of the in vivo potential of an Ag to drive B cell activation. We are performing biophysical interactions analyses and using high-resolution microscopy to define the physico-chemical properties of BCR-Ag interactions that govern signaling and activation thresholds for BCR triggering and the BCR endocytic function in antigen internalization. The overall objective of these studies is to bridge the quantitative biophysical and membrane dynamics measurements of Ag-BCR interactions to ex-vivo and in-vivo B cell activation. This NIAID-funded research is a collaboration with co-investigators Professor Michael Reth (University of Freiburg, Germany) and Dr. Laurent Verkoczy (San Diego Biomedical Research Institute, CA).
Immunogen Design for Induction of HIV gp41 Broadly Neutralizing Antibodies. This research project addresses the critical problem of vaccine induction of disfavored HIV-1 antibody lineages, like those that target the membrane proximal external region (MPER) of HIV Env gp41. This program combines structure and lineage-based vaccine development strategies to design immunogens that will induce bnAb lineages that are not polyreactive and therefore easier to induce. The overall objective of this program grant is to develop and test sequential immunogens that will initiate and induce HIV-1 bnAb lineages like the potent MPER bnAb DH511. Using a germline-targeting (GT) epitope scaffold design and a prime/boost strategy, we are testing induction of DH511-like bnAbs in knock-in (KI) mice models expressing the DH511 germline receptors. This P01 research program is in collaboration with Dr. William Schief (The Scripps Research Institute, CA), who leads the team that are designing germline targeting (GT)-scaffold prime and boost immunogens and Dr. Ming Tian at Harvard University who developed relevant knock-mice models for the study.
Justin Joseph Pollara
Dr. Justin Pollara is a member of the Duke Human Vaccine Institute and the Duke Center for Human Systems Immunology, and is Associate Director of the Duke Center for AIDS Research (CFAR) Developmental Core. He received his PhD from North Carolina State University and completed his postdoctoral training as a recipient of the Duke NIH Interdisciplinary Research Training Program in AIDS (IRTPA) T32 award in the laboratory of Dr. Guido Ferrari. He joined the faculty of the Duke Department of Surgery in 2016.
A common theme of research performed in Dr. Pollara’s laboratory is a focus on interactions between innate and adaptive immunity. Dr. Pollara’s work has contributed significantly to the understanding of the roles played by non-neutralizing antibodies in limiting HIV-1 disease progression, and in prevention of infection or control of virus replication in preclinical and clinical HIV-1 vaccine trials. Dr. Pollara’s research has also identified specific components of the immune response that reduce the risk of vertical transmission of both HIV-1 and human cytomegalovirus. The Pollara lab characterizes the phenotype and functionality of antibody-interacting innate immune cells and explores how natural genetic variation in antibodies and antibody receptors may contribute to vaccine responsiveness and immune competence. Further, with a strong interdisciplinary and collaborative approach, the Pollara Lab has broadened its scope beyond infectious diseases and is now actively leading studies aimed at understanding how inflammation, antibodies, innate immune cells, and newly described populations of T cells promote allograft injury that underlies rejection of transplanted organs.
Garnett H. Kelsoe
- Lymphocyte development and antigen-driven diversification of immunoglobulin and T cell antigen receptor genes.
2. The germinal center reaction and mechanisms for clonal selection and self - tolerance. The origins of autoimmunity.
3. Interaction of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses, DNA motifs, collaborations in bioinformatics.
6. Humoral immunity to influenza and HIV-1.
Guido Ferrari
The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations within and outside of Duke, the Ferrari Lab has expanded its focus of research to include the ontogeny of HIV-1 specific immune responses that work by eliminating HIV-1 infected cells and how these can be induced by AIDS vaccine candidates.
Georgia Doris Tomaras
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor of Molecular Genetics and Microbiology and is a Fellow of the American Academy of Microbiology (AAM) and a Fellow of the American Association for the Advancement of Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology (CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her national and international leadership roles include: Executive Management Team (EMT) leader and mPI for the HIV Vaccine Trials Network (HVTN); Director of Lab Sciences (HVTN); and Chair of NIH Vaccine Research Center (VRC) Board of Scientific Counselors. Her prior leadership roles include serving as the Director of Research, Duke Human Vaccine Institute (DHVI); Director of the DHVI Training Program; Associate Director of DHVI Research; Co-Director of the Interdisciplinary Research Training Program in AIDS (IRTPA) Duke; Chair of the National Institutes of Health (NIH) AIDS Vaccine Research Subcommittee (AVRS), and Advisory Counsel member of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID). Dr. Tomaras’ primary research focus is deciphering mechanisms of protective human immunity and identification of immune correlates of protection to further development of effective vaccines against infectious diseases.
Barton Ford Haynes
Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology, and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology, and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine Institute, Bart Haynes is leading a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses, and HIV/AIDS.
To work on the AIDS vaccine problem, his group has been awarded two large consortium grants from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) (2005-2012), and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) (2012-2019) to conduct discovery science to speed HIV vaccine development. In July 2019, his team received the third of NIH “CHAVI” awards to complete the HIV vaccine development work - CHAV-D.
Since the beginning of the COVID-19 pandemic, Haynes and the DHVI Team has been working non-stop to develop vaccines, rapid and inexpensive tests and therapeutics to combat the pandemic. Since March 2020, he has served as a member of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) committee to advise on COVID-19 vaccine development, and served as the co-chair of the ACTIV subcommittee on vaccine safety. Haynes is the winner of the Alexander Fleming Award from the Infectious Disease Society of America and the Ralph Steinman Award for Human Immunology Research from the American Association of Immunologists. He is a member of the National Academy of Medicine, National Academy of Inventors and the American Academy of Arts and Sciences.
About the Haynes LaboratoryThe Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.
Mucosal Immune Responses in Acute HIV Infection
The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.
The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.
The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.
Immunogen Design
To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.
Mucosal Immune Responses in TB and Influenza
The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.
Michael Anthony Moody
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 mPI of a U01 program to develop a syphilis vaccine; this program is a collaboration with mPI 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).
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.