HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria.

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2014-08-13

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Abstract

Monoclonal antibodies derived from blood plasma cells of acute HIV-1-infected individuals are predominantly targeted to the HIV Env gp41 and cross-reactive with commensal bacteria. To understand this phenomenon, we examined anti-HIV responses in ileum B cells using recombinant antibody technology and probed their relationship to commensal bacteria. The dominant ileum B cell response was to Env gp41. Remarkably, a majority (82%) of the ileum anti-gp41 antibodies cross-reacted with commensal bacteria, and of those, 43% showed non-HIV-1 antigen polyreactivity. Pyrosequencing revealed shared HIV-1 antibody clonal lineages between ileum and blood. Mutated immunoglobulin G antibodies cross-reactive with both Env gp41 and microbiota could also be isolated from the ileum of HIV-1 uninfected individuals. Thus, the gp41 commensal bacterial antigen cross-reactive antibodies originate in the intestine, and the gp41 Env response in HIV-1 infection can be derived from a preinfection memory B cell pool triggered by commensal bacteria that cross-react with Env.

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10.1016/j.chom.2014.07.003

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Trama, A, MA Moody, SM Alam, F Jaeger, B Lockwood, R Parks, K Lloyd, C Stolarchuk, et al. (2014). HIV-1 envelope gp41 antibodies can originate from terminal ileum B cells that share cross-reactivity with commensal bacteria. Cell Host Microbe, 16(2). pp. 215–226. 10.1016/j.chom.2014.07.003 Retrieved from https://hdl.handle.net/10161/9021.

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Scholars@Duke

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 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).

Alam

S. Munir Alam

Professor in Medicine

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.
Wiehe

Kevin J Wiehe

Norman L. Letvin Associate Professor in Medicine

Dr. Kevin Wiehe is the 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.

Tomaras

Georgia Doris Tomaras

Professor in Surgery

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.  

 


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