Quentin J Sattentau
Professor in Immunology
The Sir William Dunn School of Pathology
South Parks Road,
Oxford OX1 3RE, UK
Tel/Fax: +44 1865 275511
The movie shows a macrophage engulfing three HIV-GFP-infected T cells. The macrophage then becomes infected, illustrating a highly efficient mechanism for HIV-1 spread between T cells and macrophages (courtesy of Amy Baxter)
HIV-1 interactions with T cells and macrophages
Rebecca Russell, Amy Baxter, Tao Dong and Chris Duncan
Viruses use two mechanisms to spread within a host: release of cell-free particles and direct, cell-to-cell spread. Cell-cell spread of HIV may confer advantages over cell-free spread, such as more rapid viral dissemination, and may modulate certain intracellular pathways. Using systems based on live and fixed cell imaging techniques, PCR for viral RNA and DNA and analysis of cell activation pathways we are investigating the molecular cell biology of HIV-1 interaction with its target cells. We coined the term “virological synapse” in 2002, and were the first group to demonstrate such an HIV-1-induced structure in T cells. We are currently investigating the interactions between HIV-1-infected T cells and macrophages. Macrophages efficiently take up HIV-1 infected T cells and degrade them, potentially representing an innate mechanism of HIV-1 resistance. However, during this process macrophages may become infected, thereby generating a long-lived reservoir of HIV-1 infection. Understanding these virus-cell interactions will yield insight into the pathogenesis of HIV-1 infection.
Funding: The MRC UK, The Wellcome Trust, UK
Collaborations: Sonja Welsch, Heidelberg, Germany; Sriram Subramaniam, NIH, USA
HIV neutralising antibody vaccine studies
Rebecca Russell, Gemma Needham, Torben Schiffner
Despite intense activity by the international research community, we still do not have an effective vaccine against HIV-1 infection. Neutralising antibodies are an important component of the anti-HIV immune response and an effective vaccine will need to elicit such antibodies. We have a growing understanding of the antigenicity of the target of HIV-specific neutralising antibodies, the viral glycoproteins, Env. Nevertheless, no laboratory has yet induced the requisite high levels of neutralising antibodies following immunisation and the problem appears to be due to an unfocussed antibody response and the innately poor immunogenicity of HIV Env. We are attempting to focus the antibody response to the relevant neutralization epitopes on Env by a strategy of ‘immune silencing’ of irrelevant epitopes that has been developed by our group in collaboration with B. Davis in the Department of Chemistry. This approach uses glycan conjugation to the antigen followed by enzymatic glycan polymerization. In a parallel study we are working to overcome the conformational flexibility intrinsic to HIV-1 Env by using chemical cross-linking. It is hoped that this will provide a more rigid framework for B cell recognition and help define the parameters of B cell immunodominance related to epitope flexibility and topology. Finally we are attempting to understand how endogenous and extrinsic glycans affect the antigenicity and immunogenicity of HIV-1 Env by structural and molecular modelling analyses coupled with functional in vitro and in vivo studies.
Funding: The International AIDS Vaccine Initiative, The Bill and Melinda Gates Foundation, The James Martin 21st Century School Vaccine Institute
Collaborations: Ben Davis and Karolis Leonavicius, Chemistry, Oxford; Chris Scanlan and Camille Bonomelli, Biochemistry Oxford.
Novel adjuvants for systemic and mucosal immunity
Frank Wegmann, Will Hillson, Amin Moghaddam
Vaccines that rely upon subunit antigens or killed microorganisms may be lacking in immunogenicity. This is true of HIV-1 Env, which does not carry any intrinsic activators of innate immunity. Since HIV-1 vaccination may require immune responses at the mucosal surfaces, we are interested in adjuvants that may elicit immune responses both systemically and mucosally. In this context we have discovered two adjuvants that may have potential use in man with respect to vaccination against HIV-1 and other pathogens. Carbopol is a polyanionic gel that triggers a robust Th1-type adaptive immune response that is protective when formulated with influenza HA against lethal influenza challenge in vivo, and elicits strong antibody responses against HIV-1 Env in various in vivo models. Polyethyleneimine (PEI) is a cationic polymer that has strong adjuvant activity both systemically and mucosally, and drives a balanced Th1/Th2-type response in vivo. When formulated with influenza HA or HSV gD, PEI protects against lethal challenge with influenza and HSV respectively after in vivo immunization. Neither adjuvant is dependent upon TLR activation for its activity - PEI requires activation of intracellular dsDNA sensors in an Irf-3-dependent manner.
Funding: The Bill and Melinda Gates Foundation, The International AIDS Vaccine Initiative, The James Martin 21st Century School Vaccine Institute
Collaborations: Ali Harandi, Gothenburg University, Sweden; Catharina Svanborg, Lundt University, Sweden; Richard Flavell, HHMI, Yale University, USA.
Oxidative stress in hypersensitivity and allergy
Amin Moghaddam, Will Hillson
Reactive carbonyls are adducted to a variety of antigens by various pathways including treatment with aldehydes, oxidation, and by enzymatic activity. The presence of reactive carbonyls can increase the immunogenicity of antigens, and we have recently shown that their presence drives a Th2 bias. These properties of carbonyls have implications for allergic and autoimmune phenomena. We have established in vivo models based on hypersensitivity to vaccination with Respiratory Syncytial Virus (RSV), peanut allergy and asthma. We are also investigating the molecular mechanisms underlying the immune modulating activity of reactive carbonyls, and are investigating scavenger receptors and other innate immune pathways.
Collaborations: David Artis, U. Penn USA; Clare Lloyd, Imperial College London; Chris Scanlan, Biochemistry Oxford; Subhankar Mukhopadhayay and Kevin Malloy, Pathology Oxford.
Additional laboratory support
Š The James Martin 21st Century School Vaccine Institute
Š Jenner Vaccine Institute
Š Dormeur Investment Service Ltd.
Ms Amy Baxter, Wellcome Trust 4 year PhD Programme in Infection and Immunity
Ms Adjoa Smalls-Mantey, NIH-Oxford Program DPhil student
Dr. Chris Duncan MD: Wellcome Trust-funded PhD Programme for Clinicans (co-supervisor Sir Andrew McMichael, WIMM)
Mr. William Hillson, BSc, EPA-funded DPhil probationer
Dr. Amin Moghaddam MD, MSc: Senior Postdoctoral Research Scientist
Ms Gamma Needham BSc: Research Assistant and Assistant Laboratory Manager
Dr. Rebecca Russell BSc, PhD: IAVI-funded Postdoctoral Research Scientist and Laboratory Manager
Dr. Quentin Sattentau, BSc, PhD: Laboratory PI
Mr. Torben Schiffner, BSc: Departmental DPhil student
Dr. Frank Wegmann, BSc, PhD: Gates Foundation Grand Challenge Postdoctoral Scientist
Previous members of the Oxford laboratory
Dr. Sinead Brady, PhD, IAVI-funded Postdoctoral Research Scientist (2007-2009)
Dr. Sarah Brinckmann, EU (Europrise)-funded DPhil student (2009-2012)
Dr. Katherine Gantlett (née Fowler), Wellcome Trust Infection and Immunity Dphil (2002-2005): now Vaccine Clinical trials manager, The Jenner Vaccine Institute, University of Oxford
Dr. Fedde Groot BSc, PhD, amFAR Postdoctoral Research Fellow (2007-2009): now Graduate-entry medicine, University of Oxford
Dr. Clare Jolly, PhD, Wellcome Trust then MRC-funded Postdoctoral Research Scientist (2000-2008): now MRC Career Development Award Fellow, UCL, London UK
Dr. Emma Jones, Dphil, EU-funded Postdoctoral Research Scientist (2005-2006): now Postdoctoral Research Staff, Cardiff University, Wales
Dr. Leo Kong, NIH-Oxford program DPhil student (2008-2010), now postdoctoral Researcher, Ian Wilson lab, Scripps Research Institute, La Jolla, CA, USA
Dr. George Krashias BSc, MSc, Bodossaki Foundation DPhil Student (2006-2009): now Lecturer, University of Nicosia, Cyprus
Ms. Karoliina Laamanen BSc, Bill and Melinda Gates Foundation-funded Graduate Research Assistant (2006-2010): now Senior Technical Assistant at the Helsinki Blood Sevice, Finland
Dr. Nicola Martin BM, DPhil, MRC-funded Dphil student (2006-2009): now clinical school medicine, University of Oxford
Dr. Stefanie Michor, Bill and Melinda Gates Foundation funded DPhil (2005-2009): now
Dr. Ivonne Mitar, BSc, DPhil, MRC-funded Research Assistant and Dphil student (2002-2007): now Staff member, Health Interactions, Scientific Consultancy, UK
Ms. Cynthia Robson, BSc, Laboratory Manager and Graduate Research Assistant (2005-2007): now Funding Administrator, Auckland University, New Zealand
Dr. Daniela Romer, BSc, MSc, DPhil, EU-funded DPhil student (2003-2007): now Medical Department of Sanofi-Aventis Germany
Dr. Catherine Sargent, MD, MRC-funded DPhil student (2006-2009)
Dr. Neil Sheppard, BSc, MRC-funded DPhil student (2003-2006), Gates Foundation-funded Postdoctoral Scientist (2006-2007): now Senior Scientist, Vaccine Discovery Group, Pfizer La Jolla, CA USA
Dr. Samer Sourial, BSc, PhD, Postdoctoral Research Scientist (2007-2008): now Graduate-entry Medical Student, Liverpool UK
Dr. Giulia Zanetti, Wellcome Trust funded DPhil (2006-2009): now Postdoctoral Scientist, University of Berkley, USA
4. Moghaddam AE, Gartlan KH, Kong L and QJ (2011). . 187:1626-33.
23. Jolly, C and Sattentau, QJ (2004). Retroviral Spread by Induction of Virological Synapses. Traffic 5: 643—650.
24. Piguet, V and Sattentau, QJ (2004). Dangerous Liasons at the Virological Synapse. J. Clin. Invest. 114: 2-8.