Retroviral Immunology

 

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

quentin.sattentau@path.ox.ac.uk

 

 

 

 

 

 

 

The movie above represents a 3D model of HIV-1 particles (red spheres) moving between an infected T cell (plasma membrane in red) and an uninfected, receptor-expressing T lymphocyte (plasma membrane in green) across a virological synapse. Tomography and modelling by Dr Sonja Welsch.

 

 

 

*      Research Interests

 

*      Group Members

 

*      Recent Publications

 

News: QJ Sattentau will be on Leverhulme-Award funded teaching sabbatical leave from MT 2009-MT 2010

 

Research interests

 

HIV-1 interactions with T cells and macrophages

Rebecca Russell, Amy Baxter 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 Òvirological synapseÓ 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; Kay Grunewald, STRUBI, Oxford

 

HIV neutralising antibody vaccine studies

Frank Wegmann, Rebecca Russell, Gemma Needham, Torben Schiffner, Leo Kong

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 Ôimmune silencingÕ 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 areattempting 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 Heiko Schuster, Department of Chemistry, University of Oxford, Chris Scanlan and Camille Bonomelli, Department of Biochemistry, The University of Oxford.

 

Novel adjuvants for systemic and mucosal immunity

Frank Wegmann, Sarah Brinckmann, Leo Kong, Kate Gartlan

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, and we are currently investigating their mechanism of action.

Funding: The Bill and Melinda Gates Foundation, EUROPRISE EU Network of Excellence, The International AIDS Vaccine Initiative, The James Martin 21st Century School Vaccine Institute

Collaborations: Jon Heeney, Department of Veterinary Science, University of Cambridge

Patent filed: PCT/GB2007/000979 - Novel adjuvant

Patent filed: GB0805356.3 – vaccine adjuvant composition

 

Reactive carbonyls in allergy and autoimmunity

Amin Moghaddam, Kate Gartlan, William 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: Clare Lloyd, Imperial College London

Patent: filed ICOY/P28613GB - Reactive carbonyls as immune modulators

Additional laboratory support

á      The laboratory is supported by The James Martin 21st Century School Vaccine Institute

á      Q. Sattentau is a Jenner Vaccine Institute Investigator

á      The laboratory acknowledges support from Dormeur Investment Service Ltd.

 

Group members

 

Ms Amy Baxter, Wellcome Trust 4 year PhD Programme in Infection and Immunity

 

Ms. Sarah Brinckmann BSc: Europrise (EU)-Funded DPhil Student

 

Dr. Chris Duncan MD: Wellcome Trust-funded PhD Programme for Clinicans

 

Dr. Kate Gartlan BSc, PhD: EPA-funded Postdoctoral Research Scientist

 

Mr. William Hillson, BSc, EPA-funded DPhil probationer

 

Mr Leo Kong BSc: NIH-Oxford Programme DPhil Student

 

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

 

Co-supervised staff and students

Dr. Catherine Sargent MD: MRC-funded DPhil Student with Prof. Sir Andrew McMichael, WIMM, University of Oxford

 

Dr. Chris Duncan MD: Wellcome Trust-funded PhD Programme for Clinicans with Prof. Sir Andrew McMichael, WIMM, University of Oxford

 

Previous members of the Oxford laboratory

 

Dr. Katherine Gantlett (nŽe Fowler), Wellcome Trust Infection and Immunity Dphil (2002-2005): now Vaccine Clinical trials manager, The Jenner Vaccine Institute, University of Oxford

 

Dr. Emma Jones, Dphil, EU-funded Postdoctoral Research Scientist (2005-2006): now Postdoctoral Research Staff, Cardiff University, Wales

 

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. Ivonne Mitar, BSc, DPhil, MRC-funded Research Assistant and Dphil student (2002-2007): now Staff member, Health Interactions, Scientific Consultancy, UK

 

Dr. Daniela Romer, BSc, MSc, DPhil, EU-funded DPhil student (2003-2007): now Medical Department of Sanofi-Aventis Germany

 

Ms. Cynthia Robson, BSc, Laboratory Manager and Graduate Research Assistant (2005-2007): now Funding Administrator, Auckland University

 

Dr. Clare Jolly, PhD, Wellcome Trust then MRC-funded Postdoctoral Research Scientist (2000-2008): now MRC Career Development Award Fellow, UCL London UK

 

Dr. Sinead Brady, PhD, IAVI-funded Postdoctoral Research Scientist (2007-2009): now

 

Dr. Giulia Zanetti, Wellcome Trust funded DPhil (2006-2009): now Postdoctoral Scientist, University of Berkley, USA

 

Dr. Stefanie Michor, Bill and Melinda Gates Foundation funded DPhil (2005-2009): now

 

Dr. Nicola Martin BM, DPhil, MRC-funded Dphil student (2006-2009): now clinical school medicine, University of Oxford

 

Dr. Fedde Groot BSc, PhD, amFAR Postdoctoral Research Fellow (2007-2009): now Graduate-entry medicine, University of Oxford

 

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. George Krashias BSc, MSc, Bodossaki Foundation DPhil Student (2006-2009): now Lecturer, University of Nicosia, Cyprus

 

Selected recent publications (from a total of 140)

 

  1. Kong L, Sheppard NC, Stewart-Jones GB, Robson CL, Chen H, Xu X, Krashias G, Bonomelli C, Scanlan CN, Kwong PD, Jeffs SA, Jones IM and Sattentau QJ (2010). Expression system-dependent modulation of HIV-1 envelope glycoprotein antigenicity and immunogenicity. J. Mol. Biol. 403: 131-147.
  2. Krashias G, Simon AK, Wegmann F, Kok WL, Ho LP, Stevens D, Skehel J, Heeney JL, Moghaddam AE and Sattentau QJ (2010). Potent adaptive immune responses induced against HIV-1 gp140 and influenza virus HA by a polyanionic carbomer. Vaccine 28: 2482-9.
  3. Martin N, Welsch S, Jolly C, Briggs JA, Vaux D and Sattentau QJ (2010). Virological synapse-mediated spread of human immunodeficiency virus type 1 between T cells is sensitive to entry inhibition. J. Virol.  84: 3516-27.
  4. Martin M and Sattentau QJ (2009). Cell-to-cell HIV-1 spread and its implications for immune evasion. Curr. Opinion in HIV and AIDS 4: 143-149.
  5. Romer D, Brighty DW, Robson CL, Sattentau QJ (2009). Candidate polyanionic microbicides inhibit human T cell lymphotropic virus type-1 receptor interactions, cell-free infection and cell-cell spread. Antimicrob. Agents Chemother. 53:678-687.
  6. Sattentau QJ (2008). Avoiding the void: animal virus cell-to-cell spread. Nature Reviews Microbiology 6: 815-826.
  7. Groot F, Welsch S and Sattentau QJ. (2008). Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses. Blood 111: 4660-4663.
  8. Sattentau QJ (2008). HIVÕs gut feeling. Nature Immunology 9: 225-227.
  9. Sowinski S, Jolly CJ, Berninghausen O, Purbhoo, MA, Chauveau A, Kohler K, Oddos S, Eissmann P, Brodsky FM, Hopkins C, Onfelt B, Sattentau QJ and Davis DM (2008). Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nature Cell Biology 10: 211-219.
  10. Sattentau QJ (2008) Correlates of antibody-mediated protection against HIV infection. Curr. Opinion in HIV and AIDS 3: 211-219.

11.  Montefiori D, Sattentau QJ, Flores J, Esparza J, Mascola J, Working group convened by the Global HIV vaccine Enterprise (2008). Antibody-based HIV-1 vaccines: recent developments and future directions. Plos Medicine 4: e348.

  1. Jolly C and Sattentau QJ (2007). Regulated secretion from CD4+ T cells. Trends in Immunology 28: 474-481.
  2. Jolly C and Sattentau QJ (2007). Adhesion molecule interactions facilitate human immunodeficiency virus type-1-induced virological synapse formation between T cells. J. Virol. 81: 13916-13921.
  3. Jolly C and Sattentau QJ. HIV-1 assembly, budding and cell-cell spread in T cells takes place in tetraspanin-enriched plasma membrane. J. Virol. 81: 7873-7884.
  4. Gantlett K, Weber JN and Sattentau QJ (2007). Synergistic inhibiton of HIV-1 infection by combinations of soluble polyanions with other potential microbicides. Antiviral Research, 75: 188-197.
  5. Jolly C, Mitar I and Sattentau QJ (2007). Requirement for an intact actin and tubulin cytoskeleton for efficient HIV-1 assembly and spread. J. Virol. 81: 5547-5560.
  6. Sheppard NC, Bates AC and Sattentau QJ (2007). A functional human IgM response to HIV-1 Env after immunization with NYVAC-HIV C. AIDS 21: 524-527.
  7. Zanetti G, Briggs JAG, Grunewald K, Sattentau QJ* and Fuller SD* *Joint corresponding authors. (2006). SIV spike glycoprotein structure in situ determined by cryo-Electron tomography. Plos Pathogens 2:e83
  8. Moghaddam A, Olszewska W, Wang B, Tregoning JS, Helson R, Sattentau QJ* and Openshaw PJM* *Joint senior authors (2006). A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Nature Medicine 12: 905-907.
  9. Zhou, T, Hamer, D, Hendrickson, WA, Sattentau, QJ and Kwong, PD. (2005). Interfacial metal and antibody recognition. PNAS USA 102: 14575.
  10. Jolly C and Sattentau QJ. (2005). Human Immunodeficiency virus type-1 virological synapse formation in T cells requires lipid raft integrity. J. Virol. 79: 12088-12094.
  11. Vives RR, Imberty A, Sattentau QJ and Lortat-Jacob H. (2005). Heparan sulfate targets the HIV-1 envelope glycoprotein gp120 coreceptor binding site. J. Biol. Chem. 280:21353-7.

23. Mitchison NA, Sattentau QJ. (2005). Fundamental Immunology and What it Can Teach us About HIV Vaccine Development. Curr Drug Targets Infect Disord. 5:87-93.

24. Sheppard N, Sattentau QJ. (2005). The prospects for vaccines against HIV-1: more than a field of long-term non-progression? Expert Rev Mol Med. 7:1-21.

25. Jolly, C and Sattentau, QJ. (2004). Retroviral Spread by Induction of Virological Synapses. Traffic 5: 643—650.

26. Piguet, V and Sattentau, QJ. (2004). Dangerous Liasons at the Virological Synapse. J. Clin. Invest. 114: 2-8.

  1. Jolly C, Kashefi K, Hollinshead M and Sattentau QJ. (2004) HIV-1 cell-to-cell transfer across an Env-induced, actin-dependent synapse. J. Exp Med. 199: 283-193.
  2. Pinon JD, Klasse P-J, Jassal SR, Welson S, Weber JN, Brighty DW, and Sattentau, QJ (2003). Human T cell leukemia virus type-1 envelope glycoprotein gp46 interacts with cell surface heparan sulfate proteoglycans. J. Virol. 2003 77: 9922-9930.