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 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)

 

 

 

*      Research Interests

 

*      Group members

 

*      Recent publications

 

Research interests

 

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 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; 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 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 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

á      The James Martin 21st Century School Vaccine Institute

á      Jenner Vaccine Institute

á      Dormeur Investment Service Ltd.

 

Group members

 

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 (nŽe 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

 

Selected recent publications (from a total of 160)

 

  1. Wegmann F, Gartlan KH, Harandi AM, Brinckmann SA, Coccia M, Hillson WR, Kok WL, Cole S, Ho LP, Lambe T, Puthia M, Svanborg C, Scherer EM, Krashias G, Williams A, Blattman JN, Greenberg PD, Flavell RA, Moghaddam AE, Sheppard NC and Sattentau QJ (2012). Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. Nature Biotechnol. 2012 Aug 26.
  2. Sattentau QJ (2011). Vaccinology: A sweet cleft in HIV's armour. Nature. 480(7377): 324-5.
  3. Jolly C, Welsch S, Michor S and Sattentau QJ (2011). The regulated secretory pathway in CD4(+) T cells contributes to human immunodeficiency virus type-1 cell-to-cell spread at the virological synapse. PLoS Pathog. 7(9): e1002226.

4.     Moghaddam AE, Gartlan KH, Kong L and Sattentau QJ (2011).  Reactive carbonyls are a major Th2-inducing damage-associated molecular pattern generated by oxidative stress. J Immunol. 187:1626-33.

5.     Welsch S, Groot F, KrŠusslich HG, Keppler OT and Sattentau QJ (2011). Architecture and regulation of the HIV-1 assembly and holding compartment in macrophages. J Virol. 85: 7922-7.

6.     Wegmann F, Krashias G, LŸhn K, Laamanen K, Vieira S, Jeffs SA, Shattock RJ and Sattentau QJ (2011). A novel strategy for inducing enhanced mucosal HIV-1 antibody responses in an anti-inflammatory environment. PLoS One. 6: e15861.

  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. Sattentau QJ (2008). Avoiding the void: animal virus cell-to-cell spread. Nature Reviews Microbiology 6: 815-826.
  5. 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.
  6. Sattentau QJ (2008). HIVÕs gut feeling. Nature Immunology 9: 225-227.
  7. 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.
  8. Sattentau QJ (2008) Correlates of antibody-mediated protection against HIV infection. Curr. Opinion in HIV and AIDS 3: 211-219.
  9. Jolly C and Sattentau QJ (2007). Regulated secretion from CD4+ T cells. Trends in Immunology 28: 474-481.
  10. 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.
  11. Jolly C and Sattentau QJ (2007). HIV-1 assembly, budding and cell-cell spread in T cells takes place in tetraspanin-enriched plasma membrane. J. Virol. 81: 7873-7884.
  12. 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.
  13. Zanetti G, Briggs JAG, Grunewald K, Sattentau QJ and Fuller SD (2006). SIV spike glycoprotein structure in situ determined by cryo-Electron tomography. Plos Pathogens 2:e83
  14. 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.
  15. Zhou T Hamer D Hendrickson WA Sattentau QJ and Kwong PD (2005). Interfacial metal and antibody recognition. PNAS USA 102: 14575-14582.
  16. 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.

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.

  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.