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.
*
Retrovirus-receptor interactions: the virological
synapse
Rebecca Russell, Catherine Sargent
and Amy Baxter
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 replication and dissemination and resistance to elements of
the humoral immune response. We have established
systems based on imaging techniques (confocal and
electron microscopy), fluorescence-tagging technology (eg.
green fluorescent protein) and molecular biology and biochemical techniques, to
investigate cell-cell spread of HIV-1. Upon contact with receptor-bearing
cells, HIV-1-infected T cells induce the formation of a Òvirological
synapseÓ (VS) in which viral receptors and adhesion molecules rapidly co-cluster
with viral envelope glycoproteins. 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 characterising the molecular associations underlying the formation of
the VS in T cells and its role in viral spread and pathogenesis. Recently we
demonstrated that HIV-infected macrophages are equally able to form VS with T
cells and transmit virus, and infected T cells can transmit virus to
macrophages. We are investigating the function of the VS in transfer of virus
by endocytic compared to plasma membrane fusion
routes, the role of inhibitors in preventing VS assembly and function, and the
role of apoptosis in HIV-1-infected T cell uptake by macrophages.
Funding: amFAR
Collaborations: Sonja Welsch, Heidelberg,
Germany; Kay Grunewald, STRUBI, Oxford
HIV neutralising antibody vaccine studies
Frank Wegmann, Rebecca Russell, Amin Moghaddam, George Krashias, Sarah Brinckmann, and Karoliina Laamanen
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 epitopes by a strategy of Ôimmune
silencingÕ of irrelevant epitopes that has been
developed by our group. We are working to overcome the conformational
flexibility intrinsic to HIV-1 Env by using chemical
cross-linking. Moreover, we are attempting to improve the immunogenicity of Env by harnessing elements of the innate immune response.
We have discovered two new types of adjuvant, one which
is Th-1 biasing agent, the other a Th-2-biasing agent. Both have been patented.
Promising results in preclinical immunogenicity studies will be followed by
incorporation of the novel antigens and adjuvants
into phase-1 clinical trials.
Funding: The Bill and Melinda Gates Foundation
Collaborations: Simon Jeffs, Imperial College
London, Jon Heeney, University
of Cambridge
Patent filed:
PCT/GB2007/000979 - Novel adjuvant
Patent filed: GB0805356.3 – vaccine adjuvant composition
Structure/function studies on the HIV envelope glycoproteins
Our extensive collaboration with
Stephen Fuller at the Wellcome Trust Structural
Biology Centre has allowed us to investigate the structure of the SIV spike in
situ on the virion particle. This has revealed
information relating to Env structure and function,
with particular relevance to antibody immune evasion by HIV-1. Future studies
are aimed at elucidating the HIV-1 spike structure, either in its unligated form, or engaged by ligands
such as neutralising antibodies and receptor mimics.
Funding: The International AIDS Vaccine Initiative (IAVI)
Collaborations: Kay Grunewald, STRUBI, Oxford
The Bill and Melinda Gates Grand Challenge Project
Frank Wegmann and George Krashias
In the context of the Grand
Challenges in Global Health, established by the Bill and Melinda Gates
Foundation, we and several other institutions were awarded a consortium grant
to develop a mucosal immunisation system in which vaginal microbicides
will be combined with HIV-1 Env antigen for vaginal
immunisation. The microbicide-antigen formulation
would be expected to induce local mucosal immunity in the form of neutralising IgA antibodies, that would add to
the barrier against incoming virus. If successful, this strategy would be the
first self-applied, mucosally-active vaccine. We have established in vivo models of
vaginal immunisation, and have demonstrated successful induction of Env-specific mucosal IgA and IgG in the presence of vaginal microbicide.
These preclinical studies are informing associated clinical trials that started
earlier this year.
Funding: The Bill and Melinda Gates Grand Challenge Award
Reactive carbonyls in allergy and autoimmunity
Amin Moghaddam, Kate Gartlan, Louise Pilsbury and
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
Ms. Sarah Brinckmann
BSc: Europrise (EU)-Funded DPhil Student
Dr. Kate Gartlan
BSc, PhD: EPA-funded Postdoctoral Research Scientist
Mr. William Hillson, BSc, EPA-funded DPhil probationer
Mr Leo Kong BSc: NIH-funded DPhil Student
Mr. George Krashias
BSc, MSc: Bodossaki Foundation DPhil Student
Ms. Karoliina
Laamanen BSc: Bill and
Melinda Gates Foundation-funded Graduate Research Assistant
Dr. Amin
Moghaddam MD, MSc: Bill and Melinda Gates-funded
Postdoctoral Research Scientist
Ms. Louise Pilsbury
BSc, MSc: Industrially-funded DPhil student
Dr. Rebecca Russell BSc, PhD:
IAVI-funded Postdoctoral Research Scientist
Dr. Catherine Sargent MD: MRC-funded DPhil Student
Dr. Quentin Sattentau, BSc, PhD: Laboratory PI
Dr. Frank Wegmann,
BSc, PhD: Gates Foundation Grand Challenge Postdoctoral Scientist
Co-supervised staff and students
Mr. Mark Hassall, PhD student,
(with Prof. Neil Almond, National Institute for Biological Standards and
Controls, and the Open University)
Previous members of the Oxford laboratory
Dr. Katherine Gantlett (nŽe Fowler), Wellcome
Trust Infection and Immunity Dphil (2002-2005): Vaccine
Clinical trials manager, The Jenner Institute, University of Oxford, UK.
Dr. Emma Jones, Dphil, EU-funded Postdoctoral Research Scientist
(2005-2006): Postdoctoral Research Staff, Cardiff University, Wales.
Dr. Neil Sheppard, BSc, MRC-funded
DPhil student (2003-2006), Gates Foundation-funded Postdoctoral Scientist
(2006-2007): Scientist, Vaccine Discovery Group, Pfizer UK.
Dr. Samer
Sourial, BSc, PhD, Postdoctoral
Research Scientist (2007-2008): Graduate-entry Medical Student,
Liverpool UK.
Dr. Ivonne
Mitar, BSc, DPhil, MRC-funded research assistant and Dphil student (2002-2007): Staff member, Health
Interactions, Scientific Consultancy, UK.
Dr. Daniela Romer, BSc, MSc, DPhil, EU-funded DPhil
student (2003-2007): Medical Department of Sanofi-Aventis
Germany.
Ms. Cynthia Robson, BSc,
Laboratory Manager and Graduate Research Assistant (2005-2007): Funding
Administrator, Auckland University.
Dr. Clare Jolly, PhD, Wellcome Trust then MRC-funded Postdoctoral Research
Scientist (2000-2008): MRC-Career Development Award Fellow, UCL London UK.
Dr. Sinead Brady, PhD,
IAVI-funded Postdoctoral Research Scientist (2007-2009):
Dr. Giulia Zanetti,
Wellcome Trust funded DPhil (2006-2009): Postdoctoral
Scientist, University of Berkley, USA.
Dr. Stefanie Michor, Bill and Melinda Gates Foundation funded DPhil
(2005-2009):
Dr. Nicola Martin BM, DPhil, MRC-funded
Dphil student (2006-2009), 2BM medical student.
Selected recent publications (from a total of 136)
8. 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.
20. 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.
21. 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.
22. Jolly, C and
Sattentau, QJ. (2004). Retroviral Spread by Induction of Virological
Synapses. Traffic 5:
643—650.
23. Piguet, V and
Sattentau, QJ. (2004). Dangerous Liasons at the Virological Synapse. J. Clin. Invest.
114: 2-8.
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Departmental
2006/7: FHS
ÒInfection and ImmunityÓ option course co-organiser
2004-2007: FHS
examiner in medical and physiological sciences
Organiser of FHS
theme ÒHIV and AIDSÓ, lectures and tutorials to FHS in Medical Sciences [link to lectures]
Lecturer in
Medical Sciences to 1st BM part-II on ÒHIV and AIDSÓ [link to lecture]
Practical class to
1st BM part-II ÒLymphocyte phenotyping and
Flow CytometryÓ [link to course]
Lecturer on ÒHIV virologyÓ
in the Biochemistry Department, Oxford University [link to lecture]
Lecturer on HIV
virology for the MSc taught course on Immunology, NDM, Oxford
University [link to
lecture]
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College
Tutorial Fellow in
Molecular Microbiology and Infection and Immunity at Magdalen
College Oxford (sabbatical leave MT 2009 – HT 2011)
Organising Medical
Tutor in Medical and Physiological Sciences at Magdalen
College, Oxford