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Principal areas of research
T cell Immune responses to HIV and Influenza
Biography
Andrew McMichael qualified in Medicine in 1968 and obtained a PhD in Immunology at NIMR supervised by Ita Askonas and Alan Williamson in 1974. He first showed that virus specific CD8 T cells were HLA restricted and, later, Alain Townsend in his group demonstrated that virus derived peptides were presented to T cells by MHC class I molecules. Since 1987 he has studied the T cell response to HIV, with a particular interest in virus escape from T cell recognition. For the last five years he has focussed on HIV vaccines. His group have designed and tested two candidate HIV vaccines in phase I clinical trials. His group has also been involved in developing novel methods for measuring T cell responses, such as HLA tetramer staining.
He is Director of the Weatherall Institute of Molecular Medicine in Oxford University and is Honorary Director of the Medical Research Council Human Immunology Unit.
Research
His laboratory has 4 projects.
1. Molecular understanding of HIV infection (Alison Simmons, Astrid Iversen)
Analysing early molecular events in HIV infection. Alison Simmons has shown that HIV attachment to DC SIGN on dendritic cells initiates an intracellular signalling pathway that favours infection by the virus. She has also shown how the virus protein nef can activate infected cells, enhancing virus replication. Astrid Iversen is working on how the HIV protein vif contributes to virus variability, how virus escapes T cell immune responses and why the HIV C subtype is more aggressive and is spreading faster than other HIV subtypes.
2. Analysis of cellular immune responses in acute HIV infection (CHAVI programme, Nilu Goonetillkeke)
Nilu Goonetilleke and the CHAVI team are studying the T cell immune response to HIV in 60 patients with acute HIV infection. We are using peptides matched to autologous virus sequence to examine T cell responses from the time of earliest detection of virus in blood. We are examining the evolution of the T cell immune response in the context of all other immune responses and changes in the virus. We are also examining people who are exposed to HIV but not infected, looking for resistance factors. These projects are part of the NIH Center for HIV Vaccine Immunology (CHAVI).
3. Use of vaccination to control ongoing HIV infection (Lucy Dorrell and Tomas Hanke)
Tomas Hanke has made a series of HIV vaccines (see his linked website) that we have been tested in phase 1 clinical trials in HIV negative volunteers. The DNA-MVA vaccine combination stimulated detectable T cell responses in all recipients. We are now testing whether we can use the same vaccines to enhance T cell immunity in HIV infected patients on anti-HIV drugs with a view to withdrawing drug treatment.
4. The role of T cell immunity in influenza virus infection (collaboration with Xiaoning Xu and Tao Dong)
Given the threat of a new influenza virus pandemic, we are working with the MRC Flu-watch programme, monitoring influenza virus infection in 1000 healthy volunteers recruited through a network of general practices. So far 600 have been followed through the 2006/7 winter and their anti-influenza virus T cell responses and antibody responses measured before and after the flu season. The study is designed to determine whether pre-existing T cell immunity protects against natural influenza virus infection. (See also Xiaoning Xu and Tao Dong sites). We are also exploring the role of innate immunity in protection against early influenza virus infection (Ling Pei Ho) and the nature of the dominant T cell receptor that binds to the conserved influenza matrix peptide in the HLA-A2 molecule (Guillaume Stewart-Jones).
Key publications
Hodges A, Sharrocks K, Edelmann M, Baban D, Moris A, Schwartz O,
Drakesmith H, Davies K, Kessler B, McMichael A, Simmons A. 2007. Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication. Nat Immunol 8: 569-77
Iversen AK, Stewart-Jones G, Learn GH, Christie N, Sylvester-Hviid C, Armitage AE, Kaul R, Beattie T, Lee JK, Li Y, Chotiyarnwong P, Dong T, Xu X, Luscher MA, MacDonald K, Ullum H, Klarlund-Pedersen B, Skinhoj P, Fugger L, Buus S, Mullins JI, Jones EY, van der Merwe PA, McMichael AJ. 2006. Conflicting selective forces affect T cell receptor contacts in an immunodominant human immunodeficiency virus epitope. Nat Immunol 7: 179-89
Goonetilleke N, Moore S, Dally L, Winstone N, Cebere I, Mahmoud A, Pinheiro S, Gillespie G, Brown D, Loach V, Roberts J, Guimaraes-Walker A, Hayes P, Loughran K, Smith C, De Bont J, Verlinde C, Vooijs D, Schmidt C, Boaz M, Gilmour J, Fast P, Dorrell L, Hanke T, McMichael AJ. 2006. Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes. J Virol 80: 4717-28
Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P, Goonetilleke N, Rostron T, Rowland-Jones S, Hanke T, McMichael A. 2006. Expansion and diversification of virus-specific T cells following immunization of human immunodeficiency virus type 1 (HIV-1)-infected individuals with a recombinant modified vaccinia virus Ankara/HIV-1 Gag vaccine. J Virol 80: 4705-16
McMichael AJ. 2006. HIV vaccines. Annu Rev Immunol 24: 227-55
Stewart-Jones GB, McMichael AJ, Bell JI, Stuart DI, Jones EY. 2003. A structural basis for immunodominant human T cell receptor recognition. Nat Immunol 4: 657-63
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