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Podcast 'Aiming for a HIV vaccine'
HLA-E bound to the signal peptide VMAPRTLVL (VL9) (left) and HIV Gag RL9 (right). Crystal structures of each were determined and are overlaid by DAMMI bead models derived from small angle x-ray scatter (SAXS) of the same complexesin solution. The lower affinity peptide RL9 shows a more amorphous low resolution structure in solutions. (Walters et al Cell Reports 2022, in press)
Andrew McMichael
Professor of Molecular Medicine
Classical and Non-Classical T cell responses.
I have studied human T cell immune responses since 1974, with a particular interest in virus specific HLA restricted CD8 T cells. In the 1980s, working with Alain Townsend we found that they recognised peptides bound to HLA molecules. After this early work on influenza, my group worked on HIV-1 for many years studying CD8 T cell responses in early infection and how virus escapes by mutating peptide epitopes, compromising the immune control of the infection. I was involved in vaccine development work and have been a member of the Scientific Leadership Group of the NIAID Center for HIV AIDS Vaccine Development consortium since 2005.
My interest in HLA has included non-classical HLA molecules and their relativesm in particular CD1 and recently the HLA-E. In 1988 Veronique Braud in my group showed that HLA-E bound to a conserved nonamer peptide derived from the signal sequence of classical HLA class I molecules and that this was recognised by the NKG2A/C receptors on natural killer cells, regulating their function. In 2016, we joined a collaboration with Louis Picker and colleagues at OHSU, who had shown that T cells stimulated in rhesus macaques by a cytomegalovirus vectored SIV vaccine are HLA-E restricted. These T cells are able to clear acute SIV infection in approximately 50% of animals after virus challenge. This led us (Geraldine Gillespie, Simon Brackenridge, Lucy Walters, Max Quastel) to explore how HLA-E binds a broad range of peptides, some in an atypical fashion, determining their molecular structures. Using in vitro priming techniques, we (Hongbing Yang, Hong Sun) have been able to demonstrate human CD8 T cells specific for HIV, SARS Coronavirus-2 and self antigenic peptides presented by HLA-E. We are currently working on virus specific and tumour specific HLA-E restricted T cells with an interest in developing immuno-therapies that could be applied universally because of the very limited polymorphism of HLA-E.
Recent publications
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The antibodies 3D12 and 4D12 recognise distinct epitopes and conformations of HLA-E.
Journal article
Brackenridge S. et al, (2024), Frontiers in immunology, 15
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High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation
Journal article
Huisman BD. et al, (2023), Nature Communications, 14
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Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides.
Journal article
Yang X. et al, (2022), Nature
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Immune signature atlas of vaccines: learning from the good responders.
Journal article
Pedroza-Pacheco I. and McMichael AJ., (2022), Nature immunology
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Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies
Journal article
BORROW P. and McMichael AJ., (2022), Nature Reviews Immunology