Professor of Molecular Medicine
Our HIV vaccines have completed five small phase I clinical trials and one large phase I/II clinical trials in London and Oxford. The vaccine is DNA encoding HIV clade A gag p24 and p17 plus a string of epitopes, and the same inserted into recombinant Modified Vaccinia Virus Ankara (MVA). Both stimulate strong CD8+ T cell responses in mice and macaques. In humans both have stimulated measurable CD8+ T cell responses in HIV low risk, uninfected volunteers. Current work is focussing on improving immunogenicity and working out assays for measuring immune responses that are likely to be protective against HIV infection. We tested the effect of those vaccines on boosting T cell responses in HIV infected patients who are on anti-retroviral drugs, with the aim of interrupting drug treatment when the T cell response is enhanced. Encouraging boosts are seen using the MVA-HIVA vaccine.
Nef (key virus protein in virus pathogenesis) initiates a programme of transcription closely similar to that triggered by T cell receptor activation. This favours HIV virus replication. Nef also alters the composition of proteins in cell signalling site, and exclusion of certain regulators favours the activation state.
We continue to explore selection of HIV-1 mutants by the immune response. T cells are very sensitive to small changes in the composition, orientation or flexibility of the exposed peptide bound to HLA. We are studying the immunodominant SLYNTVATL epitope presented by HLA-A2, showing selection of a sequence of mutations that impair T cell recognition. Why the T cells do not respond by new primary responses to the variants is also under investigation.
HLA-E–restricted, Gag-specific CD8
T cells can suppress HIV-1 infection, offering vaccine opportunities
Yang H. et al, (2021), Science Immunology, 6
CD4+ T Follicular Helper Cells in Human Tonsils and Blood Are Clonally Convergent but Divergent from Non-Tfh CD4+ Cells.
Brenna E. et al, (2020), Cell reports, 30, 137 - 152.e5
Capturing the antigen landscape: HLA-E, CD1 and MR1.
Ogg G. et al, (2019), Current opinion in immunology, 59, 121 - 129
Topological perspective on HIV escape.
McMichael AJ. and Carrington M., (2019), Science, 364, 438 - 439
Author Correction: Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding
Walters LC. et al, (2018), Nature Communications, 9