Lucy Walters

3rd Year Prize Winner 2018

After my BSc from Imperial College London and MSc from Oxford University in Integrated Immunology, I began my Bill & Melinda Gates Foundation funded DPhil with Associate Professor Geraldine Gillespie and Professor Sir Andrew McMichael (FRS) in collaboration with Professor Louis Picker and Professor E. Yvonne Jones (FRS).

Preposterously, as with many diseases, the prognosis following the acquisition of an HIV infection typically depends on the country in which you happen to be born. However, an effective vaccine would even the playing field.

During my DPhil I have been working on an unconventional Cytomegalovirus-vectored HIV vaccination strategy which elicited unprecedented, sterile immune protection in pre-clinical trials. The extensive repertoire of immune evasion strategies deployed by HIV is thought to have largely accounted for the limited successes of more conventional vaccine approaches trialled over the last few decades.

Remarkably, non-classical MHC-E-restricted CD8+ T cells have been implicated as immune correlates of protection for this unconventional vaccine. I have crystallographically characterised these responses generating six crystal structures of human MHC-E (HLA-E) in complex with various epitopes including the universal, HIV-derived ‘supertope’, RL9HIV (Walters, Lucy C. et al, 2018 Nature Communications). Strikingly, this ‘supertope’ adopts an alternative conformational motif in the HLA-E peptide binding groove resulting in a novel solvent exposure profile with implications for immunogenicity and T cell receptor interaction. This is the first structural evidence that HLA-E can bind and present pathogen-derived peptides to CD8+ T cells as previous structures were crystallised in complex with class I MHC-derived signal peptides. I have also crystallised HLA-E in complex with multiple Mycobacterium tuberculosis epitopes following the identification of non-classical HLA-E-restricted CD8+ T cell responses during active infection.

A second focus of my DPhil has been the development and optimisation of two alternative peptide binding affinity assays to more broadly validate and relatively quantitate Cytomegalovirus-vectored vaccine-identified SIV and HIV-derived epitope binding to HLA-E (Hansen, Scott G. et al, 2016 Science).

Going forward, we have started to investigate the structural basis underlying HIV/SIV-specific MHC-E-restricted CD8+ T cell recognition.

Publications:

• Walters, Lucy C., Karl Harlos, Simon Brackenridge, Daniel Rozbesky, Jordan R. Barrett, Vitul Jain, Thomas S. Walter et al. "Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding." Nature communications 9, no. 1 (2018): 3137. 
• Hansen SG, We HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, Reed JS, Gilbride RM, Ainslie E, Morrow DW, Ford JC, Selseth AN, Pathak R, Malouli D, Legasse AW, Axthelm MK, Nelson JA, Gillespie GM, Walters LC, Brackenridge S, Sharpe HR, Lόpez CA, Frϋh K, Korber BT, McMichael AJ, Gnanakaran S, Sacha JB, Picker LJ.  "Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E." Science 351.6274 (2016): 714-720.