Design of a HIV vaccine to stimulate protective HLA-E-restricted T cell responses

Project Overview

There is still an urgent global need for a prophylactic HIV vaccine. Although efforts to develop a vaccine for the last 30 years have proved unsuccessful, recent advances now make this goal an achievable prospect. It has been shown, by our American collaborator Louis Picker, that a recombinant cytomegalovirus (CMV) vaccine can enable more than 50% of vaccinated monkeys to eradicate Simian Immunodeficiency Virus (SIV) infection early after challenge (1). This is unprecedented and, if it could be translated into humans, would give an effective vaccine against HIV. A key feature of the CMV vaccine is that it stimulates unusual CD8 T cell responses that are responsible for the clearance of SIV. These T cells are restricted by the monkey equivalents of HLA-E and HLA-Class II (2), and recent evidence suggests that the HLA-E-restricted T cells may be particularly important. Our laboratory made critical discoveries on the function of HLA-E nearly 20 years ago (3), findings that are now highly relevant to our HIV vaccine work. We have recently shown how HLA-E binds to virus peptides (4). However how HLA-E-peptide complexes are generated within the cell, traffic to the cell surface and stimulate T cell responses is not known.  In addition, the level and dynamics of expression of HLA-E-peptide and HLA-Ia-peptide complexes on human CD4 T cells infected with transmitted-founder strains of HIV needs to be determined. In this project, a combination of molecular and cellular approaches will be employed to address these questions. Newly developed methodologies including the RUSH technique (5) will be employed to synchronize the exit of labeled HLA-E molecules from the endoplasmic reticulum enabling imaging of its intracellular trafficking.  In addition, T cell clones specific for HLA-E and HIV peptides (or T cell lines transduced to express T cell receptors that recognise HLA-E complexed with HIV peptides) will be generated to provide a sensitive method of detecting as few as 10 HIV-peptide-HLA-E complexes on the surface of each infected cell. Together these techniques will enable us to determine where and how peptides bind to the HLA-E molecules and reach the cell surface. This information will be central to the design of vaccines that can stimulate this type of immune response. 

References

(1) Hansen, S.G., et al. 2013. Immune clearance of highly pathogenic SIV infection. Nature 502:100-104.

(2) Hansen, S.G., et al. 2016. Broadly targeted CD8(+) T cell responses restricted by major histocompatibility complex E. Science 351:714-720.

(3) Braud, V.M. et al. 1998. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795-799.

(4) Walters LC et al. 2018. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nature Communications 9:3137.

[5]  Boncompain, G., S. et al. 2012. Synchronization of secretory protein traffic in populations of cells. Nature methods 9:493-498.

 

Training Opportunities

The student will work with a small group developing HIV vaccines led by the supervisors and funded by MRC, NIH and the Gates Foundation, and will interact with other students and post-docs working on related projects. He/she will receive training in a breadth of cellular, molecular, immunological and virological techniques. More generic research training, e.g. in experimental design, data interpretation, statistical analysis and presentation and writing skills will also be provided.

The student will take part in group meetings and journal clubs and will be encouraged to attend seminars given by internal and external speakers. They will also have the opportunity to attend and present their data and national and international meetings.

Theme

Immunology & Infectious Disease

Admissions

Project reference number: 957

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor Persephone Borrow NDM Research Building Oxford University, NDM Research Building GBR persephone.borrow@ndm.ox.ac.uk
Associate Professor Geraldine Gillespie NDM Research Building Oxford University, NDM Research Building GBR geraldine.gillespie@ndm.ox.ac.uk
Professor Sir Andrew J McMichael NDM Research Building Oxford University, NDM Research Building GBR andrew.mcmichael@ndm.ox.ac.uk

There are no publications listed for this DPhil project.