Antigen processing of HIV for presentation by HLA-E

Project Overview

Recently it has been shown that a recombinant cytomegalovirus (CMV) vaccine can enable more than 50% of vaccinated monkeys to eradicate simian immunodeficiency virus (SIV) early after infection (1). This is unprecedented and, if it could be translated into humans, could give an effective vaccine against HIV. An important 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 MHC-E-restricted T cells may be particularly important. Our laboratory made critical discoveries on the function of HLA-E nearly 20 years ago (3) and has now connected this to our HIV vaccine work. The main aim of this project will be to examine how HLA-E binds virus peptides, traffics them to the cell surface and primes T cell responses. 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 will be compared. We will use two tools for this work. The first is to apply newly developed methodologies including the RUSH technique (4) which will synchronize exit of labelled HLA-E molecules from the endoplasmic reticulum enabling us to image intracellular trafficking. The second will be the use of T cell clones specific for HLA-E and HIV peptides that will give us a very sensitive method of detecting particular peptide-HLA-E complexes that are presented on the cell surface. The information gained will be valuable in designing vaccines that can stimulate this type of immune response.

(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) 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
Dr 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.