|This structural image illustrates how a commonly selected T cell receptor recognised an ususually long peptide presented by B*57 subtypes associated with slower progression to AIDS.|
|Section A of this figure illustrates that the -237TNFa promoter polymorphism which is inherited on a B*57 genetic background, can alter the ability of the promoter to produce TNFa mRNA. Part B demonstrates that the B*57-linked polymorphism arises in promoter regions containing CpG islands, which are prone to methylation in peripheral blood cells, with potential implication for epigenetic control of TNFa.|
|These FACS profiles demonstrate that even the smallest differences between MHC class I B*57 subtypes, where the peptides are presented in identical formats, can alter their ability to prime certain CD8+ T cells but not others (*).|
Associate Professor, Principal Investigator, Group Head / PI, Member of congregation and Supervisor
To produce an effective HIV-1 vaccine it is vital that we understand both the host and viral factors influencing the success of the immune response. In terms of host factors we know that CD8+ T cells play a critical role in the control of HIV-1 replication, and this is best illustrated by the strong association of a small number of MHC class I molecules with slower progression to AIDS. As MHC class I molecules select the repertoire of viral epitopes presented to CD8+ T cell, they shape the immune response against HIV. We are interested in the Caucasian MHC class I molecules, HLA B*5701 and the African counterpart, HLA-B*5703, which consistently associate with prolonged AIDS-free survival. Both B*57 subtypes present a broad spectrum of HIV-1 epitopes derived from the gag protein, a highly conserved HIV proteins whose specific targeting is thought to favourably contribute to sustained viral control. However, it is not entirely clear why a variety of MHC class I molecules that also present conserved epitopes do not effectively control HIV-1. The particular aims of our work is to understand how HIV-infected HLA-B*57+patients achieve longterm control of HIV-1, and whether this relates to the antigen presentation and/or the nature of responding CD8+ T cell repertoire. We are specifically interested in diverse aspects of CD8+ T cell recognition, particularly structural and biophysical aspects of the B*57-TCR interaction, but also in terms of the nature of T cell priming, the importance of naive precursor frequencies and the efficacy of B*57-restricted T cells. In terms of antigen presentation we are interested in molecular features, particularly in relation to the biochemical features of antigen acquisition and processing, the dependence of different antigens on the various components of the antigen presentation machinery and antigen presenting cell types, and the kinetics/patterns of epitope recognition during early infection. Finally, we are also interested in genetic polymorphisms inherited on the B*57 background, particularly those which are present in immune response genes, including the TNFa promoter and Heat Shock Protein 70 family, to understand if these contribute to B*57-mediated control of HIV.
Primary and secondary functions of HLA-E are determined by stability and conformation of the peptide-bound complexes.
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Mouse and human antibodies bind HLA-E-leader peptide complexes and enhance NK cell cytotoxicity.
Li D. et al, (2022), Commun Biol, 5
Discovery of HLA-E-Presented Epitopes: MHC-E/Peptide Binding and T-Cell Recognition.
Ruibal P. et al, (2022), Methods in molecular biology (Clifton, N.J.), 2574, 15 - 30
Incoming HIV virion-derived Gag Spacer Peptide 2 (p1) is a target of effective CD8+ T cell antiviral responses.
Yang H. et al, (2021), Cell reports, 35
HLA-E–restricted, Gag-specific CD8
T cells can suppress HIV-1 infection, offering vaccine opportunities
Yang H. et al, (2021), Science Immunology, 6