Project Details
Projekt
Human cytomegalovirus manipulation of HLA class I by US10
Applicant
Dr. Anne Halenius, Ph.D.
Subject Area
Virology
Immunology
Immunology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 398367752
While antigenic peptides presented by HLA class I (HLA-I) on infected cells activate CD8+ T cells, NK cells express both inhibiting and activating receptors for HLA-I. This HLA-I-guided multi-axis system challenges strategies of viral HLA-I inhibition. We observed a pronounced HLA-I geno- and allotype-specific regulation by HCMV-encoded US10. Whereas HLA-A allotypes were resistant to US10, HLA-B/C/E/G molecules were blocked to a variable extent. HLA-B regulation correlated with tapasin dependency, but this was not the case for HLA-C. Instead, US10 uniquely bound to HLA-C and G molecules in their β2m-assembled form, suggesting that US10 has evolved a strategy to specifically target HLA-C and -G. In this project, we will resolve the impact of US10 on CD8+ T cells and NK cells and elucidate the molecular mechanisms by which US10 manipulates HLA-I (with P01, P04 and Z01). We will determine the HLA-C ligandome in the presence and absence of US10 both in HCMV-infected fibroblasts and in BJ5ta fibroblasts stably expressing various HLA-C allotypes. We will investigate the expansion of HCMV-specific HLA-C-restricted CD8+ T cells and their activation potential in the presence of US10. To investigate the significance of US10 on NK-cell KIR receptor recognition of infected cells, we will express soluble KIR receptors and screen for binding. In parallel, the role of US10 in modifying the HLA-E ligandome will be determined.
DFG Programme
Research Units
