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Human cytomegalovirus manipulation of HLA class I antigen representation

Upon infection, cytomegaloviruses, which belong to the family of Betaherpesviridae, persist for a lifetime with phases of latency, reactivation, and viral dissemination. Because of their exceptional coding capacity and coevolution with their hosts throughout mammalian history, cytomegaloviruses have developed a multitude of sophisticated strategies to counteract the host immune response.

For immunocompromised individuals human cytomegalovirus (HCMV)-related complications are a major cause of morbidity and mortality. In immunocompetent hosts, the regular subclinical course of HCMV infection nevertheless deeply impacts immune cell subsets, resulting in prolonged expansion of virus-specific CD8+ memory T cells and so-called adaptive natural killer (NK) cells with unique functional profiles. For both responses polymorphic HLA class I molecules play a central role as expansion of memory CD8+ T cells is driven by antigenic viral peptides presented by HLA class I molecules and NK cells bear inhibitory receptors that engage with HLA class I. We investigate how HCMV copes with this dual HLA class I function and orchestrates recognition by CD8+ T cells and NK cells throughout the protracted HCMV replication cycle.

By studying cytomegalovirus immune manipulation we also wish to deepen our understanding of the molecular mechanisms of the host immune system. In addition, such investigations may provide intriguing views into the evolutionary arms race between viruses and the immune system.

We found that the HCMV encoded glycoproteins US10 and US11 regulate HLA class I in a highly geno- and allotype-specific manner. On the basis of this we hypothesize that HCMV has evolved tailored strategies for distinct HLA class I features and functions in order to conduct inhibition of critical immune cell recognition.

Currently we are focusing on the following projects:

  1. Mechanistic analysis of HCMV and HLA-A co-evolution
  2. Genotype-dependent manipulation of HLA class I by HCMV encoded US10
  3. Identification and regulation of naturally presented CD8+ T-cell epitopes in HCMV infection

Our research is funded by the DFG FOR 2830 "Advanced Concepts in Cellular Immune Control of Cytomegalovirus"

 

Selected References:

  1. Gerke C, Bauersfeld L, Oberhardt V, Jürges C, Spaapen RM, Mussolino C, Le-Trilling VTK,  Trilling M, Dölken L,  Erhard F, Hofmann M,  Hengel H, Momburg F,  Halenius A. 2023. Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning. BioRxiv (Link)

  2. Lübke M, Spalt S, Kowalewski DJ, Zimmermann C, Bauersfeld L, Nelde A, Bichmann L, Marcu A, Peper JK, Kohlbacher O, Walz JS, Le-Trilling VTK, Hengel H, Rammensee HG, Stevanović S, Halenius A. 2020. Identification of HCMV-derived T cell epitopes in seropositive individuals through viral deletion models. Journal of Experimental Medicine. 217(3):jem.20191164 (Link)

  3. Zimmermann C, Kowalewski D, Bauersfeld L, Hildenbrand A, Gerke C, Schwarzmüller M, Le-Trilling VTK, Stevanovic S, Hengel H, Momburg F, Halenius A. 2019. HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11. PLoS Pathogens 15(9):e1008040 (Link)

Institute of Virology

Hermann-Herder-Strasse 11
D-79104 Freiburg

Head

Prof. Dr. med. Hartmut Hengel
hartmut.hengel@uniklinik-freiburg.de