HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11

Abstract

To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with β2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome.

Identification of HCMV-derived T cell epitopes in seropositive individuals through viral deletion models

“…Interestingly, HLA-I down-regulation by AD169VarL wild-type virus varied strongly between fibroblasts. HLA-B*44:02 is expressed at very low levels in mock-treated MRC-5 cells but is strongly induced in HCMV-infected cells (Zimmermann et al, 2019). This indicates that HLA-B*44:02 might be responsible for the apparent lower level of reduction by AD169VarL compared with mock-treated cells.…”

“…We observed strongly induced numbers of HLA-B*44:02 ligands in ΔUS2-6-infected cells, i.e., in the presence of US11 expression. This was indeed surprising, and we have begun to address the molecular mechanisms behind this phenomenon (Zimmermann et al, 2019). Thus, immunoevasins affect not only the efficiency, but also the quality of antigen presentation.…”

Targeting the latent human cytomegalovirus reservoir with virus specific nanobodies

“…This region encodes several proteins that interfere with antigen presentation by, for example, downregulating MHC Class I and II molecules 19,20,21 . Though it should be pointed out, that this HCMV IE2-YFP virus does encode US11 (as shown by RT-qPCR, Figure 3D), which can downregulate some MHC Class I molecules 22,23 . However, to ensure that our observations would also be recapitulated with a virus with a full complement of immune evasins, we repeated the co-culture experiments described above with a HCMV strain containing an intact US2-6 region.…”

Assessing Anti-HCMV Cell Mediated Immune Responses in Transplant Recipients and Healthy Controls Using a Novel Functional Assay

“…What this may reflect is that incoming HCMV proteins are processed and presented for T cell recognition prior to the virus interfering with this process, as has been suggested for Epstein-Barr virus (Forrest et al, 2018 ). It should also be noted that the ability of some HCMV immunoevasins to prevent MHC class I processing and presentation is dependent on the genotype of the host [e.g., US2 cannot bind HLA-B * 07 and * 27 as efficiently as HLA-A genotypes (Gewurz et al, 2001 ; Reddehase, 2002 ); US11 degrades HLA-A but is less effective against HLA-B, with HLA-B * 44:02 particularly resistant (Zimmermann et al, 2019 )]. Thus, the HLA genotype of the donor will contribute to the effectiveness of HCMV evasion of CD8 + T cell control.…”