The HHV-6A Proteins U20 and U21 Target NKG2D Ligands to Escape Immune Recognition.

Abigael Eva Chaouat,Barbara Seliger,Dominik Schmiedel,Ofer Mandelboim

doi:10.3389/fimmu.2021.714799

Abstract

The coevolution of the human immune system and herpesviruses led to the emergence and diversification of both cellular danger molecules recognized by immune cells on the one hand and viral countermeasures that prevent the expression of these proteins on infected cells on the other. There are eight ligands for the activating receptor NKG2D in humans – MICA, MICB, ULBP1-6. Several of them are induced and surface-expressed on herpesvirus-infected cells to serve as danger signals to activate the immune system. Therefore, these ligands are frequently targeted for suppression by viral immune evasion mechanisms. Mechanisms to downregulate NKG2D ligands and thereby escape immune recognition have been identified in all other human herpesviruses (HHV), except for HHV-6A. In this study, we identify two HHV-6A encoded immunoevasins, U20 and U21, which suppress the expression of the NKG2D ligands ULBP1 and ULBP3, respectively, during infection. Additionally, MICB is targeted by a so far unexplored viral protein. Due to the diminished NKG2D ligand surface expression on infected cells, recognition of HHV-6A infected cells by innate immune cells is impaired. Importantly, our study indicates that immune escape mechanisms between the related herpesviruses HHV-6A and HHV-6B are evolutionary conserved as the same NKG2D ligands are targeted. Our data contribute an additional piece of evidence for the importance of the NKG2D receptor – NKG2D ligand axis during human herpesvirus infections and sheds light on immune evasion mechanisms of HHV-6A.

Highlights

The Roseola family of human herpes viruses (HHV) belongs to the b-herpesviruses and consists of three members: human herpesviruses (HHV)-6A, HHV-6B and HHV-7 [1]
To test whether HHV-6A infection leads to changes in the NKG2D ligand expression during the lytic phase of the viral life cycle, we infected two susceptible cell lines, HSB-2 and JJhan, with the HHV-6A strain GS. 72 hours post infection, we stained the cells for the NKG2D ligands MICA, MICB, ULBP1, ULBP2 and ULBP3
Since ULBP3 is not expressed on HSB-2 cells, we overexpressed this ligand in HSB-2 cells and confirmed its loss after infection with HHV-6A (“ULBP3-HIS”)

Summary

Introduction

The Roseola family of human herpes viruses (HHV) belongs to the b-herpesviruses and consists of three members: HHV-6A, HHV-6B and HHV-7 [1]. Unlike other viruses of this family, HHV-6A is not clearly linked to childhood diseases, but rather as a pathogen threatening immunosuppressed patients, for example patients following hematopoietic stem cell transplantation [2, 3]. HHV-6A was associated with the autoimmune disease Hashimoto’s thyroiditis [4]. The interaction of HHV-6A with the immune system is fragmentarily understood. HHV-6 was previously shown to downregulate the TCR complex [5] as well as CD45 [6] thereby impairing T cell activation. NK cell lines were directly infected with HHV-6, which resulted in reduced NK activity [7]

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