Structural basis for the interaction of human herpesvirus 6B tetrameric glycoprotein complex with the cellular receptor, human CD134.

Mitsuhiro Nishimura,Bochao Wang,Lidya Handayani Tjan,Akiko Kawabata,Bernadette Dian Novita,Yasuko Mori,Taiki Aoshi,Takayuki Kato,Aika Wakata,Huamin Tang,Anna Lystia Poetranto,Ekaterina E Heldwein

doi:10.1371/journal.ppat.1008648

Abstract

A unique glycoprotein is expressed on the virus envelope of human herpesvirus 6B (HHV-6B): the complex gH/gL/gQ1/gQ2 (hereafter referred to as the HHV-6B tetramer). This tetramer recognizes a host receptor expressed on activated T cells: human CD134 (hCD134). This interaction is essential for HHV-6B entry into the susceptible cells and is a determinant for HHV-6B cell tropism. The structural mechanisms underlying this unique interaction were unknown. Herein we solved the interactions between the HHV-6B tetramer and the receptor by using their neutralizing antibodies in molecular and structural analyses. A surface plasmon resonance analysis revealed fast dissociation/association between the tetramer and hCD134, although the affinity was high (KD = 18 nM) and comparable to those for the neutralizing antibodies (anti-gQ1: 17 nM, anti-gH: 2.7 nM). A competition assay demonstrated that the anti-gQ1 antibody competed with hCD134 in the HHV-6B tetramer binding whereas the anti-gH antibody did not, indicating the direct interaction of gQ1 and hCD134. A single-particle analysis by negative-staining electron microscopy revealed the tetramer's elongated shape with a gH/gL part and extra density corresponding to gQ1/gQ2. The anti-gQ1 antibody bound to the tip of the extra density, and anti-gH antibody bound to the putative gH/gL part. These results highlight the interaction of gQ1/gQ2 in the HHV-6B tetramer with hCD134, and they demonstrate common features among viral ligands of the betaherpesvirus subfamily from a macroscopic viewpoint.

Highlights

Human herpesvirus 6B (HHV-6B) is the major causative pathogen of the exanthema subitum contracted during infancy, with high fever followed by a skin rash [1]
Primary infection of human herpesvirus 6B (HHV-6B) with fever and roseola occurs for almost all children, and HHV-6B remains in the host as a latent infection
human herpesvirus 6B (HHV6B)’s unique gH/gL/gQ1/gQ2 complex recognizes the cellular receptor, i.e., human CD134, which is essential for the entry of the virus into the host’s cells

Summary

Introduction

Human herpesvirus 6B (HHV-6B) is the major causative pathogen of the exanthema subitum contracted during infancy, with high fever followed by a skin rash [1]. The prognosis of HHV-6B infection is benign in most cases, the infection sometimes progresses to encephalitis, leaving neurological sequelae [2]. The primary infected HHV-6B virus establishes latency and persists in the body as long as the host lives. The latent HHV-6B virus reactivates in response to stimulation such as immune-compromised conditions, drugs, and fatigue. In immunocompromised patients — especially recipients of hematopoietic stemcell transplantation — the latent HHV-6B reactivates, proliferates, and progresses to severe encephalitis at a high rate [2,3,4,5]. A human host’s immune system is able to prevent HHV-6B infection. It is of importance to understand how HHV-6B is controlled by a host’s immunity

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