Recently, a research team led by Prof. BI Guoqiang from University of Science and Technology of China (USTC) of the Chinese Academy of Sciences, in cooperation with the team led by Prof. ZHOU Zhenghong from University of California and MEI Ye from East China Normal University, obtained the near-atomic resolution structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes. The study was published in Nature Communications.

Human herpesvirus 6B (HHV-6B) belongs to the β-herpesvirus subfamily of the Herpesviridae. Difficulties in cultivating HHV-6B have prevented high-resolution structural studies and limited our understanding of its assembly.

HHV-6 infects nearly all human beings by the age of three and often results in fever, diarrhea, and the roseola rash. Herpesviruses - such as herpes simplex, chicken pox, and the Epstein - Barr virus - have a tendency of establishing life-long latency, activating later in life with many clinical manifestations; HHV-6 follows a similar cycle. HHV-6 reactivation in brain tissue can cause cognitive dysfunction, permanent disability, and death.

In this study, the researchers have employed a plethora of cutting-edge cryoEM techniques and a sub-particle reconstruction method to work with very little and minimally purified HHV-6B sample.

They successfully determined the near-atomic resolution structure of HHV-6B using crude, minimally purified samples, derived the atomic model of both the HHV-6B capsid, and showed a capsid-binding pattern of pU11 that differs from capsid-associated tegument complex (CATC) binding patterns found in human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV).

The finding represented the fifth-ever human herpesvirus whose capsid structure has been described at atomic level, following HCMV, herpes simplex virus 1 and 2. HHV-6B’s capsid structure is similar to known capsid structures of other herpesviruses with only minor differences.

The atomic model derived revealed that binding between capsid-vertex specific components (CVSC) and the capsid of herpesviruses is not determined solely by the availability of triplex binding sites on the capsid. It is natural to expect the binding pattern of CVSC tegument proteins on pentons to be dictated by the availability of its binding partners.

The researchers predicted that CVSC complexes are present in HHV-6B, but only bind to the portal vertex and peri-portal triplexes. Owing to the importance of CVSC in viral propagation, fully understanding the nature of CVSC binding could prove valuable towards the development of pharmaceutical drugs.

Looking forward, the significance of the atomic structure of HHV-6B transcends basic knowledge about HHV-6B capsid and tegument assembly.

Protein phosphorylation has been recognized as a common mechanism for regulating biological functions. Drugs against infection, inflammation, cancers, or neurodegeneration target phosphorylation pathways of human proteins. Understanding the atomic structure of the phosphorylated protein pU11 in HHV-6B may prove vital to designing anti-viral drugs and vaccines against this virus.

Comparison of CATC-capsid-binding patterns in HHV-6B, MCMV, and HCMV. (Image by ZHANG Yibo et al.)