Endogenous Human Herpesvirus: Germ line integration and effects on host cell and organism

Introduction

Endogenous viruses present in the human genome control physiological processes, modulate aging, and can cause diseases. Intriguingly, a herpesvirus has entered the human germ line by integrating its genome into telomeres of germ cells and is present in about 80 million people.

Background

The virus, human herpesvirus 6 (HHV-6), can reactivate from the integrated state, which is associated with a number of diseases. These include:

• Seizures
• Encephalitis
• Heart failure
• Graft rejection

We recently analyzed the virus genomes present in hundreds of individuals with this inherited chromosomally-integrated HHV-6 (iciHHV-6). The data show that today’s endogenous virus sequences are quite diverse and derived from dozens of independent integration events that were passed on for generations.

Knowledge Gaps

There are critical gaps in our knowledge on the functionality of iciHHV-6 genomes with respect to:

1. Virus replication
2. Gene expression and latency
3. Its effects on the host cell
4. The role of telomere shortening that occurs during aging on virus reactivation

Project Goals

ENDo-HERPES will make use of novel technology to close these gaps and provide the basis for elucidating whether diseases are associated with or caused by iciHHV-6. Specifically, we will:

1. Identify which iciHHV-6 genomes are still functional and could contribute to disease development.
2. Determine iciHHV-6 integration sites within the highly repetitive telomere region and assess the integration and reactivation process on the DNA level.
3. Investigate the effects of the iciHHV-6 genome on host cells and if telomere shortening can induce reactivation.

Methodology

The proposal utilizes state-of-the-art technology and pioneers new approaches, particularly when investigating the integration sites of endogenous virus genomes and the mechanisms facilitating integration and reactivation.

Conclusion

Altogether, we will shed light on the life cycle and effects on the host cells of this endogenous herpesvirus present in the genome of about 1% of the human population.