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

Descripción del proyecto

Virus herpes hereditarios en el genoma humano

Los virus han modelado la evolución humana, y algunos han incrustado permanentemente su ADN en nuestro genoma. Un ejemplo llamativo es el virus herpes humano de tipo 6 (VHH-6), que se integró en los telómeros de las células germinales y que actualmente hereda alrededor del 1 % de la población mundial. Aunque suele ser silencioso, el VHH-6 puede reactivarse y se ha relacionado con convulsiones, encefalitis, insuficiencia cardiaca y complicaciones en los trasplantes. El objetivo del proyecto ENDo-HERPES, financiado por el CEI, es investigar qué genomas virales heredados siguen siendo funcionales y cómo se integran y reactivan en los telómeros. Mediante el uso de tecnologías genómicas avanzadas, en el proyecto se aclarará si este virus incrustado contribuye a las enfermedades humanas y de qué manera, y si se ve influido por el acortamiento de los telómeros relacionado con el envejecimiento.

Objetivo

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. 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 and graft rejection. We recently analysed the virus genomes present in hundreds of individuals with this inherited chromosomally-integrated HHV-6 (iciHHV-6). The data show that todays endogenous virus sequences are quite diverse and derived from dozens of independent integration events that were passed on for generations. There are critical gaps in our knowledge on the functionality of iciHHV-6 genomes with respect to virus replication, gene expression and latency, its effects on the host cell, and the role of telomere shortening that occurs during aging on virus reactivation. 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; and 3) investigate the effects of the iciHHV-6 genome on host cells and if telomere shortening can induce reactivation. 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. 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.