HHV-6B IE1 inhibits DNA damage signaling pathway leading to genomic instability

Results suggest a possible link between genomic instability and iciHHV-6 associated disease.

Host cells activate a variety of defense mechanisms when they are infected by a virus. Viruses able to inhibit these host cell defense mechanisms are more able to successfully replicate and spread.

A new study from Chu de Québec-Université Laval Research Center examined this dynamic by infecting permissive MOLT-3 cell lines with HHV-6B. Using a series of microscopy- and cytometry-based approaches, the team examined how HHV-6B manipulates cellular factors that safeguard genomic instability in infected cells, as well as how these factors affect HHV-6B genome replication and chromosomal integration.

They noted that HHV-6B infection suppresses one common host defense mechanism: activation of the ataxia-telangiectasia mutated (ATM) serine/threonine protein kinase, which promotes signaling to repair DNA double-strand breaks (DSBs). They further identified immediate-early protein 1 (IE1) as the primary cause of this effect. IE1 achieves this result, in part, by interacting and colocalizing with a complex of meiotic recombination 11 homolog 1 (MRE11) and ATP-binding cassette–ATPase (Rad50) and Nijmegen breakage syndrome protein 1 (NBS1), that triggers the activation of ATM upon the detection of DNA breaks. HHV-6B IE1 localizes to DSBs in an NBS1-dependent manner, and inhibits ATM signaling through its C-terminal domain, thereby inhibiting homology-directed DNA repair (HDR).

The team also found that viral integration of HHV-6B into the host’s telomeres is not strictly dependent on NBS1. This finding was surprising, given that it has been widely assumed that integration occurs through HDR, and that NBS1 is critical to this repair pathway.

These findings may have relevance to the biological and clinical effects of inherited chromosomally-integrated HHV-6 (iciHHV6). Inherited chromosomally integrated HHV-6 appears to occur more frequently in women with spontaneous abortion (Miura 2021), pre-eclampsia (Gaccioli 2020) and adults with angina pectoris (Gravel 2015) and transplant patients with iciHHV-6 are more likely to develop acute GVHD (Hill 2017). However, the mechanism behind these reported disease associations remain unexplained.  Spontaneous IE1 expression has been detected in the cells of subjects with iciHHV6. This new report raises the possibility that people with iciHHV6 are more likely to have genomic instability, and that this might predispose to the development of iciHHV-6-associated diseases.

 Read the full article: Collin 2024