Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are ubiquitous betaherpesviruses
that infects humans within the first years of life and establishes latency in
various cell types. Both viruses can integrate their genomes into telomeres of
host chromosomes in latently infected cells. The molecular mechanism of viral
integration remains elusive. Intriguingly, HHV-6A, HHV-6B and several other
herpesviruses harbor arrays of telomeric repeats (TMR) identical to human
telomere sequences at the ends of their genomes. The HHV-6A and HHV-6B genomes
harbor two TMR arrays, the perfect TMR (pTMR) and the imperfect TMR (impTMR).
To determine if the TMR are involved in virus integration, we deleted both
pTMR and impTMR in the HHV-6A genome. Upon reconstitution, the TMR mutant
virus replicated comparable to wild type (wt) virus, indicating that the TMR
are not essential for HHV- 6A replication. To assess the integration
properties of the recombinant viruses, we established an in vitro integration
system that allows assessment of integration efficiency and genome maintenance
in latently infected cells. Integration of HHV-6A was severely impaired in the
absence of the TMR and the virus genome was lost rapidly, suggesting that
integration is crucial for the maintenance of the virus genome. Individual
deletion of the pTMR and impTMR revealed that the pTMR play the major role in
HHV-6A integration, whereas the impTMR only make a minor contribution,
allowing us to establish a model for HHV-6A integration. Taken together, our
data shows that the HHV-6A TMR are dispensable for virus replication, but are
crucial for integration and maintenance of the virus genome in latently
infected cells