One step closer to understanding HHV-6A/B chromosomal integration

The mechanisms leading to HHV-6A/B integration is a subject of intense research by several laboratories.  A new paper in PLoS Pathogens provides some understanding as to how HHV-6A/B may integrate host chromosomes.

Herpesviruses have a two-phase life cycle.  A phase where the virus actively grows and typically causes diseases or clinical manifestation and a phase of dormancy where the virus is literally “sleeping” with little to no protein expression. Among human herpesviruses, HHV-6A/B have the unique ability to establish dormancy by inserting their DNA into the host chromosomes. In doing so, the virus can remain dormant for long periods of time and avoid immune detection. A team led by Louis Flamand, PhD in Canada has found an explanation for some of the mystery behind the phenomenon of HHV-6 chromosomal integration.

HHV-6A/B integration takes place at the ends of chromosomes in a specialized region referred to as the telomeres that consist in several hundred repeats of the TTAGGG motif.  Associated with telomeres are proteins known as the shelterin that serve to protect the telomeres. Two of the shelterin proteins, TRF1 and TRF2, specifically bind the TTAGGG motif and serve as scaffold to recruit other shelterin proteins.  In their paper, Gilbert-Girard et al report that during HHV-6A/B infection, the number of TTAGGG repeats increases significantly.  Such increase resulted from the actively replicating viral DNA that also contains TTAGGG repeats.  TRF1 and TRF2 were experimentally shown to bind to the viral DNA during infection.  Joining TRF2 at a viral replication centers and at telomeres was the HHV-6 immediate-early 2 (IE2) protein.  The presence of TRF2 was needed for IE2 to efficiently localize at telomeres.  Lastly, by reducing the expression of TRF2, the authors observed an important decline in the ability of HHV-6A/B to integrate into host chromosomes pointing out for a role of TRF2 in HHV-6A/B integration.

The authors conclude that the recruitment of TRF2 to the viral DNA may serve two purposes.  First, as with telomeres, TRF2 may protect viral DNA ends from being recognized as broken pieces of DNA needing repair.  Second, TRF2 may facilitate the recombination between the viral and cellular TTAGGG motifs resulting in viral genome integration.  Of interest, the current work represents a nice follow-up to previous work from the Kaufer group indicating that the viral TTAGGG repeats were essential for the ability of HHV-6A to efficiently integrate (Wallaschek 2016).

Read the full text: Gilbert-Girard 2020