Activation of ciHHV-6 by telomeric circle formation

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Dr. Bhupesh Prusty and his associates in Professor Thomas Rudel’s laboratory at Biozentrum University have presented additional evidence that shortened telomeres can cause the release and possible activation of integrated HHV-6. Their work has previously shown that Chlamydia trachomatis infection activates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. In an article published by PLoS Genetics this month, Dr. Prusty expands on the theory that a transient shortening of telomeric ends (whether induced via Chlamydia infection or otherwise) may subsequently lead to increased telomeric circle formation and incomplete reconstitution of circular viral genomes containing single viral direct repeats, supporting a t-circle based mechanism for ciHHV-6 activation. Click here to read the abstract.

Chromosomally integrated HHV-6 (ciHHV-6) is found in 0.8 to 0.85% of normal controls in the US and the UK, but the prevalence in patient populations is much higher. HHV-6 can be activated by certain drugs such as HDAC inhibitors (TSA) or steroids. Prusty’s group found that Chlamydia infection is a natural cause of latent HHV-6 reactivation, but the molecular mechanism of this reactivation is poorly understood. The authors propose that HHV-6 utilizes the telomere maintenance machinery of the host cell to leave its latent state and initiate replication to form new viral DNA. As a consequence of interfering with the telomere maintenance machinery, the release of integrated virus is triggered.

The authors note that the chromosomal integration may have important medical consequences for several million people worldwide. See our interview with Dr. Prusty and Professor Rudel.

Last fall, Dr. Nicola Royle used single telomere length analysis (STELA) assays to show that short, unstable telomeric repeats at the site of HHV-6 integration facilitate the release of viral genomes. Dr. Royle suggested that transplant physicians should consider screening for ciHHV-6. (News article here.)

In vivo evidence of ciHHV-6 activation first came from investigators at the University of Rochester who found that several infants not born with ciHHV-6, acquired an active HHV-6 infection from their ciHHV-6 mothers. Dr. Louis Flamand’s laboratory at Laval University in Quebec confirmed this evidence by sequencing the virus strain of the mother-child pairs. In each case, the strain of the non-ciHHV-6 infant matched the ciHHV-6 strain of the mother, establishing that the integrated strain of the ciHHV-6 mothers had activated and was passed to the infants  transplacentally. Several investigators have now questioned whether it is advisable for individuals with ciHHV-6 to donate blood or organs.

A review and Q & A on ciHHV-6 can be downloaded here.