Abstract
More than 95% of the human population is infected with human herpesvirus-6 (HHV-6) during early childhood and maintains latent HHV-6 genomes either in an extra-chromosomal form or as a chromosomally integrated HHV-6 (ciHHV-6). In addition, approximately 1% of humans are born with an inheritable form of ciHHV-6 integrated into the telomeres of chromosomes. Immunosuppression and stress conditions can reactivate latent HHV-6 replication, which is associated with clinical complications and even death. We have previously shown that Chlamydia trachomatis infection reactivates ciHHV-6 and induces the formation of extra-chromosomal viral DNA in ciHHV-6 cells. Here, we propose a model and provide experimental evidence for the mechanism of ciHHV-6 reactivation. Infection with Chlamydia induced a transient shortening of telomeric ends, which subsequently led to increased telomeric circle (t-circle) formation and incomplete reconstitution of circular viral genomes containing single viral direct repeat (DR). Correspondingly, short t-circles containing parts of the HHV-6 DR were detected in cells from individuals with genetically inherited ciHHV-6. Furthermore, telomere shortening induced in the absence of Chlamydia infection also caused circularization of ciHHV-6, supporting a t-circle based mechanism for ciHHV-6 reactivation.
Highlights
Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen with .90% seroprevalence in healthy adults
One possible way by which Human herpesviruses (HHVs)-6 achieves this state is by integrating into the telomeric ends of human chromosomes, which are highly repetitive sequences that protect the ends of chromosomes from damage
Various stress conditions can reactivate latent HHV-6 increasing the severity of multiple human disorders
Summary
Human herpesvirus 6 (HHV-6) is a ubiquitous pathogen with .90% seroprevalence in healthy adults. The process of viral latency is not completely understood, in some cases it is achieved by the integration of the viral genome into telomeric regions of host cell chromosomes (ciHHV-6) [1], and subsequently vertically transmitted through the germ line [1,2,3]. 1% of the human population carries genetically inherited HHV-6. HHV-6 persists in a dormant state with minimal viral transcription or translation in human host cells and without the production of infectious virions and any detectable clinical complications. Under various physiological conditions, latent HHV-6 is reactivated and forms infectious viral particles (for further details see reviews [4,5,6]). Reactivated HHV-6 has been associated with various human diseases [7,8,9,10]
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