Variation in human herpesvirus 6B telomeric integration, excision, and transmission between tissues and individuals

Abstract

Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.

Genomic analysis of hyperparasitic viruses associated with entomopoxviruses

“…Some herpesviruses can integrate within the telomeres at the end of chromosomes in animals ( Gennart et al. 2015 , Wood et al. 2021 ), and more recently, some herpesvirus-related viruses were shown to integrate in the telomeres of thraustochytrid protists ( Collier et al.…”

Transmission Dynamics of Human Herpesviruses and Other Blood DNA Viruses from Whole Genome Sequences of Families

“…When we matched the candidate integration sites to public sequences using NCBI’s BLAST, all sequences matched to isolate HHV or endogenous HHV sequences. In particular, sequences matched to studies studying integrated HHV diversity [3, 56, 57, 21, 23].…”

Polinton-like Viruses Associated with Entomopoxviruses Provide Insight into Replicon Evolution

“…Connections between chromosomal ends and mobile elements have been described in diverse systems. Some herpesviruses can integrate within the telomeres at the end of chromosomes in animals (Gennart et al 2015;Wood et al 2021), and more recently, some herpesvirus-related viruses were shown to integrate in the telomeres of thraustochytrid protists (Collier et al 2023). In circular chromosomes of bacteria, many mobile elements integrate into the chromosome dimer resolution site located near the replication terminus (Midonet and Barre 2014;Midonet and Barre 2016).…”