Abstract
Human herpesvirus -6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes. Viral integration can occur in several cell types, including germinal cells, resulting in individuals that harbor the viral genome in every cell of their body. The integrated genome is efficiently silenced but can sporadically reactivate resulting in various clinical symptoms. To date, the integration mechanism and the subsequent silencing of HHV-6A/B genes remains poorly understood. Here we investigate the genome-wide chromatin contacts of the integrated HHV-6A in latently-infected cells. We show that HHV-6A becomes transcriptionally silent upon infection of these cells over the course of seven days. In addition, we established an HHV-6–specific 4C-seq approach, revealing that the HHV-6A 3D interactome is associated with quiescent chromatin states in cells harboring integrated virus. Furthermore, we observed that the majority of virus chromatin interactions occur toward the distal ends of specific human chromosomes. Exploiting this finding, we established a 4C-seq method that accurately detects the chromosomal integration sites. We further implement long-read minION sequencing in the 4C-seq assay and developed a method to identify HHV-6A/B integration sites in clinical samples.
Highlights
Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two closely related and ubiquitous betaherpesviruses (Zerr et al, 2005)
This study provides a better understanding of the chromatin programs that may regulate HHV-6A latency and provide novel diagnostic methods to determine chromosomal integration sites
Cells were infected with recombinant HHV-6A virus expressing green fluorescent protein (GFP) under the control of the major immediate-early (IE) HCMV promoter (Tang et al, 2010a; Wallaschek et al, 2016)
Summary
Human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) are two closely related and ubiquitous betaherpesviruses (Zerr et al, 2005). Most people are infected with HHV-6B as infants, while the etiology of HHV-6A remain poorly defined (Okuno et al, 1989; De Bolle et al, 2005). HHV-6A/B establishes latency in the host for life (Flamand, 2018). During this latent state, viral gene expression and viral load are not detectable (Saviola et al, 2019). The virus can sporadically reactivate in the host, resulting in the production of infectious virions and viral transmission (Endo et al, 2014). HHV-6A/B reactivation has been linked to a variety of pathologies including encephalitis, graft rejection and a spectrum of other diseases (Aimola et al, 2020)
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