Fine mapping of an apparently targeted latent human herpesvirus type 6 integration site in chromosome band 17p13.3

Abstract

An unusually high level of latent HHV-6 infection has been documented in the peripheral blood and/or bone marrow cells of a small group of patients with predominantly malignant lymphoid disorders, and in at least one healthy individual. We have shown previously in peripheral blood mononuclear cells (PBMCs) of three patients, two with a history of lymphoma and one with multiple sclerosis, a specific target site for latent integration of the full-length HHV-6 viral genome on the distal short arm of chromosome 17, in band p13.3. Fluorescence in situ hybridization (FISH) procedures were used to map more precisely the location of the viral integration site in one of those patients, relative to two known oncogenes mapped previously, namely CRK, and the more telomeric ABR oncogene. It is shown that the HHV-6 integration site is located at least 1,000 kb telomeric of ABR, and is very likely to map close to or within the telomeric sequences of 17p. This finding is significant given that human telomeric-like repeats flank the terminal ends of the HHV-6 genome. Cytogenetic studies showed evidence of karyotype instability in the peripheral blood cells infected latently.

Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy

“…More evidence for the latency-establishing potential of HHV-6 comes from reports on the integration of the HHV-6 genome into the host cell DNA, both in vivo and in vitro, at the ends of chromosomes 1, 17, and 22 (88,89,250). These findings are supported by the presence of human telomeric-like repeat sequences at the HHV-6 genome termini (142), since the integration site in chromosome 17 was shown to be within the telomeric sequences (297). Furthermore, HHV-6 pU94 may function in a similar way as the adenoassociated virus (AAV) rep gene products, which mediate sitespecific DNA integration in human cells (383).…”

Dermatological Skin Diseases Associated with Human Herpes Viruses 6, 7 and 8: Review

“…9,10 Virüsün bu kromozomal etkileşiminin nasıl kontrol edildiği bilinmemektedir. 8,10 Anne sütünün bulaşa etkisi ise tartışmalıdır. 5 HHV-6 ile primer enfeksiyon sıklıkla hayatın ilk iki yılında ortaya çıkmaktadır.…”

Human Herpesvirus 6 Latency Characterized by High Viral Load: Chromosomal Integration in Many, but Not All, Cells

“…In the 3 patients carrying an apparently complete HHV-6 genome available for fluo escent in situ hybridization analysis, the viral genome was found to be integrated at the telomeric end of the short arm of chromosome 17, on band 17p13.3, in 50%, 77%, and 53% of the metaphase cells derived from PHA-stimulated PBMCs [6]. Further analysis of one of these patients by 2 different observers of nonstimulated interphase PBMCs showed a single discrete integration signal in 45% and 52% of 100 cells scored [8]. Of interest, cytogenetic experiments showed evidence of karyotype instability in latently infected PBMCs that was possibly related to the integrated virus [8].…”

“…Since then, few other investigators have described a similar phenomenon, suggesting the possible vertical transmission of chromosomally integrated HHV-6 [6,7]. Several different chromosomes have been implicated [8]. Further studies are needed to advance our knowledge of this particular form of viral persistence.…”