Chromosomal integration of an avian oncogenic herpesvirus reveals telomeric preferences and evidence for lymphoma clonality

Abstract

BackgroundHerpesviruses are a major health concern for numerous organisms, including humans, causing both acute and chronic infections recurrent over an individual's lifespan. Marek's disease virus (MDV) is a highly contagious herpesvirus which causes a neoplastic condition in chicken populations. Several vertebrate-infecting herpesviruses have been shown to exist in an integrated state during latent periods of infection. However the status of MDV during latency has been a topic of debate.ResultsHere we employed high-resolution multi-color fluorescence in situ hybridization (FISH) to show integration of MDV at the telomeres of chicken chromosomes. Cytogenomic mapping of the chromosomal integrations allowed us to examine the clonal relationships among lymphomas within individuals, whereas analysis of tumors from multiple individuals indicated the potential for chromosomal preferences.ConclusionsOur data highlight that substantive genome-level interactions between the virus and host exist, and merit consideration for their potential impact and role in key aspects of herpesvirus pathobiology including infection, latency, cellular transformation, latency-breaks and viral evolution.

Temporal Kinetics of Marek's Disease Herpesvirus: Integration Occurs Early after Infection in Both B and T Cells

“…Seven tumors had 80-89% and 2 ∼ 65% such cells. These results support an earlier work [Robinson et al, 2010] showing that MDV integrations are a characteristic feature of tumor cell populations. Of the 16 tumors expressing the homogeneous MDV profile, the average number of integrations was 5 (range 2-7).…”

“…Prior work showing that MDV integrates into the chicken chromosomes at or near the telomeres focused on late-stage tumors or cell lines derived from tumors Robinson et al, 2010;Kaufer et al, 2011]. Thus, the time frame of MDV integration relative to the MDV life cycle was unknown.…”

“…2 C). The fourth phenotype, MDV-integrated-only, was previously described in a study of late-stage lymphomas [Robinson et al, 2010] wherein MDV-genome hy- 147 bridization signals (distinct, punctate, intense-bright signals) are found only within the chromosomes (contiguous with chromosome architecture) at the telomeres ( fig. 2 D).…”

“…The FISH procedures were as described previously [Robinson at al., 2010], and the preparations were stained using one drop of DAPI:Vectashield (1: 9) (Vector Laboratories, Inc.).…”

“…In fact, it was previously thought that herpesvirus genomes were maintained solely as circular episomes in the host nucleus [Morissette and Flamand, 2010]. first reported MDV in an integrated state in chicken host chromosomes, and more recently we [Robinson et al, 2010] and others [Kaufer et al, 2011] expanded the cytogenetic and molecular evidence for integration, showing that oncogenic MDV integrates in or near the telomeres of chicken chromosomes in late-stage lymphomas and that this is a key feature of tumor cell populations. MDV is not the only herpesvirus known to integrate into host DNA; both the Epstein-Barr virus and the human herpesvirus-6 (HHV6) are capable of integration into the host genome [Morissette and Flamand, 2010;Desfarges and Ciuffi, 2012].…”