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Special Issue "Viruses and Telomeres"

A special issue of Viruses (ISSN 1999-4915).

Deadline for manuscript submissions: closed (15 May 2017)

Special Issue Editors

Guest Editor
Prof. Paul M. Lieberman

The Wistar Institute, Philadelphia, PA 19104, USA
Website | E-Mail
Interests: human gammaherpesvirus latency; and telomere chromatin regulation
Guest Editor
Prof. Benedikt B. Kaufer

Institut für Virologie, Freie Universität Berlin, Germany
Website | E-Mail
Interests: herpesvirus latency and integration into host telomeres

Special Issue Information

Dear Colleagues,

Viruses and telomeres share fundamental genetic and evolutionary properties.  Telomeres are repetitive sequences at the ends of linear chromosomes of most organisms that are associated with a number of proteins. They counteract the loss of genetic material and can be maintained by a self-replication mechanism mediated by the telomerase complex.  In many ways, the extension of telomeres resembles virus replication, and both share a clear evolutionary origin.  It is therefore no surprise that many viruses have pirated components of telomeres and/or telomerase, including the telomeric repeats and telomerase RNA. Beyond that, viruses aquired the ability to modulate telomere maintenance and structure, including induction of telomerase activation or viral integration into host telomeres.  In some cases, viruses and telomeres have a conflict of interest, with telomeres working to maintain host genome integrity and viruses seeking to be unleashed from these restraints.   In other cases, viruses can take advantage of the telomere heterochromatin to establish latent or persistent infections in long-lived and dividing cells.  How these interactions between viruses and host chromosomes are regulated and lead to pathogenesis is the subject of this volume. 

Prof. Paul M. Lieberman
Prof. Benedikt B. Kaufer
Guest Editors

Manuscript Submission Information

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Keywords

  • telomere
  • virus
  • TERRA
  • telomerase
  • integration
  • Human Herpesvirus 6
  • Marek’s Disease Virus
  • Epstein-Barr Virus

 

Published Papers (9 papers)

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Review

Open AccessReview Telomere Dynamics in Immune Senescence and Exhaustion Triggered by Chronic Viral Infection
Viruses 2017, 9(10), 289; doi:10.3390/v9100289
Received: 14 June 2017 / Revised: 28 September 2017 / Accepted: 29 September 2017 / Published: 5 October 2017
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Abstract
The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the
[...] Read more.
The progressive loss of immunological memory during aging correlates with a reduced proliferative capacity and shortened telomeres of T cells. Growing evidence suggests that this phenotype is recapitulated during chronic viral infection. The antigenic volume imposed by persistent and latent viruses exposes the immune system to unique challenges that lead to host T-cell exhaustion, characterized by impaired T-cell functions. These dysfunctional memory T cells lack telomerase, the protein capable of extending and stabilizing chromosome ends, imposing constraints on telomere dynamics. A deleterious consequence of this excessive telomere shortening is the premature induction of replicative senescence of viral-specific CD8+ memory T cells. While senescent cells are unable to expand, they can survive for extended periods of time and are more resistant to apoptotic signals. This review takes a closer look at T-cell exhaustion in chronic viruses known to cause human disease: Epstein–Barr virus (EBV), Hepatitis B/C/D virus (HBV/HCV/HDV), human herpesvirus 8 (HHV-8), human immunodeficiency virus (HIV), human T-cell leukemia virus type I (HTLV-I), human papillomavirus (HPV), herpes simplex virus-1/2(HSV-1/2), and Varicella–Zoster virus (VZV). Current literature linking T-cell exhaustion with critical telomere lengths and immune senescence are discussed. The concept that enduring antigen stimulation leads to T-cell exhaustion that favors telomere attrition and a cell fate marked by enhanced T-cell senescence appears to be a common endpoint to chronic viral infections. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Regulation of Telomere Homeostasis during Epstein-Barr virus Infection and Immortalization
Viruses 2017, 9(8), 217; doi:10.3390/v9080217
Received: 3 July 2017 / Revised: 25 July 2017 / Accepted: 26 July 2017 / Published: 9 August 2017
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Abstract
The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect
[...] Read more.
The acquisition of unlimited proliferative potential is dependent on the activation of mechanisms for telomere maintenance, which counteracts telomere shortening and the consequent triggering of the DNA damage response, cell cycle arrest, and apoptosis. The capacity of Epstein Barr virus (EBV) to infect B-lymphocytes in vitro and transform the infected cells into autonomously proliferating immortal cell lines underlies the association of this human gamma-herpesvirus with a broad variety of lymphoid and epithelial cell malignancies. Current evidence suggests that both telomerase-dependent and -independent pathways of telomere elongation are activated in the infected cells during the early and late phases of virus-induced immortalization. Here we review the interaction of EBV with different components of the telomere maintenance machinery and the mechanisms by which the virus regulates telomere homeostasis in proliferating cells. We also discuss how these viral strategies may contribute to malignant transformation. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessFeature PaperReview The Telomeric Response to Viral Infection
Viruses 2017, 9(8), 218; doi:10.3390/v9080218
Received: 9 July 2017 / Revised: 6 August 2017 / Accepted: 6 August 2017 / Published: 9 August 2017
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Abstract
The ends of linear genomes, whether viral or cellular, can elicit potent DNA damage and innate immune signals. DNA viruses entering the nucleus share many features with telomeres in their ability to either suppress or co-opt these pathways. Here, we review some of
[...] Read more.
The ends of linear genomes, whether viral or cellular, can elicit potent DNA damage and innate immune signals. DNA viruses entering the nucleus share many features with telomeres in their ability to either suppress or co-opt these pathways. Here, we review some of the common mechanisms that viruses and telomeres use to manage the DNA damage and innate immune response pathways. We highlight recent studies on the role of the telomere repeat-containing RNA (TERRA) in response to viral infection. We discuss how TERRA can be activated through a p53-response element embedded in a retrotransposon-like repeat found in human subtelomeres. We consider how TERRA can function as a danger signal when secreted in extracellular vesicles to induce inflammatory cytokines in neighboring cells. These findings suggest that TERRA may be part of the innate immune response to viral infection, and support the hypothesis that telomeres and viruses utilize common mechanisms to maintain genome integrity and regulate innate immunity. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Latency, Integration, and Reactivation of Human Herpesvirus-6
Viruses 2017, 9(7), 194; doi:10.3390/v9070194
Received: 21 June 2017 / Revised: 18 July 2017 / Accepted: 20 July 2017 / Published: 24 July 2017
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Abstract
Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation.
[...] Read more.
Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation. In about 1% of the human population, human herpes virus-6 (HHV-6) integration into germline cells allows the viral genome to be passed down from one generation to the other; this condition is called inherited chromosomally integrated HHV-6 (iciHHV-6). This review will cover the history of HHV-6 and recent works that define the biological differences between HHV-6A and HHV-6B. Additionally, HHV-6 integration and inheritance, the capacity for reactivation and superinfection of iciHHV-6 individuals with a second strain of HHV-6, and the role of hypomethylation of human chromosomes during integration are discussed. Overall, the data suggest that integration of HHV-6 in telomeres represent a unique mechanism of viral latency and offers a novel tool to study not only HHV-6 pathogenesis, but also telomere biology. Paradoxically, the integrated viral genome is often defective especially as seen in iciHHV-6 harboring individuals. Finally, gaps in the field of HHV-6 research are presented and future studies are proposed. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Drosophila: Retrotransposons Making up Telomeres
Viruses 2017, 9(7), 192; doi:10.3390/v9070192
Received: 9 June 2017 / Revised: 14 July 2017 / Accepted: 17 July 2017 / Published: 19 July 2017
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Abstract
Drosophila and extant species are the best-studied telomerase exception. In this organism, telomere elongation is coupled with targeted retrotransposition of Healing Transposon (HeT-A) and Telomere Associated Retrotransposon (TART) with sporadic additions of Telomere Associated and HeT-A Related (TAHRE), all three specialized non-Long Terminal
[...] Read more.
Drosophila and extant species are the best-studied telomerase exception. In this organism, telomere elongation is coupled with targeted retrotransposition of Healing Transposon (HeT-A) and Telomere Associated Retrotransposon (TART) with sporadic additions of Telomere Associated and HeT-A Related (TAHRE), all three specialized non-Long Terminal Repeat (non-LTR) retrotransposons. These three very special retroelements transpose in head to tail arrays, always in the same orientation at the end of the chromosomes but never in interior locations. Apparently, retrotransposon and telomerase telomeres might seem very different, but a detailed view of their mechanisms reveals similarities explaining how the loss of telomerase in a Drosophila ancestor could successfully have been replaced by the telomere retrotransposons. In this review, we will discover that although HeT-A, TART, and TAHRE are still the only examples to date where their targeted transposition is perfectly tamed into the telomere biology of Drosophila, there are other examples of retrotransposons that manage to successfully integrate inside and at the end of telomeres. Because the aim of this special issue is viral integration at telomeres, understanding the base of the telomerase exceptions will help to obtain clues on similar strategies that mobile elements and viruses could have acquired in order to ensure their survival in the host genome. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Chromosomally Integrated Human Herpesvirus 6: Models of Viral Genome Release from the Telomere and Impacts on Human Health
Viruses 2017, 9(7), 184; doi:10.3390/v9070184
Received: 2 June 2017 / Revised: 30 June 2017 / Accepted: 5 July 2017 / Published: 12 July 2017
Cited by 1 | PDF Full-text (1297 KB) | HTML Full-text | XML Full-text
Abstract
Human herpesvirus 6A and 6B, alongside some other herpesviruses, have the striking capacity to integrate into telomeres, the terminal repeated regions of chromosomes. The chromosomally integrated forms, ciHHV-6A and ciHHV-6B, are proposed to be a state of latency and it has been shown
[...] Read more.
Human herpesvirus 6A and 6B, alongside some other herpesviruses, have the striking capacity to integrate into telomeres, the terminal repeated regions of chromosomes. The chromosomally integrated forms, ciHHV-6A and ciHHV-6B, are proposed to be a state of latency and it has been shown that they can both be inherited if integration occurs in the germ line. The first step in full viral reactivation must be the release of the integrated viral genome from the telomere and here we propose various models of this release involving transcription of the viral genome, replication fork collapse, and t-circle mediated release. In this review, we also discuss the relationship between ciHHV-6 and the telomere carrying the insertion, particularly how the presence and subsequent partial or complete release of the ciHHV-6 genome may affect telomere dynamics and the risk of disease. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview Telomeres and Telomerase: Role in Marek’s Disease Virus Pathogenesis, Integration and Tumorigenesis
Viruses 2017, 9(7), 173; doi:10.3390/v9070173
Received: 23 May 2017 / Revised: 15 June 2017 / Accepted: 26 June 2017 / Published: 4 July 2017
Cited by 1 | PDF Full-text (1111 KB) | HTML Full-text | XML Full-text
Abstract
Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract
[...] Read more.
Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG)n that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek’s disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview LMP1 and Dynamic Progressive Telomere Dysfunction: A Major Culprit in EBV-Associated Hodgkin’s Lymphoma
Viruses 2017, 9(7), 164; doi:10.3390/v9070164
Received: 15 May 2017 / Revised: 12 June 2017 / Accepted: 22 June 2017 / Published: 27 June 2017
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Abstract
Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed–Sternberg (RS) cells in classical EBV-positive Hodgkin’s lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In
[...] Read more.
Epstein–Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is expressed in germinal-center-derived, mononuclear Hodgkin (H) and multinuclear, diagnostic Reed–Sternberg (RS) cells in classical EBV-positive Hodgkin’s lymphoma (cHL). LMP1 expression in EBV-negative H-cell lines results in a significantly increased number of RS cells. In a conditional, germinal-center-derived B-cell in vitro system, LMP1 reversibly down-regulates the shelterin proteins, telomeric repeat binding factor (TRF)1, TRF2, and protection of telomeres (POT)1. This down-regulation is associated with progressive 3D shelterin disruption, resulting in telomere dysfunction, progression of complex chromosomal rearrangements, and multinuclearity. TRF2 appears to be the key player. Thus, we hypothesize that the 3D interaction of telomeres and TRF2 is disrupted in H cells, and directly associated with the formation of H and RS cells. Using quantitative 3D co-immuno-TRF2-telomere fluorescent in situ hybridization (3D TRF2/Telo-Q-FISH) applied to monolayers of primary H and RS cells, we demonstrate TRF2-telomere dysfunction in EBV-positive cHL. However, in EBV-negative cHL a second molecular mechanism characterized by massive up-regulation of TRF2, but attrition of telomere signals, is also identified. These facts point towards a shelterin-related pathogenesis of cHL, where two molecularly disparate mechanisms converge at the level of 3D Telomere–TRF2 interactions, leading to the formation of RS cells. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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Open AccessReview HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomally Integrated HHV-6A/B
Viruses 2017, 9(7), 160; doi:10.3390/v9070160
Received: 30 May 2017 / Revised: 21 June 2017 / Accepted: 22 June 2017 / Published: 26 June 2017
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Abstract
Unlike other human herpesviruses, human herpesvirus 6A and 6B (HHV-6A/B) infection can lead to integration of the viral genome in human chromosomes. When integration occurs in germinal cells, the integrated HHV-6A/B genome can be transmitted to 50% of descendants. Such individuals, carrying one
[...] Read more.
Unlike other human herpesviruses, human herpesvirus 6A and 6B (HHV-6A/B) infection can lead to integration of the viral genome in human chromosomes. When integration occurs in germinal cells, the integrated HHV-6A/B genome can be transmitted to 50% of descendants. Such individuals, carrying one copy of the HHV-6A/B genome in every cell, are referred to as having inherited chromosomally-integrated HHV-6A/B (iciHHV-6) and represent approximately 1% of the world’s population. Interestingly, HHV-6A/B integrate their genomes in a specific region of the chromosomes known as telomeres. Telomeres are located at chromosomes’ ends and play essential roles in chromosomal stability and the long-term proliferative potential of cells. Considering that the integrated HHV-6A/B genome is mostly intact without any gross rearrangements or deletions, integration is likely used for viral maintenance into host cells. Knowing the roles played by telomeres in cellular homeostasis, viral integration in such structure is not likely to be without consequences. At present, the mechanisms and factors involved in HHV-6A/B integration remain poorly defined. In this review, we detail the potential biological and medical impacts of HHV-6A/B integration as well as the possible chromosomal integration and viral excision processes. Full article
(This article belongs to the Special Issue Viruses and Telomeres)
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