Late‐phase human herpesvirus 6B reactivation in hematopoietic stem cell transplant recipients

Miura, Hiroki; Kawamura, Yoshiki; Hattori, Fumihiko; Tanaka, Makito; Kudo, Kazuko; Ihira, Masaru; Yatsuya, Hiroshi; Takahashi, Yoshiyuki; Kojima, Seiji; Yoshikawa, Tetsushi

doi:10.1111/tid.12916

Cited by 6 publications

(5 citation statements)

References 41 publications

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“…In support, the integrated HHV-6B genome is generally intact and conserved without any gross rearrangements or mutations [ 17 ]. Furthermore, the integrated HHV-6B genome can express genes and lead to complete viral reactivation [ 2 , 10 , 18 , 19 ]. Until now, viral or cellular proteins involved in HHV-6B integration remains to be fully characterized.…”

Section: Introductionmentioning

confidence: 99%

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The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres

Collin¹,

Gravel²,

Kaufer

et al. 2020

PLoS Pathog

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Human herpesvirus 6B (HHV-6B) is a betaherpesvirus capable of integrating its genome into the telomeres of host chromosomes. Until now, the cellular and/or viral proteins facilitating HHV-6B integration have remained elusive. Here we show that a cellular protein, the promyelocytic leukemia protein (PML) that forms nuclear bodies (PML-NBs), associates with the HHV-6B immediate early 1 (IE1) protein at telomeres. We report enhanced levels of SUMOylated IE1 in the presence of PML and have identified a putative SUMO Interacting Motif (SIM) within IE1, essential for its nuclear distribution, overall SUMOylation and association with PML to nuclear bodies. Furthermore, using PML knockout cell lines we made the original observation that PML is required for efficient HHV-6B integration into host chromosomes. Taken together, we could demonstrate that PML-NBs are important for IE1 multiSUMOylation and that PML plays an important role in HHV-6B integration into chromosomes, a strategy developed by this virus to maintain its genome in its host over long periods of time.

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Section: Introductionmentioning

confidence: 99%

“…Following primary infection, HHV-6B enters in latency. In immunocompromised patients such as hematopoietic stem cell transplantation recipients, HHV-6B frequently reactivates from latency and can cause serious medical complications [2][3][4]. During latency, most herpesviruses maintain their genome as a circularized episome.…”

Section: Introductionmentioning

confidence: 99%

The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres

Collin¹,

Gravel²,

Kaufer

et al. 2020

PLoS Pathog

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“…This phenomenon is referred to as inherited chromosomally integrated HHV-6 (iciHHV-6). Importantly, HHV-6 reactivation from the integrated state is associated with various diseases, including graft-versus-host disease, encephalitis, and heart disease (12)(13)(14)(15)(16)(17)(18). More recently, a study indicated that telomeres carrying integrated HHV-6 are shorter and more unstable (19), which, in turn, could influence aging and/or diseases of individuals with iciHHV-6.…”

mentioning

confidence: 99%

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Wight

Aimola

Aswad

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Next-generation sequencing technologies allowed sequencing of thousands of genomes. However, there are genomic regions that remain difficult to characterize, including telomeres, centromeres, and other low-complexity regions, as well as transposable elements and endogenous viruses. Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) are closely related viruses that infect most humans and can integrate their genomes into the telomeres of infected cells. Integration also occurs in germ cells, meaning that the virus can be inherited and result in individuals harboring the virus in every cell of their body. The integrated virus can reactivate and cause disease in humans. While it is well established that the virus resides in the telomere region, the integration locus is poorly defined due to the low sequence complexity (TTAGGG)n of telomeres that cannot be easily resolved through sequencing. We therefore employed genome imaging of the integrated HHV-6A and HHV-6B genomes using whole-genome optical site mapping technology. Using this technology, we identified which chromosome arm harbors the virus genome and obtained a high-resolution map of the integration loci of multiple patients. Surprisingly, this revealed long telomere sequences at the virus−subtelomere junction that were previously missed using PCR-based approaches. Contrary to what was previously thought, our technique revealed that the telomere lengths of chromosomes harboring the integrated virus genome were comparable to the other chromosomes. Taken together, our data shed light on the genetic structure of the HHV-6A and HHV-6B integration locus, demonstrating the utility of optical mapping for the analysis of genomic regions that are difficult to sequence.

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“…In healthy subjects, HHV-6B reactivation is mostly subclinical and controlled by the immune system. However, in immunocompromised individuals, HHV-6B reactivation can be problematic and occasionally life-threatening (5),(6),(7). In case of HHV-6A, several reports have associated the virus with neurodegenerative diseases such as multiple sclerosis and more recently with Alzheimer’s disease (8), (9), (10), (11).…”

Section: Introductionmentioning

confidence: 99%

“…In support, the integrated HHV-6A/B genomes are generally intact and conserved without any gross rearrangements or mutations (17). Furthermore, integrated HHV-6A/B genomes can express genes and lead to complete viral reactivation (18)(19),(20),(7). Reactivation of HHV-6A/B can be life threatening for immunocompromised hosts.…”

Section: Introductionmentioning

confidence: 99%

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

Collin

Gravel

Kaufer

et al. 2018

Preprint

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18 Human herpesviruses 6A and 6B (HHV-6A/B) are two betaherpesviruses that readily 19 integrate their genomes into the telomeres of human chromosomes. To date, the cellular 20 or viral proteins that facilitate HHV-6A/B integration remain elusive. In the present study, 21 we demonstrate that the immediate early protein 1 (IE1) of HHV-6A/B colocalizes with 22 telomeres during infection. Moreover, IE1 associates with PML-NBs, a nuclear complex 23 that regulates multiples cellular mechanism including DNA repair and antiviral responses.24 Furthermore, we could demonstrate that IE1 targets all PML isoforms and that both 25 proteins colocalize at telomeres. To determine the role of PML in HHV-6A/B integration, 26 we generated PML knockout cell lines using CRISPR/Cas9. Intriguingly, in the absence of 27 PML, the IE1 protein could still localize to telomeres albeit less frequently. More 28 importantly, HHV-6A/B integration was impaired in the absence of PML, indicating that 29 it plays a role in the integration process. Taken together, we identified the first cellular 30 protein that aids in the integration of HHV-6A/B and shed light on this targeted integration 31 mechanism. 32 33 Author summary 34 Human herpesviruses type 6A and 6B are relatively common viruses whose infections can 35 be life threatening in patients with a compromised immune system. A rather unique feature 36 of these viruses is their ability to integrate their genome in human chromosomes.37 Integration takes place is a specialized region of the chromosomes known as telomeres, a 38 region that controls cellular lifespan. To date, the mechanisms leading to HHV-6A and 39 HHV-6B integration remain elusive. Our laboratory has identified that the IE1 protein of 3 40 HHV-6A and HHV-6B target the telomeres. Moreover, we have shown that IE1 associates 41 with a cellular protein, PML, that is responsible for the regulation of important cellular 42 mechanisms such as the life span of cells and DNA repair. Hence, we studied the role of 43 PML in HHV-6 integration. Our study demonstrates that in absence of PML, the HHV-6A 44 and HHV-6B integrate 50-70% less frequently. Thus, our study unveils the first cellular 45 protein involved in HHV-6A and HHV-6 chromosomal integration. 46 47 4 49 Human herpesviruses type 6A and 6B (HHV-6A/B) are members of the betaherpesvirinae 50 that were isolated in the 1980's. In 2013, the International Committee on Taxonomy of 51 Viruses recognized HHV-6A and HHV-6B as distinct viral species (1). HHV-6B is known 52 as the etiologic agent of exanthem subitum, a childhood disease whose symptoms include, 53 fever, occasional skin rash and respiratory distress (2). HHV-6A is much less characterized 54 than HHV-6B. Considering that many HHV-6A/B proteins share 90-95% homology, the

show abstract

Late‐phase human herpesvirus 6B reactivation in hematopoietic stem cell transplant recipients

Abstract: Late-phase HHV-6B infection in HSCT recipients was associated with worse outcomes. The full spectrum of clinical features of the infection has not been fully elucidated, and therefore, recipients with high-risk factors for late-phase HHV-6B infection should be carefully monitored.

Cited by 6 publications

References 41 publications

The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres

The Promyelocytic Leukemia Protein facilitates human herpesvirus 6B chromosomal integration, immediate-early 1 protein multiSUMOylation and its localization at telomeres

Unbiased optical mapping of telomere-integrated endogenous human herpesvirus 6

Role of PML-Nuclear Bodies in Human Herpesvirus 6A and 6B Genome Integration

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