HHV-6 infection after allogeneic hematopoietic stem cell transplantation: From chromosomal integration to viral co-infections and T-cell reconstitution patterns

Bonnafous, Pascale; Gilis, Lila; Barraco, Fiorenza; Labussière‐Wallet, Hélène; Duscastelle-Leprêtre, Sophie; Nicolini, Franck‐Emmanuel; Ferry, Tristan; Morisset, Stéphane; Michallet, Mauricette; Ader, Florence; Bachy, Emmanuel; Balsat, Marie; Bienvenu, Anne‐Lise; Billaud, Geneviève; Biron, F.; Boibieux, A.; Chidiac, Christian; Conrad, Anne; Ducastelle-Leprêtre, Sophie; Dumitrescu, Oana; Dupont, Damien; Escuret, Vanessa; Frobert, Émilie; Grateau, Adeline; Heiblig, Maël; Maréchal, Marion Le; Lebras, Laure; Lina, B.; Li-na, Gao; Quintela, Adrien; Miailhes, Patrick; Michallet, Anne‐Sophie; Monneret, Guillaume; Morfin-Sherpa, Florence; Perpoint, Thomas; Montclos, M. Peyrouse de; Picot, Stéphane; Poitevin-Later, Françoise; Ranc, A.G.; Roux, Sandrine; Salles, Gilles; Saison, J.; Sénéchal, Agathe; Sobh, Mohamad; Thomas, Xavier; Valour, Florent; Wattel, Éric

doi:10.1016/j.jinf.2015.09.039

Cited by 29 publications

(35 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge, no data on JCPyV and other transplant-associated infections are currently available. Certainly, we cannot compare our study with the data of Quintela et al [8] since the authors analyzed a very heterogenic population of stem cell-transplanted patients and the analysis was focused on chromosomal integration, viral coinfections, and T-cell reconstitution patterns.…”

Section: Discussionmentioning

confidence: 84%

“…Quintela et al [8] reported that HHV-6 infection in allogeneic stem cell transplanted patients is significantly associated with CMV and BKPyV infections. To our knowledge, no data on JCPyV and other transplant-associated infections are currently available.…”

Section: Discussionmentioning

confidence: 99%

“…However, there are also sparse data for JCPyV in comparison to BKPyV. The correlation with other opportunistic infections like cytomegalovirus (CMV), human herpes virus 6 (HHV-6), or Epstein-Barr virus (EBV) and the association with GvHD are controversially discussed [8,9,10,11]. Since BKPyV and JCPyV are important pathogens in allogeneic stem cell transplantation, it is important to know the risk factors and associated infections.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

Schneidewind

Neumann²,

Knoll³

et al. 2017

Acta Haematol

View full text Add to dashboard Cite

Background: The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed. Methods: We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years. Results: Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (<10%). There was no association of BKPyV or JCPyV with CMV reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death. Conclusion: We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

Schneidewind

Neumann²,

Knoll³

et al. 2017

Acta Haematol

View full text Add to dashboard Cite

show abstract

“…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%

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

Collin

Gravel

Kaufer

et al. 2018

Preprint

View full text Add to dashboard Cite

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

“…In a minority of children, HHV-6B infection causes grave disease with severe neurological complications, up to lethal encephalitis (7–9). HHV-6A and HHV-6B enter into a latency state, from which they can be reactivated (10–12). Reactivation of HHV-6B following immunosuppressive treatment for bone marrow and other transplantations can result in delayed transplant engraftment and central nervous system (CNS) complications, as well as lethal encephalitis (13–17).…”

Section: Introductionmentioning

confidence: 99%

Human Herpesvirus 6A Exhibits Restrictive Propagation with Limited Activation of the Protein Kinase R-eIF2α Stress Pathway

Sharon

Frenkel

2017

J Virol

View full text Add to dashboard Cite

The eIF2α protein plays a critical role in the regulation of translation. The production of double-stranded RNA (dsRNA) during viral replication can activate protein kinase R (PKR), which phosphorylates eIF2α, leading to inhibition of the initial step of translation. Many viruses have evolved gene products targeting the PKR-eIF2a pathway, indicating its importance in antiviral defense. In the present study, we focused on alternations of PKR-eIF2a pathway during human herpesvirus 6A (HHV-6A) infection while monitoring viral gene expression and infectious viral yields. We have found increased phosphorylated PKR as well as phosphorylated eIF2α coincident with accumulation of the late gp82-105 viral protein. The level of total PKR was relatively constant, but it decreased by 144 h postinfection. The phosphorylation of eIF2a led to a moderate increase in activating transcription factor 4 (ATF4) accumulation, indicating moderate inhibition of protein translation during HHV-6A infection. The overexpression of PKR led to decreased viral propagation coincident with increased accumulation of phosphorylated PKR and phosphorylated eIF2a. Moreover, addition of a dominant negative PKR mutant resulted in a moderate increase in viral replication. HHV-6A exhibits relatively low efficiency of propagation of progeny virus secreted into the culture medium. This study suggests that the replicative strategy of HHV-6A involves a mild infection over a lengthy life cycle in culture, while preventing severe activation of the PKR-eIF2α pathway.IMPORTANCE Human herpesvirus 6A (HHV-6A) and HHV-6B are common, widely prevalent viruses, causing from mild to severe disease. Our study focused on the PKR-eIF2α stress pathway, which limits viral replication. The HHV-6 genome carries multiple genes transcribed from the two strands, predicting accumulation of dsRNAs which can activate PKR and inhibition of protein synthesis. We report that HHV-6A induced the accumulation of phosphorylated PKR and phosphorylated eIF2α and a moderate increase of activating transcription factor 4 (ATF4), which is known to transcribe stress genes. Overexpression of PKR led to increased eIF2α phosphorylation and decreased viral replication, whereas overexpression of a dominant negative PKR mutant resulted in a moderate increase in viral replication. These results suggest that the HHV-6A replication strategy involves restricted activation of the PKR-eIF2α pathway, partial translation inhibition, and lower yields of infectious virus. In essence, HHV-6A limits its own replication due to the inability to bypass the eIF2α phosphorylation.

show abstract

HHV-6 infection after allogeneic hematopoietic stem cell transplantation: From chromosomal integration to viral co-infections and T-cell reconstitution patterns

Cited by 29 publications

References 39 publications

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

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

Human Herpesvirus 6A Exhibits Restrictive Propagation with Limited Activation of the Protein Kinase R-eIF2α Stress Pathway

Contact Info

Product

Resources

About