Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity

Strenger, Volker; Kayser, Simone; Witte, Kai; Laßner, Dirk; Schwinger, Wolfgang; Jahn, Gerhard; Urban, Christian; Feuchtinger, Tobias

doi:10.1016/j.cmi.2015.10.006

Cited by 15 publications

(16 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The absence of reactivation in all inherited ciHHV-6A-positive recipients who received ciHHV-6-negative donor cells (n ϭ 6) generates speculation about whether there may be an immune response in inherited ciHHV-6-positive individuals that reduces the risk of reactivation of latent HHV-6B. Along those lines, recent work showed increased HHV-6-specific functionally active immune responses in individuals with inherited ciHHV-6 (17).…”

Section: Discussionmentioning

confidence: 94%

Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR

et al. 2016

View full text Add to dashboard Cite

eThe presence of inherited chromosomally integrated human herpesvirus 6 (ciHHV-6) in hematopoietic cell transplant (HCT) donors or recipients confounds molecular testing for HHV-6 reactivation, which occurs in 30 to 50% of transplants. Here we describe a multiplex droplet digital PCR clinical diagnostic assay that concurrently distinguishes between HHV-6 species (A or B) and identifies inherited ciHHV-6. By applying this assay to recipient post-HCT plasma and serum samples, we demonstrated reactivation of HHV-6B in 25% (4/16 recipients) of HCT recipients with donor-or recipient-derived inherited ciHHV-6A, underscoring the need for diagnostic testing for HHV-6 infection even in the presence of ciHHV-6. Human herpesvirus 6A and -B (HHV-6A and -B) are known to be able to integrate within human chromosomal subtelomeric regions through homologous recombination at HHV-6 direct repeat regions (1). If this integration occurs within germ line cells, the offspring produced from those cells carry a copy of HHV-6A or -B in every nucleated cell; this condition is called inherited chromosomally integrated HHV-6A or -B (ciHHV-6A or -B) (2). The presence of ciHHV-6A or -B in every cell of the body has unknown effects (3), but two recent studies suggested a link between inherited ciHHV-6A or -B and angina pectoris (4, 5). Also, several reports have demonstrated HHV-6 reactivation and associated disease from inherited ciHHV-6 (6, 7).HHV-6B reactivation (but not HHV-6A reactivation) occurs in 30 to 50% of hematopoietic cell transplant (HCT) recipients, typically within the first 2 to 6 weeks posttransplantation. This has been associated with complications, such as central nervous system dysfunction, fever and rash, myelosuppression, graft rejection, and acute graft-versus-host disease (GVHD), some of which have also been reported after solid organ transplantation (8). While further research is needed to determine the clinical significance of inherited ciHHV-6A or -B after transplantation, it is well recognized that inherited ciHHV-6A or -B complicates molecular diagnostic testing for HHV-6B reactivation (9, 10). Specifically, tissue and blood samples from patients with inherited ciHHV-6A or -B will have high levels of HHV-6A or -B detected by routine quantitative PCR (qPCR), obscuring detection of HHV-6B reactivation.To aid in the recognition of inherited ciHHV-6 in the transplant setting, we recently developed a clinical droplet digital PCR (ddPCR) assay to identify inherited ciHHV-6 in cellular patient specimens (11). A subsequent study demonstrated the utility of ddPCR in distinguishing HHV-6A and -B (12). Here we describe an improved assay that identifies inherited ciHHV-6 and determines which species, HHV-6A or HHV-6B, is responsible for the integration by using a single reaction mixture. We also show that this assay can aid in the diagnosis of reactivated HHV-6B in HCT recipients with inherited ciHHV-6A, which further highlights the need for improved diagnostics for HHV-6 reactivation, particularly in immunosuppressed patien...

show abstract

Section: Discussionmentioning

confidence: 94%

Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR

et al. 2016

View full text Add to dashboard Cite

show abstract

“…33 However, HHV-6-antigen-specific cytokine responses can be detected in individuals with iciHHV-6, suggesting the condition may not be immunologically silent. 34 Our understanding of the immunologic effects of prior herpesvirus infections continues to evolve. A large study investigating the effect of Epstein-Barr virus seropositivity on outcomes in HCT recipients with acute leukemia found an association between donor seropositivity and acute and chronic GVHD they attribute to Epstein-Barr virus-infected donor B-cell activity.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6

Hill

Magaret

Hall-Sedlak³

et al. 2017

Blood

View full text Add to dashboard Cite

• Inherited ciHHV-6 was detected in 1.4% of HCT recipients and 0.9% of their donors.• Acute GVHD grades 2-4 and cytomegalovirus viremia were more frequent when recipients or donors had inherited ciHHV-6.Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear.We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post-HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P 5 .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P 5 .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post-HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms. (Blood. 2017;130(8):1062-1069

show abstract

“…Peptide epitopes confirmed here for U14, U90, and U95 had sequence homology to the related betaherpesviruses HHV-6A (all epitopes) and HHV-7 (nine epitopes) (see Table S2 in the supplemental material), suggesting possible cross-reactivity. Twenty-one epitopes had identity with the iciHHV-6B genomic sequence (GenBank accession number KY315520.1), and albeit beyond the purview of this study, it would be interesting to test if these epitopes are recognized by HHV-6B-specific T cells in a cohort with iciHHV-6B (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Approach to the CD4 T-Cell Response to Human Herpesvirus 6B

Hanson

Цветкова

Rerolle

et al. 2019

J Virol

View full text Add to dashboard Cite

Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) are populationprevalent betaherpesviruses with intermittent lytic replication that can be pathogenic in immunocompromised hosts. Elucidation of the adaptive immune response is valuable for understanding pathogenesis and designing novel treatments. Knowledge of T-cell antigens has reached the genome-wide level for CMV and other human herpesviruses, but study of HHV-6 is at an earlier stage. Using rare-cell enrichment combined with an HLA-agnostic, proteome-wide approach, we queried HHV-6B-specific CD4 T cells from 18 healthy donors with each known HHV-6B protein. We detected a low abundance of HHV-6-specific CD4 T cells in blood; however, the within-person CD4 T-cell response is quite broad: the median number of open reading frame (ORF) products recognized was nine per person. Overall, the data expand the number of documented HHV-6B CD4 T-cell antigens from approximately 11 to 60. Epitopes in the proteins encoded by U14, U90, and U95 were mapped with synthetic peptides, and HLA restriction was defined for some responses. Intriguingly, CD4 T-cell antigens newly described in this report are among the most population prevalent, including U73, U72, U95, and U30. Our results indicate that selection of HHV-6B ORFs for immunotherapy should consider this expanded panel of HHV-6B antigens. RESULTS Peripheral blood of healthy donors contains HHV-6B-specific CD4 T cells that can be enriched in vitro.The initial cohort of 53 healthy donors was 34% male, and the median age at the time of blood draw was 40 years (range, 21 to 68 years). To ascertain the frequency of HHV-6B-specific CD4 T cells in peripheral blood, peripheral blood mononuclear cells (PBMCs) were assayed by an interleukin-2 (IL-2)/interferon gamma (IFN-␥) intracellular cytokine cytometry (ICC) assay (Fig. 1A). Donors had virus-specific cell populations that were of low abundance but clearly discernible in most subjects. Responses were typically less than 0.1% of total CD4 T cells, with an overall median of 0.048% (Fig. 1B).Given the low abundance of HHV-6-reactive CD4 T cells in PBMCs, we enriched these cells from 42 donors prior to interrogation of the HHV-6B protein library. These donors were chosen based on PBMC availability and a detectable response to HHV-6B ex vivo.

show abstract

Individuals with inherited chromosomally integrated human herpes virus 6 (ciHHV-6) have functionally active HHV-6 specific T-cell immunity

Cited by 15 publications

References 18 publications

Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR

Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR

Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6

Genome-Wide Approach to the CD4 T-Cell Response to Human Herpesvirus 6B

Contact Info

Product

Resources

About