Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6

Greninger, Alexander L.; Knudsen, Giselle M.; Roychoudhury, Pavitra; Hanson, Derek J.; Sedlak, Ruth Hall; Xie, Hong; Guan, Jon; Nguyen, Thuy; Peddu, Vikas; Boeckh, Michael; Huang, Meei Li; Cook, Linda; Depledge, Daniel P.; Zerr, Danielle M.; Koelle, David M.; Gantt, Soren; Yoshikawa, Tetsushi; Caserta, Mary T.; Hill, Joshua A.; Jerome, Keith R.

doi:10.1186/s12864-018-4604-2

Cited by 49 publications

(72 citation statements)

References 62 publications

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“…One possible explanation for the abundance of U85‐derived epitopes among the eluted peptides is the relatively high affinity for DRB1*03:01 (IC 50 = 18 nM). Another potential explanation might be a high abundance of the protein in infected cells, but although previous work has demonstrated expression of the U85 gene as an immediate‐early transcript in HHV‐6B‐infected SupT1 cells , the protein product was not detected in a recent proteomic study of cell lysates . The reason for this is not known, but the presence of specific T‐cell responses suggests that expression of the U85 protein and generation of the CD4 T‐cell epitope also occurs during natural infections.…”

Section: Discussionmentioning

confidence: 97%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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Human herpes virus 6B (HHV‐6B) is a widespread virus that infects most people early in infancy and establishes a chronic life‐long infection with periodic reactivation. CD4 T cells have been implicated in control of HHV‐6B, but antigenic targets and functional characteristics of the CD4 T‐cell response are poorly understood. We identified 25 naturally processed MHC‐II peptides, derived from six different HHV‐6B proteins, and showed that they were recognized by CD4 T‐cell responses in HLA‐matched donors. The peptides were identified by mass spectrometry after elution from HLA‐DR molecules isolated from HHV‐6B‐infected T cells. The peptides showed strong binding to matched HLA alleles and elicited recall T‐cell responses in vitro. T‐cell lines expanded in vitro were used for functional characterization of the response. Responding cells were mainly CD3+CD4+, produced IFN‐γ, TNF‐α, and low levels of IL‐2, alone or in combination, highlighting the presence of polyfunctional T cells in the overall response. Many of the responding cells mobilized CD107a, stored granzyme B, and mediated specific killing of peptide‐pulsed target cells. These results highlight a potential role for polyfunctional cytotoxic CD4 T cells in the long‐term control of HHV‐6B infection.

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Section: Discussionmentioning

confidence: 97%

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

et al. 2019

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“…Of note, only seven other published iciHHV‐6B (four US and three Asiatic) strains had a different entire U39 sequence. The phylogenetic analysis showed that the same partial sequence was found in 18 community HHV‐6B strains (of which nine US strains) but was clearly different from those of 74 others including 20 US strains, with one to 10 differences among the 16 single nucleotide polymorphisms highlighted for HHV‐6B (Figure A,B) . This led us to suggest that the DNA detected in the blood corresponded to iciHHV‐6B originated from the liver and unlikely from an endogenous community strain.…”

Section: Resultsmentioning

confidence: 99%

“…The part of U39 sequenced in the transplanted liver and the plasma of the recipient was compared to published sequences of different HHV-6B and iciHHV-6B strains from different countries. 7,14,18,19 Only the different sequences represented by a reference strain were used to build a phylogenetic tree using the Maximum Likelihood Table 1). These results were compatible with the presence of iciHHV-6B in the donor (≥1 copy per cell).…”

Section: Phylogenetic Analysis Of a Part Of U39 Genementioning

confidence: 99%

“…US strains, with one to 10 differences among the 16 single nucleotide polymorphisms highlighted for HHV-6B ( Figure 1A,B). 7,14,18,19 This led us to suggest that the DNA detected in the blood corresponded to iciHHV-6B originated from the liver and unlikely from an endogenous community strain.…”

Section: Identity Of Hhv-6b U39 Sequences In the Donor And The Recimentioning

confidence: 99%

“…In this clinical case, the persistence of HHV-6B DNA in blood and liver biopsies despite treatment with ganciclovir and foscarnet led to the F I G U R E 1 Molecular phylogenetic analysis of a part of U39 from HHV-6B and iciHHV-6B strains. The part of the U39 gene from nucleotide 760 to 1154 (Seq#1 part, 395 bp) sequenced in the transplanted liver and the plasma of the recipient (TCH-B1 US) was compared to published sequences of different HHV-6B and iciHHV-6B strains from different countries 7,13,14,19. (A) The Maximum Likelihood phylogenetic analysis was conducted via MEGA7 (1000 replicates, bootstrap values indicated for each node) with General Time Reversible model using only different sequences represented by a reference strain20,21 ; (B) the single nucleotide polymorphisms among the different reference strains are detailed, as well as the total number of published strains sharing these sequences (including US strains) exploration of various hypotheses concerning the pathophysiology of this viral infection.The diagnosis of iciHHV-6B in the donor resulted from studies of the allograft where ≥1 copy of HHV-6B genome/cell was found in addition to positive HHV-6 PCR in donor gallbladder sections.…”

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Evaluation of liver failure in a pediatric transplant recipient of a liver allograft with inherited chromosomally integrated HHV‐6B

Bonnafous

Phan

Himes

et al. 2019

Journal of Medical Virology

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Background Active infections of human herpesvirus 6B (HHV‐6B) are frequent in immunocompromised recipients after transplantation. Nevertheless, they need to be distinguished from latent inherited chromosomally integrated genomes (iciHHV‐6) present in about 1% of the population to avoid unnecessary administration of toxic antivirals. Methods A 5‐year‐old child presented with acute liver allograft rejection associated with HHV‐6 DNA in plasma, which led to an unfavorable outcome. We investigated the possibility of HHV‐6 infection derived from an iciHHV‐6 present in the donor's liver using molecular and histopathology studies in various tissues, including quantification of HHV‐6 DNA, genotyping, sequencing for antiviral resistance genes, relative quantification of viral transcripts, and detection of gB and gH viral proteins. Results The presence of iciHHV‐6B was evidenced in the donor with signs of reactivation in the gallbladder and transplanted liver (detection of HHV‐6B mRNA and late proteins). This localized expression could have played a role in liver rejection. Low viral loads in the recipient's plasma, with identical partial U39 sequences, were in favor of viral DNA released from the transplanted liver rather than a systemic infection. Conclusions Determination of iciHHV‐6 status before transplantation should be considered to guide clinical decisions, such as antiviral prophylaxis, viral load monitoring, and antiviral therapy.

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Human Herpesviruses 6A, 6B, and 7

Greninger,

Sedlak,

Jerome

2023

ClinMicroNow

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Human herpesvirus (HHV) 6A, HHV‐6B, and HHV‐7 are three distinct virus species that make up the Roseolovirus genus. Like HHV‐6, HHV‐7 infection is highly prevalent and infects most individuals during childhood. HHV‐7 DNA has been detected more frequently and at higher loads in affected tissues from non‐immunocompromised patients with interstitial pneumonia. Interpreting HHV‐6 detection by PCR in clinical specimens is complicated by both the ubiquity of subclinical reactivation and inherited chromosomally integrated forms. HHV‐6A and HHV‐6B can be typed through the use of species‐specific monoclonal antibodies and species‐specific PCR assays. The most usual setting for HHV‐6 testing is in the context of immunosuppression, especially hematopoietic cell or solid organ transplantation. Like all herpesviruses, HHV‐7 establishes latency after primary infection, and thus reactivation can later occur, particularly in the setting of immunodeficiency. Cytomegalovirus viremia is also more frequent among recipients with inherited chromosomally integrated HHV‐6.

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Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6

Cited by 49 publications

References 62 publications

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Naturally processed HLA‐DR3‐restricted HHV‐6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T‐cell responses

Evaluation of liver failure in a pediatric transplant recipient of a liver allograft with inherited chromosomally integrated HHV‐6B

Human Herpesviruses 6A, 6B, and 7

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