Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6

Barozzi, Patrizia; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Lagreca, Ivana; Eccheli, R.; Forghieri, Fabio; Coluccio, Valeria; Maccaferri, Monica; Paolini, Ambra; Colaci, Elisabetta; Morselli, Monica; Marasca, Roberto; Narni, Franco; Comoli, Patrizia; Campioli, Daniele; Trenti, Tommaso; Potenza, Leonardo; Luppi, Mario

doi:10.1016/j.cmi.2016.07.006

Cited by 7 publications

(8 citation statements)

References 5 publications

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“…To date, HHV-6 integration has been identified in the telomere of the X chromosome and 11 of the autosomal chromosomes (1, 6, 7, 9, 10, 11, 12, 17, 18, 19, 22) [ 36 , 40 , 41 , 43 , 46 , 59 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. However, no studies indicate that HHV-6 integration is chromosome specific.…”

Section: Future Of the Field Of Hhv-6mentioning

confidence: 99%

Latency, Integration, and Reactivation of Human Herpesvirus-6

Pantry

Medveczky

2017

Viruses

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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.

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Section: Future Of the Field Of Hhv-6mentioning

confidence: 99%

Latency, Integration, and Reactivation of Human Herpesvirus-6

Pantry

Medveczky

2017

Viruses

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“…Indeed, PBMCs of iciHHV-6A donors can be induced in vitro to produce virions, which can then infect non-integrated HHV-6A-negative cells, so, in vivo antigen expression from iciHHV-6 ORFs seems plausible ( 117 ). Presumably, T cells educated in thymi of people with iciHHV-6 would be tolerized to HHV-6 antigens; however, iciHHV-6 individuals actually have high frequencies of CD8+ T cells specific for products of U54 ( 118 ) and U90 ( 3 ), suggesting active immune surveillance. More research is needed to compare the T-cell response to HHV-6 in people with and without chromosomal integration.…”

Section: Leading Hhv-6 T-cell Antigensmentioning

confidence: 99%

“…About 1% of humans have inherited chromosomally integrated HHV-6 (ici-HHV-6) ( 2 ). Interestingly, immune tolerance has not been demonstrated and persons with ici-HHV-6 appear to maintain anti-HHV-6 cell-mediated immunity (CMI) ( 3 ). Primary infection with HHV-6B usually occurs once maternal antibodies have waned in early life ( 4 , 5 ).…”

Section: Introductionmentioning

confidence: 99%

Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6

2018

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Human herpesvirus (HHV) 6 is thought to remain clinically latent in most individuals after primary infection and to reactivate to cause disease in persons with severe immunosuppression. In allogeneic hematopoietic stem cell transplant recipients, reactivation of HHV-6 species B is a considerable cause of morbidity and mortality. HHV-6B reactivation is the most frequent cause of infectious meningoencephalitis in this setting and has been associated with a variety of other complications such as graft rejection and acute graft versus host disease. This has inspired efforts to develop HHV-6-targeted immunotherapies. Basic knowledge of HHV-6-specific adaptive immunity is crucial for these endeavors, but remains incomplete. Many studies have focused on specific HHV-6 antigens extrapolated from research on human cytomegalovirus, a genetically related betaherpesvirus. Challenges to the study of HHV-6-specific T-cell immunity include the very low frequency of HHV-6-specific memory T cells in chronically infected humans, the large genome size of HHV-6, and the lack of an animal model. This review will focus on emerging techniques and methodological improvements that are beginning to overcome these barriers. Population-prevalent antigens are now becoming clear for the CD4+ T-cell response, while definition and ranking of CD8+ T-cell antigens and epitopes is at an earlier stage. This review will discuss current knowledge of the T-cell response to HHV-6, new research approaches, and translation to clinical practice.

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“…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

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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.

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Circulating functional T cells specific to human herpes virus 6 (HHV6) antigens in individuals with chromosomally integrated HHV6

Cited by 7 publications

References 5 publications

Latency, Integration, and Reactivation of Human Herpesvirus-6

Latency, Integration, and Reactivation of Human Herpesvirus-6

Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6

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

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