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Article ; Online: Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T-cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2.

Becerra-Artiles, Aniuska / Nanaware, Padma P / Muneeruddin, Khaja / Weaver, Grant C / Shaffer, Scott A / Calvo-Calle, J Mauricio / Stern, Lawrence J

PLoS pathogens

2023 Volume 19, Issue 7, Page(s) e1011032

Abstract: Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 ... ...

Abstract	Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but the T-cell response to seasonal coronaviruses remains largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal coronavirus OC43. We identified MHC-bound peptides derived from each of the viral structural proteins (spike, nucleoprotein, hemagglutinin-esterase, membrane, and envelope) as well as non-structural proteins nsp3, nsp5, nsp6, and nsp12. Eighty MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. Fewer and less abundant MHC-I bound OC43-derived peptides were observed, possibly due to MHC-I downregulation induced by OC43 infection. The MHC-II peptides elicited low-abundance recall T-cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T-cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T-cell lines. Among the validated epitopes, spike protein S903-917 presented by DPA101:03/DPB104:01 and S1085-1099 presented by DRB115:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. Nucleoprotein N54-68 and hemagglutinin-esterase HE128-142 presented by DRB115:01 and HE259-273 presented by DPA101:03/DPB104:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow CD4 T-cell cross-reactivity after infection or vaccination, and to guide selection of epitopes for inclusion in pan-coronavirus vaccines.
MeSH term(s)	Humans ; SARS-CoV-2 ; CD4-Positive T-Lymphocytes ; Coronavirus OC43, Human ; Epitopes, T-Lymphocyte ; COVID-19 ; Hemagglutinins ; Seasons ; Esterases ; Spike Glycoprotein, Coronavirus
Chemical Substances	Epitopes, T-Lymphocyte ; Hemagglutinins ; Esterases (EC 3.1.-) ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2023-07-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1011032
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2.

Becerra-Artiles, Aniuska / Nanaware, Padma P / Muneeruddin, Khaja / Weaver, Grant C / Shaffer, Scott A / Calvo-Calle, J Mauricio / Stern, Lawrence J

bioRxiv : the preprint server for biology

2022

Abstract	Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but identification and characterization of the T cell response to seasonal human coronaviruses remain largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal human coronavirus OC43. We identified MHC-I and MHC-II bound peptides derived from the viral spike, nucleocapsid, hemagglutinin-esterase, 3C-like proteinase, and envelope proteins. Only three MHC-I bound OC43-derived peptides were observed, possibly due to the potent MHC-I downregulation induced by OC43 infection. By contrast, 80 MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. These peptides elicited low-abundance recall T cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T cell lines. Among the validated epitopes, S Author summary: There is much current interest in cellular immune responses to seasonal common-cold coronaviruses because of their possible role in mediating protection against SARS-CoV-2 infection or pathology. However, identification of relevant T cell epitopes and systematic studies of the T cell responses responding to these viruses are scarce. We conducted a study to identify naturally processed and presented MHC-I and MHC-II epitopes from human cells infected with the seasonal coronavirus HCoV-OC43, and to characterize the T cell responses associated with these epitopes. We found epitopes specific to the seasonal coronaviruses, as well as epitopes cross-reactive between HCoV-OC43 and SARS-CoV-2. These epitopes should be useful in following immune responses to seasonal coronaviruses and identifying their roles in COVID-19 vaccination, infection, and pathogenesis.
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.12.01.518643
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evaluation of a method to measure HHV-6B infection in vitro based on cell size.

Becerra-Artiles, Aniuska / Santoro, Tessa / Stern, Lawrence J

Virology journal

2018 Volume 15, Issue 1, Page(s) 4

Abstract: Background: Human herpesvirus 6 (HHV-6A and HHV-6B) infection of cell cultures can be measured by different methods, including immunofluorescence microscopy, flow cytometry, or quantification of virus DNA by qPCR. These methods are reliable and ... ...

Abstract	Background: Human herpesvirus 6 (HHV-6A and HHV-6B) infection of cell cultures can be measured by different methods, including immunofluorescence microscopy, flow cytometry, or quantification of virus DNA by qPCR. These methods are reliable and sensitive but require long processing times and can be costly. Another method used in the field relies on the identification of enlarged cells in the culture; this method requires little sample processing and is relatively fast. However, visual inspection of cell cultures can be subjective and it can be difficult to establish clear criteria to decide if a cell is enlarged. To overcome these issues, we explored a method to monitor HHV-6B infections based on the systematic and objective measurement of the size of cells using an imaging-based automated cell counter. Results: The size of cells in non-infected and HHV-6B-infected cultures was measured at different times post-infection. The relatively narrow size distribution observed for non-infected cultures contrasted with the broader distributions observed in infected cultures. The average size of cultures shifted towards higher values after infection, and the differences were significant for cultures infected with relatively high doses of virus and/or screened at longer times post-infection. Correlation analysis showed that the trend observed for average size was similar to the trend observed for two other methods to measure infection: amount of virus DNA in supernatant and the percentage of cells expressing a viral antigen. In order to determine the performance of the size-based method in differentiating non-infected and infected cells, receiver operating characteristic (ROC) curves were used to analyze the data. Analysis using size of individual cells showed a moderate performance in detecting infected cells (area under the curve (AUC) ~ 0.80-0.87), while analysis using the average size of cells showed a very good performance in detecting infected cultures (AUC ~ 0.99). Conclusions: The size-based method proved to be useful in monitoring HHV-6B infections for cultures where a substantial fraction of cells were infected and when monitored at longer times post-infection, with the advantage of being relatively fast and easy. It is a convenient method for monitoring virus production in-vitro and bulk infection of cells.
MeSH term(s)	Antigens, Viral/metabolism ; Cell Line, Tumor ; Cell Size ; Cytopathogenic Effect, Viral ; DNA, Viral/metabolism ; Herpesvirus 6, Human/physiology ; Humans ; Jurkat Cells ; ROC Curve ; Reproducibility of Results ; Roseolovirus Infections/pathology ; Roseolovirus Infections/virology ; Viral Envelope Proteins/metabolism ; Viral Load/methods
Chemical Substances	Antigens, Viral ; DNA, Viral ; Viral Envelope Proteins ; glycoprotein B, human herpesvirus-6 (148770-71-2)
Language	English
Publishing date	2018-01-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Validation Studies
ISSN	1743-422X
ISSN (online)	1743-422X
DOI	10.1186/s12985-017-0917-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Broadly recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles.

Becerra-Artiles, Aniuska / Calvo-Calle, J Mauricio / Co, Mary Dawn / Nanaware, Padma P / Cruz, John / Weaver, Grant C / Lu, Liying / Forconi, Catherine / Finberg, Robert W / Moormann, Ann M / Stern, Lawrence J

Cell reports

2022 Volume 39, Issue 11, Page(s) 110952

Abstract: Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in ... ...

Abstract	Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S
MeSH term(s)	Alleles ; CD4-Positive T-Lymphocytes ; COVID-19 ; COVID-19 Vaccines ; Epitopes, T-Lymphocyte ; HLA Antigens ; Humans ; Receptors, Antigen, T-Cell ; SARS-CoV-2 ; mRNA Vaccines
Chemical Substances	COVID-19 Vaccines ; Epitopes, T-Lymphocyte ; HLA Antigens ; Receptors, Antigen, T-Cell ; mRNA Vaccines
Language	English
Publishing date	2022-05-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110952
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2

Becerra-Artiles, Aniuska / Nanaware, Padma P. / Muneeruddin, Khaja / Weaver, Grant C. / Shaffer, Scott A. / Calvo-Calle, J. Mauricio / Stern, Lawrence J.

bioRxiv

Abstract	Seasonal "common-cold" human coronaviruses are widely spread throughout the world and are mainly associated with mild upper respiratory tract infections. The emergence of highly pathogenic coronaviruses MERS-CoV, SARS-CoV, and most recently SARS-CoV-2 has prompted increased attention to coronavirus biology and immunopathology, but identification and characterization of the T cell response to seasonal human coronaviruses remain largely uncharacterized. Here we report the repertoire of viral peptides that are naturally processed and presented upon infection of a model cell line with seasonal human coronavirus OC43. We identified MHC-I and MHC-II bound peptides derived from the viral spike, nucleocapsid, hemagglutinin-esterase, 3C-like proteinase, and envelope proteins. Only three MHC-I bound OC43-derived peptides were observed, possibly due to the potent MHC-I downregulation induced by OC43 infection. By contrast, 80 MHC-II bound peptides corresponding to 14 distinct OC43-derived epitopes were identified, including many at very high abundance within the overall MHC-II peptidome. These peptides elicited low-abundance recall T cell responses in most donors tested. In vitro assays confirmed that the peptides were recognized by CD4+ T cells and identified the presenting HLA alleles. T cell responses cross-reactive between OC43, SARS-CoV-2, and the other seasonal coronaviruses were confirmed in samples of peripheral blood and peptide-expanded T cell lines. Among the validated epitopes, S903-917 presented by DPA101:03/DPB104:01 and S1085-1099 presented by DRB115:01 shared substantial homology to other human coronaviruses, including SARS-CoV-2, and were targeted by cross-reactive CD4 T cells. N54-68 and HE128-142 presented by DRB115:01 and HE259-273 presented by DPA101:03/DPB104:01 are immunodominant epitopes with low coronavirus homology that are not cross-reactive with SARS-CoV-2. Overall, the set of naturally processed and presented OC43 epitopes comprise both OC43-specific and human coronavirus cross-reactive epitopes, which can be used to follow T cell cross-reactivity after infection or vaccination and could aid in the selection of epitopes for inclusion in pan-coronavirus vaccines.
Keywords	covid19
Language	English
Publishing date	2022-12-01
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.12.01.518643
Database	COVID19

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Article: Evaluation of a method to measure HHV-6B infection in vitro based on cell size

Becerra-Artiles, Aniuska / Tessa Santoro / Lawrence J. Stern

Virology journal. 2018 Dec., v. 15, no. 1

2018

Abstract: BACKGROUND: Human herpesvirus 6 (HHV-6A and HHV-6B) infection of cell cultures can be measured by different methods, including immunofluorescence microscopy, flow cytometry, or quantification of virus DNA by qPCR. These methods are reliable and sensitive ...

Abstract	BACKGROUND: Human herpesvirus 6 (HHV-6A and HHV-6B) infection of cell cultures can be measured by different methods, including immunofluorescence microscopy, flow cytometry, or quantification of virus DNA by qPCR. These methods are reliable and sensitive but require long processing times and can be costly. Another method used in the field relies on the identification of enlarged cells in the culture; this method requires little sample processing and is relatively fast. However, visual inspection of cell cultures can be subjective and it can be difficult to establish clear criteria to decide if a cell is enlarged. To overcome these issues, we explored a method to monitor HHV-6B infections based on the systematic and objective measurement of the size of cells using an imaging-based automated cell counter. RESULTS: The size of cells in non-infected and HHV-6B-infected cultures was measured at different times post-infection. The relatively narrow size distribution observed for non-infected cultures contrasted with the broader distributions observed in infected cultures. The average size of cultures shifted towards higher values after infection, and the differences were significant for cultures infected with relatively high doses of virus and/or screened at longer times post-infection. Correlation analysis showed that the trend observed for average size was similar to the trend observed for two other methods to measure infection: amount of virus DNA in supernatant and the percentage of cells expressing a viral antigen. In order to determine the performance of the size-based method in differentiating non-infected and infected cells, receiver operating characteristic (ROC) curves were used to analyze the data. Analysis using size of individual cells showed a moderate performance in detecting infected cells (area under the curve (AUC) ~ 0.80-0.87), while analysis using the average size of cells showed a very good performance in detecting infected cultures (AUC ~ 0.99). CONCLUSIONS: The size-based method proved to be useful in monitoring HHV-6B infections for cultures where a substantial fraction of cells were infected and when monitored at longer times post-infection, with the advantage of being relatively fast and easy. It is a convenient method for monitoring virus production in-vitro and bulk infection of cells.
Keywords	Human herpesvirus 6 ; cell culture ; correlation ; flow cytometry ; fluorescence microscopy ; monitoring ; quantitative polymerase chain reaction ; viral antigens ; viruses
Language	English
Dates of publication	2018-12
Size	p. 4.
Publishing place	BioMed Central
Document type	Article
ISSN	1743-422X
DOI	10.1186/s12985-017-0917-z
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Broadly recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles

Aniuska Becerra-Artiles / J. Mauricio Calvo-Calle / Mary Dawn Co / Padma P. Nanaware / John Cruz / Grant C. Weaver / Liying Lu / Catherine Forconi / Robert W. Finberg / Ann M. Moormann / Lawrence J. Stern

Cell Reports, Vol 39, Iss 11, Pp 110952- (2022)

2022

Abstract: Summary: Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in ... ...

Abstract	Summary: Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can affect T cell response in COVID-19. We studied T cell responses to SARS-CoV-2 and HCoVs in convalescent COVID-19 donors and identified a highly conserved SARS-CoV-2 sequence, S811-831, with overlapping epitopes presented by common MHC class II proteins HLA-DQ5 and HLA-DP4. These epitopes are recognized by low-abundance CD4 T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. T cell cross-reactivity is driven by the high conservation across human and animal coronaviruses of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC class II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly conserved CD4 T cell epitope broadly recognized across human populations.
Keywords	CP: Immunology ; CP: Microbiology ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Naturally processed HLA-DR3-restricted HHV-6B peptides are recognized broadly with polyfunctional and cytotoxic CD4 T-cell responses.

Becerra-Artiles, Aniuska / Cruz, John / Leszyk, John D / Sidney, John / Sette, Alessandro / Shaffer, Scott A / Stern, Lawrence J

European journal of immunology

2019 Volume 49, Issue 8, Page(s) 1167–1185

Abstract: 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 ... ...

Abstract	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
MeSH term(s)	Antigen Presentation ; Antigens, Viral/metabolism ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/virology ; Cells, Cultured ; Cytotoxicity, Immunologic ; Epitope Mapping ; HLA-DR3 Antigen/metabolism ; Herpesvirus 6, Human/physiology ; Humans ; Immunodominant Epitopes ; Interferon-gamma/metabolism ; Lymphocyte Activation ; Mass Spectrometry ; Peptides/metabolism ; Roseolovirus Infections/immunology
Chemical Substances	Antigens, Viral ; HLA-DR3 Antigen ; Immunodominant Epitopes ; Peptides ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2019-05-02
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201948126
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Article ; Online: Broadly-recognized, cross-reactive SARS-CoV-2 CD4 T cell epitopes are highly conserved across human coronaviruses and presented by common HLA alleles

Becerra-Artiles, Aniuska / Calvo-Calle, Jaime M / Co, Marydawn / Nanaware, Padma / Cruz, John / Weaver, Grant C / Lu, Liying / Forcini, Catherine / Finberg, Robert W / Moormann, Ann / Stern, Lawrence J

bioRxiv

Abstract: Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can impact the T cell response in COVID-19. We studied T cells recognizing SARS-CoV-2 and HCoVs in ... ...

Abstract	Sequence homology between SARS-CoV-2 and common-cold human coronaviruses (HCoVs) raises the possibility that memory responses to prior HCoV infection can impact the T cell response in COVID-19. We studied T cells recognizing SARS-CoV-2 and HCoVs in convalescent COVID-19 donors, and identified a highly conserved SARS-CoV-2 sequence S811-831, with two overlapping epitopes presented by common MHC-II proteins HLA-DQ5 and HLA-DP4. These epitopes were recognized by CD4+ T cells from convalescent COVID-19 donors, mRNA vaccine recipients, and by low-abundance CD4+ T cells in uninfected donors. TCR sequencing revealed a diverse repertoire with public TCRs. CD4+ T cell cross-reactivity was driven by the remarkably strong conservation of T cell contact residues in both HLA-DQ5 and HLA-DP4 binding frames, with distinct patterns of HCoV cross-reactivity explained by MHC-II binding preferences and substitutions at secondary TCR contact sites. These data highlight S811-831 as a highly-conserved CD4+ T cell epitope broadly recognized across human populations.
Keywords	covid19
Language	English
Publishing date	2022-01-22
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2022.01.20.477107
Database	COVID19

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Article ; Online: A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B.

Becerra-Artiles, Aniuska / Dominguez-Amorocho, Omar / Stern, Lawrence J / Calvo-Calle, J Mauricio

PloS one

2015 Volume 10, Issue 11, Page(s) e0142871

Abstract: Most of humanity is chronically infected with human herpesvirus 6 (HHV-6), with viral replication controlled at least in part by a poorly characterized CD4 T cell response. Identification of viral epitopes recognized by CD4 T cells is complicated by the ... ...

Abstract	Most of humanity is chronically infected with human herpesvirus 6 (HHV-6), with viral replication controlled at least in part by a poorly characterized CD4 T cell response. Identification of viral epitopes recognized by CD4 T cells is complicated by the large size of the herpesvirus genome and a low frequency of circulating T cells responding to the virus. Here, we present an alternative to classical epitope mapping approaches used to identify major targets of the T cell response to a complex pathogen like HHV-6B. In the approach presented here, extracellular virus preparations or virus-infected cells are fractionated by SDS-PAGE, and eluted fractions are used as source of antigens to study cytokine responses in direct ex vivo T cell activation studies. Fractions inducing significant cytokine responses are analyzed by mass spectrometry to identify viral proteins, and a subset of peptides from these proteins corresponding to predicted HLA-DR binders is tested for IFN-γ production in seropositive donors with diverse HLA haplotypes. Ten HHV-6B viral proteins were identified as immunodominant antigens. The epitope-specific response to HHV-6B virus was complex and variable between individuals. We identified 107 peptides, each recognized by at least one donor, with each donor having a distinctive footprint. Fourteen peptides showed responses in the majority of donors. Responses to these epitopes were validated using in vitro expanded cells and naturally expressed viral proteins. Predicted peptide binding affinities for the eight HLA-DRB1 alleles investigated here correlated only modestly with the observed CD4 T cell responses. Overall, the response to the virus was dominated by peptides from the major capsid protein U57 and major antigenic protein U11, but responses to other proteins including glycoprotein H (U48) and tegument proteins U54 and U14 also were observed. These results provide a means to follow and potentially modulate the CD4 T-cell immune response to HHV-6B.
MeSH term(s)	Algorithms ; Alleles ; Amino Acid Sequence ; Antigens, Viral/immunology ; CD4-Positive T-Lymphocytes/immunology ; Cell Separation ; Chromatography, Liquid ; HLA-DRB1 Chains/immunology ; Haplotypes/genetics ; Herpesvirus 6, Human/immunology ; Humans ; Immunodominant Epitopes/immunology ; Interferon-gamma/metabolism ; Mass Spectrometry ; Molecular Sequence Data ; Peptides/chemistry ; Protein Binding ; Proteomics/methods ; Reproducibility of Results ; Tissue Donors ; Viral Proteins/immunology
Chemical Substances	Antigens, Viral ; HLA-DRB1 Chains ; Immunodominant Epitopes ; Peptides ; Viral Proteins ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0142871
Database	MEDical Literature Analysis and Retrieval System OnLINE

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