Molecular Imprint of Exposure to Naturally Occurring Genetic Variants of Human Cytomegalovirus on the T cell Repertoire

Smith, Corey; Gras, Stéphanie; Brennan, Rebekah; Bird, Nicola L.; Valkenburg, Sophie A.; Twist, Kelly-Anne; Burrows, Jacqueline M.; Miles, John J.; Chambers, Daniel C.; Bell, S. C.; Campbell, Scott; Kedzierska, Katherine; Burrows, Scott R.; Rossjohn, Jamie; Khanna, Rajiv

doi:10.1038/srep03993

Cited by 18 publications

(15 citation statements)

References 46 publications

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“…Primary coinfection with genetic variants of CMV is coincident with development of strain-specific T cell immunity followed by the emergence of cross-reactive virus-specific T cells (75). Crossreactive CMV-specific T cells exhibit a highly conserved public T cell repertoire, whereas T cells directed toward specific genetic variants display oligoclonal repertoires unique to each specimen (75). Such diversity in immune response would also be expected to affect cross-reactive immune effects on allografts.…”

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

“…One strain (JP) sequenced from a clinical specimen contained two mutations including one for viral IL-10, an immune-evasion function, implying that HCMV immune evasion mutants exist in human infections (74). Primary coinfection with genetic variants of CMV is coincident with development of strain-specific T cell immunity followed by the emergence of cross-reactive virus-specific T cells (75). Crossreactive CMV-specific T cells exhibit a highly conserved public T cell repertoire, whereas T cells directed toward specific genetic variants display oligoclonal repertoires unique to each specimen (75).…”

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

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The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and cd T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

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Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

Section: Viral Genetics and Variability In Immune Responsementioning

confidence: 99%

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Kaminski

Fishman

2016

American Journal of Transplantation

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“…In addition, new strategies have been developed for concurrent characterization of the CDR3 sequences of TCR ␣ and ␤ chains in epitope-specific CD8 ϩ T cells through simultaneous amplification of CDR3␣ and CDR3␤ transcripts from single cells (12)(13)(14). Because CDR3 loops interact specifically with the MHC-bound antigenic peptide (15), CDR3 sequences serve as unique markers for clonal expansion after T cell activation.…”

Section: Human Cytomegalovirus (Cmv)mentioning

confidence: 99%

Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope

Gao

Chen

Pierce

et al. 2015

Journal of Biological Chemistry

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Background:The human public T cell response to a dominant CMV epitope features high clonal diversity. Results: Structures of two public TCRs bound to this CMV epitope and HLA-A2 reveal different recognition strategies. Conclusion: These structures show how the same public complementarity-determining region 3␣ (CDR3␣) motif can associate with different variable ␣ regions and pair with different CDR3␤s. Significance: This structural interchangeability generates a clonally diverse public TCR repertoire.

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“…It has also been demonstrated that SOT recipients show an increased duration of viremia following reactivation of multiple genotypic isolates (12), suggesting potentially reduced immunological control following coinfection. Despite these observations, and considering the critical role T cell immunity plays in the control of CMV, very little research has been performed that specifically examines the impact of genetically distinct variants of CMV on CMV-specific T cell immunity (13)(14)(15). While this is particularly relevant for R ϩ /D Ϫ HSCT patients, who are at increased risk of CMV-associated complications, immune control of CMV infection in R ϩ /D ϩ recipients could also be impacted by exposure to distinct genetic viral variants of the recipient that are not efficiently controlled by preexisting donor immunity.…”

mentioning

confidence: 99%

“…While this is particularly relevant for R ϩ /D Ϫ HSCT patients, who are at increased risk of CMV-associated complications, immune control of CMV infection in R ϩ /D ϩ recipients could also be impacted by exposure to distinct genetic viral variants of the recipient that are not efficiently controlled by preexisting donor immunity. To address the impact genetic variation has upon T cell immunity, we focused upon the immunodominant immediate early 1 gene (IE-1) of CMV, which has previously been shown to encode significant genetic variation, including within immunodominant CD8 ϩ T cell epitopes (13)(14)(15). Using pyrosequencing analysis to identify genetic variation within IE-1, and IE-1-encoded epitopespecific T cell analysis, we sought to determine the impact of genetic variation and exposure to multiple viral variants on the induction of CMV-specific T cell immunity in a cohort of HSCT recipients.…”

mentioning

confidence: 99%

Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution

Smith

Brennan

Tey

et al. 2016

J Virol

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Reconstitution of T cell immunity is absolutely critical for the effective control of virus-associated infectious complications in hematopoietic stem cell transplant (HSCT) recipients. Coinfection with genetic variants of human cytomegalovirus (CMV) in transplant recipients has been linked to clinical disease manifestation; however, how these genetic variants impact T cell immune reconstitution remains poorly understood. In this study, we have evaluated dynamic changes in the emergence of genetic variants of CMV in HSCT recipients and correlated these changes with reconstitution of antiviral T cell responses. In an analysis of single nucleotide polymorphisms within sequences encoding HLA class I-restricted CMV epitopes from the immediate early 1 gene of CMV, coinfection with genetically distinct variants of CMV was detected in 52% of patients. However, in spite of exposure to multiple viral variants, the T cell responses in these patients were preferentially directed to a limited repertoire of HLA class I-restricted CMV epitopes, either conserved, variant, or cross-reactive. More importantly, we also demonstrate that longterm control of CMV infection after HSCT is primarily mediated through the efficient induction of stable antiviral T cell immunity irrespective of the nature of the antigenic target. These observations provide important insights for the future design of antiviral T cell-based immunotherapeutic strategies for transplant recipients, emphasizing the critical impact of robust immune reconstitution on efficient control of viral infection. IMPORTANCEInfection and disease caused by human cytomegalovirus (CMV) remain a significant burden in patients undergoing hematopoietic stem cell transplantation (HSCT). The establishment of efficient immunological control, primarily mediated by cytotoxic T cells, plays a critical role in preventing CMV-associated disease in transplant recipients. Recent studies have also begun to investigate the impact genetic variation in CMV has upon disease outcome in transplant recipients. In this study, we sought to investigate the role T cell immunity plays in recognizing and controlling genetic variants of CMV. We demonstrate that while a significant proportion of HSCT recipients may be exposed to multiple genetic variants of CMV, this does not necessarily lead to immune control mediated via recognition of this genetic variation. Rather, immune control is associated with the efficient establishment of a stable immune response predominantly directed against immunodominant conserved T cell epitopes.A llogeneic hematopoietic stem cell transplantation (HSCT) can be curative of life-threatening hematological malignancies. However, due to the underlying immunodeficiency associated with HSCT and as a consequence of the immunosuppressive regimes used to prevent graft-versus-host disease following HSCT, infectious complications remain a significant burden to the treatment modality. One significant infectious complication following HSCT is caused by the ubiquitous pathogen huma...

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Molecular Imprint of Exposure to Naturally Occurring Genetic Variants of Human Cytomegalovirus on the T cell Repertoire

Cited by 18 publications

References 46 publications

The Cell Biology of Cytomegalovirus: Implications for Transplantation

The Cell Biology of Cytomegalovirus: Implications for Transplantation

Structural Basis for Clonal Diversity of the Public T Cell Response to a Dominant Human Cytomegalovirus Epitope

Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution

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