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Abstract
BackgroundHuman adenovirus (HAdV) infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Efficient antiviral T-cell responses are necessary to clear infection, which is hampered by delayed immune reconstitution and medical immunosuppression after HSCT. Protective immunity may be conferred by adoptive transfer of HAdV-specific T cells. For identification of patients at risk and monitoring of treatment responses diligent assessment of anti-HAdV cellular immune responses is crucial. The HAdV-derived protein hexon has been recognized as a major immunodominant target across HAdV species. We aimed at identifying further targets of protective anti-HAdV immune response and characterizing immunogenic epitopes.MethodsNineteen candidate nonamers from hexon and penton proteins were identified by epitope binding prediction. Peptides were synthesized and tested for in vivo immunogenicity by screening peripheral blood mononuclear cells from healthy volunteers (n = 64) and HAdV-infected stem cell recipients (n = 26) for memory T cells recognizing the candidate epitopes in the context of most common HLA alleles.ResultsFunctional CD8+ T cells recognizing seven epitopes were identified, among them four penton-derived and two hexon-derived peptides. The HLA-A*01-restricted penton-derived peptide STDVASLNY (A01PentonSTDV) and HLA-A*02-restricted hexon-derived peptide TLLYVLFEV (A02HexonTLLY) were recognized by more than half of the persons carrying the respective HLA-type.ConclusionsThus, the HAdV-derived penton protein is a novel major target of the anti-HAdV immune response. Identification of new immunodominant epitopes will facilitate and broaden immune assessment strategies to identify patients suitable for T-cell transfer. Knowledge of additional target structures may increase T-cell recovery in manufacturing processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1042-2) contains supplementary material, which is available to authorized users.
Highlights
Human adenovirus (HAdV) infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT)
Selection of potential HLA‐restricted peptide epitopes within hexon and penton protein A total of 947 hexon- and penton-derived epitope candidates restricted to HLA-types A*01, A*02, A*03, and B*08 were identified by the computer algorithms SYFPEITHI, BIMAS, and NetChop (Fig. 1)
In summary, HAdV-specific T-cell responses to novel identified immunodominant cytotoxic T lymphocyte (CTL) epitopes were observed in healthy donors, and the in vivo relevance of these identified CTL epitopes, as predicted by computer algorithms, was confirmed in HAdV-infected patients
Summary
Human adenovirus (HAdV) infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Protective immu‐ nity may be conferred by adoptive transfer of HAdV-specific T cells. Human adenovirus (HAdV) infection constitutes a major cause of morbidity and mortality in patients undergoing. Adoptive transfer of HAdVspecific T cells offers an effective and non-toxic immunotherapeutic strategy to reduce or prevent the clinical manifestation of HAdV in HSCT recipients with no or low numbers of HAdV-specific T cells [2, 8,9,10,11,12]. Monitoring HAdV-specific T-cell immunity may improve risk assessment in HSCT recipients and enhance treatment efficacy by determining the optimal time point for adoptive T-cell transfer. Since the generation of short-term in vitro generated virus-specific T-cell lines takes about 3 weeks including quality controls, the production should start even earlier at the time of high viral load in stool (>106 copies) [12, 15]
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