Respiratory syncytial virus (RSV) infection is a serious health problem in young children, immunocompromised patients, and the elderly. The development of novel prevention strategies, such as a vaccine to RSV, is a high priority. One strategy is to design a peptide-based vaccine that activates appropriate CD8+ T-cell responses. However, this approach is limited by the low number of RSV peptide epitopes defined to date that activate CD8+ T cells. We aimed to identify peptide epitopes that are presented by common human leukocyte antigen types (HLA-A*01, -A*02, and -B*07). We identify one novel HLA-A*02-restricted and two novel HLA-A*01-restricted peptide epitopes from RSV polymerase. Peptide-HLA multimer staining of specific T cells from healthy donor peripheral blood mononuclear cell, the memory phenotype of such peptide-specific T cells ex vivo, and functional IFNγ responses in short-term stimulation assays suggest that these peptides are recognized during RSV infection. Such peptides are candidates for inclusion into a peptide-based RSV vaccine designed to stimulate defined CD8+ T-cell responses.
Get full access to this article
View all access options for this article.
References
1.
AndersonLJ, DormitzerPR, NokesDJ, et al.Strategic priorities for respiratory syncytial virus (RSV) vaccine development. Vaccine, 2013; 31Suppl 2:B209–B215.
2.
BrandenburgAH, de WaalL, TimmermanHH, et al.HLA class I-restricted cytotoxic T-cell epitopes of the respiratory syncytial virus fusion protein. J Virol, 2000; 74:10240–10244.
3.
CannonMJ, OpenshawPJ, and AskonasBA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med, 1988; 168:1163–1168.
4.
de BreeGJ, van LeeuwenEM, OutTA, et al.Selective accumulation of differentiated CD8+ T cells specific for respiratory viruses in the human lung. J Exp Med, 2005; 202:1433–1442.
5.
DeVincenzoJP, WilkinsonT, VaishnawA, et al.Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Critic Care Med, 2010; 182:1305–1314.
6.
FalseyAR, HennesseyPA, FormicaMA, et al.Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med, 2005; 352:1749–1759.
7.
FujisakiH, KakudaH, ShimasakiN, et al.Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res, 2009; 69:4010–4017.
8.
GeyereggerR, FreimullerC, StevanovicS, et al.Short-term in-vitro expansion improves monitoring and allows affordable generation of virus-specific T-cells against several viruses for a broad clinical application. PloS One, 2013; 8:e59592.
9.
GoulderPJ, LechnerF, KlenermanP, et al.Characterization of a novel respiratory syncytial virus-specific human cytotoxic T-lymphocyte epitope. J Virol, 2000; 74:7694–7697.
10.
GrahamBS. Biological challenges and technological opportunities for respiratory syncytial virus vaccine development. Immunol Rev, 2011; 239:149–166.
11.
GrahamBS, BuntonLA, WrightPF, and KarzonDT. Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest, 1991; 88:1026–1033.
12.
GretenTF, KorangyF, NeumannG, et al.Peptide-beta2-microglobulin-MHC fusion molecules bind antigen-specific T cells and can be used for multivalent MHC-Ig complexes. J Immunol Methods, 2002; 271:125–135.
13.
GuntherPS, PeperJK, FaistB, et al.Identification of a novel immunodominant HLA-B*07: 02-restricted adenoviral peptide epitope and its potential in adoptive transfer immunotherapy. J Immunother, 2015; 38:267–275.
14.
HallCB, WalshEE, LongCE, and SchnabelKC. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis, 1991; 163:693–698.
15.
HallCB, PowellKR, MacDonaldNE, et al.Respiratory syncytial viral infection in children with compromised immune function. N Engl J Med, 1986; 315:77–81.
16.
HeidemaJ, de BreeGJ, De GraaffPM, et al.Human CD8(+) T cell responses against five newly identified respiratory syncytial virus-derived epitopes. J Gen Virol, 2004; 85:2365–2374.
17.
InfantesS, LorenteE, BarneaE, et al.Multiple, non-conserved, internal viral ligands naturally presented by HLA-B27 in human respiratory syncytial virus-infected cells. Mol Cell Proteomics, 2010; 9:1533–1539.
18.
IsaacsD. Should respiratory care in preterm infants include prophylaxis against respiratory syncytial virus? The case against. Paediatr Respir Rev, 2013; 14:128–129.
19.
JessenB, FallerS, KremplCD, and EhlS. Major histocompatibility complex-dependent cytotoxic T lymphocyte repertoire and functional avidity contribute to strain-specific disease susceptibility after murine respiratory syncytial virus infection. J Virol, 2011; 85:10135–10143.
20.
KimHW, CancholaJG, BrandtCD, et al.Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol, 1969; 89:422–434.
21.
LeeS, StokesKL, CurrierMG, et al.Vaccine-elicited CD8+ T cells protect against respiratory syncytial virus strain A2-line19F-induced pathogenesis in BALB/c mice. J Virol, 2012; 86:13016–13024.
22.
LuG, GonzalezR, GuoL, et al.Large-scale seroprevalence analysis of human metapneumovirus and human respiratory syncytial virus infections in Beijing, China. Virol J, 2011; 8:62.
NairH, NokesDJ, GessnerBD, et al.Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet, 2010; 375:1545–1555.
25.
NielsenM, LundegaardC, WorningP, et al.Reliable prediction of T-cell epitopes using neural networks with novel sequence representations. Protein Sci, 2003; 12:1007–1017.
26.
ObermannS, PetrykowskaS, MannsMP, et al.Peptide-beta2-microglobulin-major histocompatibility complex expressing cells are potent antigen-presenting cells that can generate specific T cells. Immunology, 2007; 122:90–97.
27.
OlsonMR, and VargaSM. Pulmonary immunity and immunopathology: lessons from respiratory syncytial virus. Exp Rev Vaccines, 2008; 7:1239–1255.
28.
OpenshawPJ, and ChiuC. Protective and dysregulated T cell immunity in RSV infection. Curr Opin Virol, 2013; 3:468–474.
29.
OstlerT, and EhlS. Pulmonary T cells induced by respiratory syncytial virus are functional and can make an important contribution to long-lived protective immunity. Eur J Immunol, 2002; 32:2562–2569.
30.
OstlerT, DavidsonW, and EhlS. Virus clearance and immunopathology by CD8(+) T cells during infection with respiratory syncytial virus are mediated by IFN-gamma. Eur J Immunol, 2002; 32:2117–2123.
31.
RockMT, McKinneyBA, YoderSM, et al.Identification of potential human respiratory syncytial virus and metapneumovirus T cell epitopes using computational prediction and MHC binding assays. J Immunol Methods, 2011; 374:13–17.
32.
Roeckl-WiedmannI, LieseJG, GrillE, et al.Economic evaluation of possible prevention of RSV-related hospitalizations in premature infants in Germany. Eur J Pediatr, 2003; 162:237–244.
33.
RomeroP, ZippeliusA, KurthI, et al.Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol, 2007; 178:4112–4119.
34.
SallustoF, GeginatJ, and LanzavecchiaA. Central memory and effector memory T cell subsets: function, generation, and maintenance. Ann Rev Immunol, 2004; 22:745–763.
35.
SchmidtAH, SollochUV, BaierD, et al.Regional differences in HLA antigen and haplotype frequency distributions in Germany and their relevance to the optimization of hematopoietic stem cell donor recruitment. Tissue Antigens, 2010; 76:362–379.
36.
ShadmanKA, and WaldER. A review of palivizumab and emerging therapies for respiratory syncytial virus. Exp Opin Biol Ther, 2011; 11:1455–1467.
37.
ShaoHY, LinYW, YuSL, et al.Immunoprotectivity of HLA-A2 CTL peptides derived from respiratory syncytial virus fusion protein in HLA-A2 transgenic mouse. PloS One, 2011; 6:e25500.
38.
SimmonsCP, HussellT, SparerT, et al.Mucosal delivery of a respiratory syncytial virus CTL peptide with enterotoxin-based adjuvants elicits protective, immunopathogenic, and immunoregulatory antiviral CD8+ T cell responses. J Immunol, 2001; 166:1106–1113.
39.
VenterM, RockM, PurenAJ, et al.Respiratory syncytial virus nucleoprotein-specific cytotoxic T-cell epitopes in a South African population of diverse HLA types are conserved in circulating field strains. J Virol, 2003; 77:7319–7329.
40.
WelliverTP, GarofaloRP, HosakoteY, et al.Severe human lower respiratory tract illness caused by respiratory syncytial virus and influenza virus is characterized by the absence of pulmonary cytotoxic lymphocyte responses. J Infect Dis, 2007; 195:1126–1136.
41.
WillsMR, CarmichaelAJ, MynardK, et al.The human cytotoxic T-lymphocyte (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. J Virol, 1996; 70:7569–7579.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
