Human respiratory syncytial virus (RSV) is a major cause of respiratory infection in children and in the elderly. The RSV fusion (F) glycoprotein has long been recognized as a vaccine candidate as it elicits cytotoxic T-lymphocyte (CTL) and antibody responses. Two murine H-2Kd-restricted CTL epitopes (F85–93 and F92–106) are known in the F protein of the A2 strain of RSV. F-specific CTL lines using BCH4 fibroblasts that are persistently infected with the Long strain of human RSV as stimulators were generated, and it was found that in this strain only the F85–93 epitope is conserved. Motif based epitope prediction programs and an F2 chain deleted F protein encoded in a recombinant vaccinia virus enabled identification of a new epitope in the Long strain, F249–258, which is presented by Kd as a 9-mer (TYMLTNSEL) or a 10-mer (TYMLTNSELL) peptide. The results suggest that the 10-mer might be a naturally processed endogenous Kd ligand. The CD8+ T-lymphocyte responses to epitopes F85–93 and F249–258 present in the F protein of RSV Long were found to be strongly skewed to F85–93 in in vitro multispecific CTL lines and in vivo during a secondary response to a recombinant vaccinia virus that expresses the entire F protein. However, no hierarchy in CD8+ T-lymphocyte responses to F85–93 and F249–258 epitopes was observed in vivo during a primary response.
BelzG. T.,
XieW.,
AltmanJ. D.,
DohertyP. C.2000; A previously unrecognized H-2Db-restricted peptide prominent in the primary influenza A virus-specific CD8+ T-cell response is much less apparent following secondary challenge. J Virol 74:3486–3493[CrossRef]
BembridgeG. P.,
LópezJ. A.,
CookR.,
MeleroJ. A.,
TaylorG.1998; Recombinant vaccinia virus coexpressing the F protein of respiratory syncytial virus (RSV) and interleukin-4 (IL-4) does not inhibit the development of RSV-specific memory cytotoxic T lymphocytes, whereas priming is diminished in the presence of high levels of IL-2 or gamma interferon. J Virol 72:4080–4087
BembridgeG. P.,
RodríguezN.,
García-BeatoR.,
NicolsonC.,
MeleroJ. A.,
TaylorG.2000; DNA encoding the attachment (G) or fusion (F) protein of respiratory syncytial virus induces protection in the absence of pulmonary inflammation. J Gen Virol 81:2519–2523
CarboneF. R.,
BevanM. J.1990; Class I-restricted processing and presentation of exogenous cell-associated antigen in vivo
. J Exp Med 171:377–387[CrossRef]
ChenW.,
AntónL. C.,
BenninkJ. R.,
YewdellJ. W.2000; Dissecting the multifactorial causes of immunodominance in class I-restricted T cell responses to viruses. Immunity 12:83–93[CrossRef]
CollinsP. L.,
ChanockR. M.,
MurphyB. R.2001; Respiratory syncytial virus. In Fields Virology, 4th edn. pp 1443–1485 Edited by
KnipeD. M.,
HowleyP. M.
Philadelphia: Lippincott Williams & Wilkins;
CristinaJ.,
LópezJ. A.,
AlboC.,
García-BarrenoB.,
GarcíaJ.,
MeleroJ. A.,
PortelaA.1990; Analysis of genetic variability in human respiratory syncytial virus by the RNase A mismatch cleavage method: subtype divergence and heterogeneity. Virology 174:126–134[CrossRef]
CroweS. R.,
TurnerS. J.,
MillerS. C.,
RobertsA. D.,
RappoloR. A.,
DohertyP. C.,
ElyK. H.,
WoodlandD. L.2003; Differential antigen presentation regulates the changing patterns of CD8+ T cell immunodominance in primary and secondary influenza virus infections. J Exp Med 198:399–410[CrossRef]
Del ValM.,
SchlichtH. J.,
RuppertT.,
ReddehaseM. J.,
KoszinowskiU. H.1991; Efficient processing of an antigenic sequence for presentation by MHC class I molecules depends on its neighboring residues in the protein. Cell 66:1145–1153[CrossRef]
EisenlohrL. C.,
YewdellJ. W.,
BenninkJ. R.1992; Flanking sequences influence the presentation of an endogenously synthesized peptide to cytotoxic T lymphocytes. J Exp Med 175:481–487[CrossRef]
FernieB. F.,
FordE. C.,
GerinJ. L.1981; The development of Balb/c cells persistently infected with respiratory syncytial virus: presence of ribonucleoprotein on the cell surface. Proc Soc Exp Biol Med 167:83–86[CrossRef]
GaddumR. M.,
CookR. S.,
WyldS. G.,
LópezJ. A.,
BustosR.,
MeleroJ. A.,
TaylorG.1996; Mutant forms of the F protein of human respiratory syncytial (RS) virus induce a cytotoxic T lymphocyte response but not a neutralizing antibody response and only transient resistance to RS virus infection. J Gen Virol 77:1239–1248[CrossRef]
García-BarrenoB.,
JorcanoJ. L.,
AukenbauerT.,
López-GalíndezC.,
MeleroJ. A.1988; Participation of cytoskeletal intermediate filaments in the infectious cycle of human respiratory syncytial virus (RSV). Virus Res 9:307–321[CrossRef]
García-BarrenoB.,
PalomoC.,
PeñasC.,
DelgadoT.,
Pérez-BreñaP.,
MeleroJ. A.1989; Marked differences in the antigenic structure of human respiratory syncytial virus F and G glycoproteins. J Virol 63:925–932
González-ReyesL.,
Ruiz-ArgüelloM. B.,
García-BarrenoB.,
CalderL.,
LópezJ. A.,
AlbarJ. P.,
SkehelJ. J.,
WileyD. C.,
MeleroJ. A.2001; Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci U S A 98:9859–9864[CrossRef]
GrahamB. S.,
BuntonL. A.,
WrightP. F.,
KarzonD. T.1991; Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest 88:1026–1033[CrossRef]
JiangS.,
BorthwickN. J.,
MorrisonP.,
GaoG. F.,
StewardM. W.2002; Virus-specific CTL responses induced by an H-2Kd-restricted, motif-negative 15-mer peptide from the fusion protein of respiratory syncytial virus. J Gen Virol 83:429–438
KeşmirC.,
NussbaumA. K.,
SchildH.,
DetoursV.,
BrunakS.2002; Prediction of proteasome cleavage motifs by neural networks. Protein Eng 15:287–296[CrossRef]
KulkarniA. B.,
CollinsP. L.,
BacikI.,
YewdellJ. W.,
BenninkJ. R.,
CroweJ. E.Jr,
MurphyB. R.1995; Cytotoxic T cells specific for a single peptide on the M2 protein of respiratory syncytial virus are the sole mediators of resistance induced by immunization with M2 encoded by a recombinant vaccinia virus. J Virol 69:1261–1264
LiX.,
SambharaS.,
LiC. X.7 other authors1998; Protection against respiratory syncytial virus infection by DNA immunization. J Exp Med 188:681–688[CrossRef]
LópezJ. A.,
VillanuevaN.,
MeleroJ. A.,
PortelaA.1988; Nucleotide sequence of the fusion and phosphoprotein genes of human respiratory syncytial (RS) virus Long strain: evidence of subtype genetic heterogeneity. Virus Res 10:249–261[CrossRef]
OlmstedR. A.,
ElangoN.,
PrinceG. A.,
MurphyB. R.,
JohnsonP. R.,
MossB.,
ChanockR. M.,
CollinsP. L.1986; Expression of the F glycoprotein of respiratory syncytial virus by a recombinant vaccinia virus: comparison of the individual contributions of the F and G glycoproteins to host immunity. Proc Natl Acad Sci U S A 83:7462–7466[CrossRef]
ParkerK. C.,
BednarekM. A.,
ColiganJ. E.1994; Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 152:163–175
PembertonR. M.,
CannonM. J.,
OpenshawP. J.,
BallL. A.,
WertzG. W.,
AskonasB. A.1987; Cytotoxic T cell specificity for respiratory syncytial virus proteins: fusion protein is an important target antigen. J Gen Virol 68:2177–2182[CrossRef]
RestifoN. P.,
BačíkI.,
IrvineK. R.,
YewdellJ. W.,
McCabeB. J.,
AndersonR. W.,
EisenlohrL. C.,
RosenbergS. A.,
BenninkJ. R.1995; Antigen processing in vivo and the elicitation of primary CTL responses. J Immunol 154:4414–4422
SrikiatkhachornA.,
BracialeT. J.1997; Virus-specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med 186:421–432[CrossRef]
StottE. J.,
TaylorG.,
BallL. A.,
AndersonK.,
YoungK. K.,
KingA. M.,
WertzG. W.1987; Immune and histopathological responses in animals vaccinated with recombinant vaccinia viruses that express individual genes of human respiratory syncytial virus. J Virol 61:3855–3861
The IMpact-RSV Study Group1998; Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102:531–537[CrossRef]
YewdellJ. W.,
BenninkJ. R.1999; Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu Rev Immunol 17:51–88[CrossRef]
ZhouX.,
MomburgF.,
LiuT.,
Abdel MotalU. M.,
JondalM.,
HämmerlingG. J.,
LjunggrenH. G.1994; Presentation of viral antigens restricted by H-2Kb, Db or Kd in proteasome subunit LMP2- and LMP7-deficient cells. Eur J Immunol 24:1863–1868[CrossRef]