Effect of natural sequence variation at the H-2Ld-restricted CD8+ T cell epitope of the murine cytomegalovirus ie1-encoded pp89 on T cell recognition.
The amino acid sequence YPHFMPTNL of pp89, the ie1-encoded product of murine cytomegalovirus (MCMV; Smith strain), constitutes an immunodominant T cell epitope recognized in association with H-2Ld. Nucleotide sequencing of MCMV isolates derived from wild mice identified variation between amino acids 147-192 of pp89 in 19 of 27 isolates, including the region encompassing the CTL epitope (amino acid residues 168-176). Four groups of isolates with naturally occurring variant sequences for the CTL epitope were defined: (1) YPHFMPPNL; (2) YPHFMPPSL; (3) YPHFIPPSL; and (4) YLDFMPPNL. The remaining isolates, and the laboratory strains K181 and Vancouver, showed complete identity with the Smith strain. Polyclonal pp89 (Smith strain)-specific CTL only weakly recognized target cells infected with MCMV from most variant groups. No lysis of cells infected with isolate N1 from group 4 was detected. Analyses of cross-reactive recognition of YPHFMPTNL peptide-coated targets by CTL primed with variant MCMV isolates showed that the group 2 and 3 isolates, G4 and K6, respectively, but not the group 4 isolate N1, elicited CTL that exhibited a cross-reactive response. Furthermore, while the group 2 and 3 isolates G4 and K6 were able to prime CTL responses that displayed reactivity to homologous pp89 variant nonapeptides, the group 4 isolate N1 failed to do so. Finally, while immunization of mice with the nonapeptide YPHFMPTNL conferred significant protection against the laboratory strain K181 [correction of Kl81], no evidence of protection was observed for the group 2 and 4 variants G4 and N1, respectively. These observations raise the possibility that clinical isolates of HCMV may also differ in sequence from potential vaccine strains at immunodominant epitopes for CD8+ T cells thus reducing the efficacy of vaccination.
Lyons
P A
PA
Department of Microbiology, University of Western Australia, Nedlands, Perth.
Allan
J E
JE
Carrello
C
C
Shellam
G R
GR
Scalzo
A A
AA
D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002478:Cells, Cultured; D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005260:Female; D006183:H-2 Antigens / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology*; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D018146:Muromegalovirus / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D016133:Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000956:Antigens, Viral; D004279:DNA, Viral; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D017874:Immediate-Early Proteins; C052612:cytomegalovirus immediate early phosphoprotein pp89