title: Partial agonist effect influences the CTL response to a heterologous dengue virus serotype.
abstract: Activation of dengue serotype-cross-reactive memory CTL during secondary dengue virus (DV) infection is thought to be important in the pathogenesis of dengue hemorrhagic fever. To model this effect, we studied the CTL responses to DV types 2 (D2V) and 3 (D3V) in PBMC from an individual previously infected with D3V. DV-specific CD8+ CTL from this donor recognized two HLA-B62-restricted epitopes on the NS3 protein, aa 71-79 (SVKKDLISY) and 235-243 (AMKGLPIRY). Both D3V-specific and D2V/D3V-cross-reactive CTL clones were detected for each epitope; all D2V-reactive CTL clones could lyse D2V-infected autologous cells. CTL responses to both epitopes were detected in bulk cultures stimulated with D3V, but PBMC stimulated with D2V recognized only the 235-243 epitope. IFN-gamma enzyme-linked immunospot assay showed that the D2V (71-79) peptide (DVKKDLISY) did not efficiently activate T cells. Analysis of a CTL clone suggests that the D2V (71-79) peptide acts as a partial agonist, able to sensitize target cells for lysis and inducing only minimal proliferation at high concentrations. These results suggest that variant peptide sequences present in the heterologous DV serotype can influence the CTL response in vivo during secondary DV infection.
authors.affiliation: Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester 01655, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zivny
authors.forename: M
authors.initials: M
authors.lastname: DeFronzo
authors.forename: W
authors.initials: W
authors.lastname: Jarry
authors.forename: J
authors.initials: J
authors.lastname: Jameson
authors.forename: J
authors.initials: J
authors.lastname: Cruz
authors.forename: F A
authors.initials: FA
authors.lastname: Ennis
authors.forename: A L
authors.initials: AL
authors.lastname: Rothman
mesh_terms: D000328:Adult; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003716:Dengue Virus / Q000145:classification* / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D020365:RNA Helicases; D012697:Serine Endopeptidases; D012703:Serotyping; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases