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Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655
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-
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.
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