High-affinity T helper epitope induces complementary helper and APC polarization, increased CTL, and protection against viral infection

Natural viral proteins do not always make optimal vaccines. We have found t hat sequence modification to increase epitope affinity for class II MHC mol ecules (epitope enhancement) can improve immunogenicity. Here we show first that a higher-affinity helper epitope-enhanced HIV vaccine not only induce s more cytotoxic T lymphocytes (CTLs), but also skews helper cells toward T h1 cytokine production and protects against HIV-1 recombinant vaccinia vira l challenge. Furthermore, we elucidate a novel mechanism in which the highe r-affinity vaccine induces dramatically more effective helper cells with a higher level of CD40L per helper cell and more positive cells, which in tur n more effectively conditions dendritic cells (DCs) for CTL activation in a second culture. The improved helper cells also induce much greater IL-12 p roduction by DCs, accounting for the reciprocal T helper polarization to Th 1, and increase costimulatory molecule expression. Thus, increasing affinit y for class Il MHC results in a complementary interaction in which T helper and antigen-presenting cells polarize each other, as well as increase CTL, and provide greater vaccine efficacy against viral infection.