435 Using Immunostimulatory Cytokines Delivered by rSV40 Vectors to Generate Powerful and Long-lasting Cell-mediated Immune Responses Against HIV Envelope gp120 H. J. McKee*, D. S. Strayer Jefferson Med Coll, Philadelphia, PA
Background: Immunostimulatory cytokines (e.g., IL-12 and IL-15 into the regimen) may promote adaptive immune responses and cytotoxic memory, respectively, and so facilitate long-term non-progression to AIDS in HIV infection. A promising approach to anti-HIV vaccine development is use of live virus vectors to deliver HIV antigens. Recombinant SV40 vectors (rSV40s) do not elicit neutralizing immune responses against themselves, and so can be used to deliver multiple boosting inoculations of antigens and cytokines. We investigated whether co-administration of IL-12 and IL-15 with HIV gp120 elicited gp120-specific immune responses.
Methods: rSV40s encoding murine IL-12, murine IL-15, and HIV-1NL4-3 gp120 were given to BALB/cJ mice monthly: SV(gp120) alone or in tandem with SV(IL-12) or SV(IL-15). The latter were given simultaneously with 3d before or 3d after SV(gp120). Biweekly sera were assayed for anti-gp120 antibody in a cell-based ELISA. Specific anti-gp120 cytolytic activity was measured by lysis of 51Cr-labeled P815 cells stably expressing gp120.
Results: Very strong gp120-specific CTL responses were observed in mice co-immunized with cytokines: = 50% IL-15, = 60% IL-12 by unselected effector cells at E:T ratios as low as 10:1, following only 2 immunizations. In mice co-immunized with gp120 and IL-15, these responses were seen = 1 month after the second injection, suggesting that co-administration of SV(IL-15) may promote CTL memory. The order of cytokine administration was important: IL-12 was effective before or after gp120, but IL-15 only augmented CTL activity if it was given 1st. These co-immunization studies included only 2 inoculations, which was insufficient to elicit significant binding antibody.
Conclusions: Recombinant SV40-derived vectors can be used successfully to delivered HIV env antigen multiple times, either alone or with other transgenes in sequence. Very powerful cytotoxic responses were seen using combinations of SV(gp120) together with immunostimulatory cytokines: resulting CTL responses were stronger and faster than in protocols involving SV(gp120) alone. Cytolytic memory was fostered when IL-15 was co-administered. Regimens combining rSV40s encoding antigens and immunostimulatory cytokines may be useful in vaccinating against HIV.
