13th International AIDS Conference Durban, South Africa - July 9-July 14, 2000

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA480)

Lisziewicz J
J. Lisziewicz, Research Institute for Genetic and Human Therapy, at Georgetown University, Med-Den SW 307, 3900 Reservoir Road, NW, Washington DC, 20007, United States, Tel.: +1 202 687 2833, Fax: +1 202 687 2907, E-mail: right@gunet.georgetown.edu

BACKGROUND: HIV-specific cell-mediated immune responses (T helper and CTL) correlate with protection. Antigen-presenting dendritic cells (DC) are the most efficient cells to induce potent cell-mediated immune responses.

METHODS: We used genetically modified dendritic cells (GM-DC) to provide efficient antigen presentation for naive T-cells. GM-DC were generated from monocyte-derived DC transduced with a plasmid DNA encoding a replication and integration defective HIV vector using a non-viral gene delivery system (polyethylenimine-mannose). Immunogenicity of GM-DC was tested in vitro and in vivo in non-human primates.

RESULTS: After a single stimulation GM-DC elicited in vitro a potent activation of autologous naive CD4 and CD8 T-cells (up to 8% of CD3 gated cells expressed intracellular IFN-g) and generated vigorous CTL responses (27% of p55-specific lysis, E:T = 100:1). Restimulation of primed T cells with HIV-antigen presenting cells confirmed the antigen-specificity of these immune responses. Autologous GM-DC injected into pigtailed macaques induced prompt, vigorous, and long-lasting CTL responses against HIV. 3 weeks after a single immunization, animals presented a vigorous effector CTL response (up to 50% of gag-specific lysis in the absence of in vitro antigenic restimulation, E:T = 100:1). Low activity of effector CTL were still found 7 months later (up to 12% of gag-specific lysis, E:T = 100:1). At this time, vigorous memory CTL response was detected (up to 40% of gag-specific lysis after antigenic stimulation, E:T = 40:1). Interestingly, no antibodies were detected, suggesting that GM-DC raised a pure Th1 type of immune response. No toxic side effects were documented.

CONCLUSIONS: We provide evidences that a novel genetic immunization with GM-DC can induce unprecedented vigorous and long lasting CTL responses. This approach might be developed for both therapeutic and preventive vaccination.

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