642 Immunogenicity of DermaVir in Na´ve and Chronically-infected Macaques J. Lisziewicz*1, J. Xu1, J. Trocio1, L. Whitman1, A. Ryder1, N. Bakare1, P. Markham2, S. Arya3, F. Lori1 1Res Inst for Genetic and Human Therapy, Washington, DC; 2Advanced BioSci Labs, Rockville, MD; and 3Natl Inst of Hlth, NCI Frederick, MD
Background: We evaluated the immunogenicity of a novel immune therapeutic agent, DermaVir, which delivers plasmid DNA to dendritic cells and suppresses viral replication during treatment interruptions in SIVmac251-infected macaques.
Methods: DermaVir was either applied ex vivo, to transduce cultured dendritic cells that were subsequently injected back, or topically, to transduce Langerhans cells. The immunogenicity was studied both in vitro and in vivo using chemically-inactivated SIV as antigen (from Dr. Lifson). In vitro, PBMC were stimulated with SIV antigen and IFN-gamma expressing cells were quantified by flow cytometer. In vivo, the SIV antigen was injected subcutaneously and delayed-type hypersensitivity (DTH) skin reaction was measured 48 h later.
Results: Three (3) weeks after the first dose, both topical and ex vivo DermaVir vaccinations of naive macaques had induced similar amounts of SIV-specific CD8 T cells (> 0.8%). However, despite repeated vaccinations, these SIV-specific T-cells progressively decreased and became undetectable (< 0.1%) in the peripheral blood. At that time, we found marked DTH responses to the SIV antigen (< 10 mm). Neither vaccination method induced antibody responses. In contrast, chronically infected macaques receiving DermaVir plus STI had progressive increase of SIV-specific T-cells (0.1%-4%), which correlated with increased control of viral replication.
Conclusions: DermaVir induced Th-1 type SIV-specific T-cell responses in both naive and infected macaques. In the absence of persistent peripheral antigenic stimulation (e.g., naive macaques) SIV-specific T-cells became memory T-cells with a frequency under the limit of detection of the in vitro assay. The existence of a memory pool was confirmed by the positive DTH test in the absence of a humoral response, similar to positive tuberculin tests in individuals infected with M. tuberculosis who did not develop antibody responses. In contrast, due to continued virus exposure, SIV-specific cells heavily patrolled the peripheral blood during chronic infection. These results elucidate the immunologic nature of the mechanism underlying the viral suppression induced by DermaVir.