647a Therapeutic Vaccination Requires Highly Active Antiretroviral Therapy J Lisziewicz *1, J Xu1, M Lewis2, J Trocio1, L Whitman1, F Lori1 1Research Institute for Genetic and Human Therapy, Washington DC and 2Southern Research Institute, Frederick, MD
Background During chronic infection the immune response only partially controls HIV/SIV. Understanding the immune system defect is pivotal to design successful immune-based therapies. MethodsIn vitro: a flow cytometry assay was used to determine HIV-specific CD8 T cell activation in response to noninfectious virus during depletion/reconstitution experiments in PBMC of HIV infected individuals. In vivo: 14 rhesus macaques chronically infected with SIVmac251 were randomized to receive only DermaVir (a topical therapeutic vaccine designed for HIV/SIV-specific immune activation by Langerhans/dendritic cells), or DermaVir with HAART (cycles of 3 weeks on, 3 weeks off HAART). ResultsIn vitro: CD4 T cell depletion of PBMC decreased HIV-specific CD8 T cell activation from 2.2% to 1.3%. CD8 cells alone, and CD8 cells reconstituted with CD4 cells, HLA-Dr cells, or CD4 plus HLA-Dr cells activated 0.1%, 1.0%, 0.6%, and 1.2% CD8 T cells, respectively. T cell activation occurred in the absence of viral gene expression and was aborted by blocking either HIV entry with neutralizing antibodies or intracellular protein processing with Brefeldin A. In vivo: HAART and DermaVir treatment restored SIV-specific CD8 T cell activation and progressively suppressed viral rebound during treatment interruptions (4.53; 3.85; 2.76; <2.30 and <2.30 log copies/ml, from baseline to fourth interruption). In the absence of HAART, DermaVir-mediated activation of SIV-specific CD8 T cells was 5 fold weaker and viral load suppression was modest (<1 log). Conclusion The results show for the first time that during chronic infection a large proportion of HIV-specific CD8 T cells are activated by CD4 T cells (instead of HLA-Dr antigen presenting cells). Since CD4 T cells lack co-stimulatory signals, the HIV-specific CD8 T cell response is deficient, and virus suppression is partial. HAART and DermaVir correct this defect: HAART eliminates the viral antigen, thereby interrupting the CD4 T cell antigen presentation defective pathway, and DermaVir provides professional antigen presenting cells restoring a correct activation of virus specific T cells.