Control of HIV-1 infection has been revolutionized with the advent of potent combination drug therapy (HAART) that dramatically lowers viral burden and partially restores host immunity in approximately 70% of patients with progressive, long term HIV-1 infection. In spite of this advance, HAART regimens can be highly toxic and cannot eliminate reservoirs of HIV-1 in the host. Thus, upon cessation of HAART, there is often a resumption of high levels of HIV-1 replication and pathogenic sequelae. We propose that this is in part due to incomplete immune control of virus replication. We hypothesize that more efficient control of HIV-1 infection during HAART can be achieved by engineering dendritic cells (DCs) to induce a more potent and enhanced breadth of anti-HIV-1 CD8+ and CD4+ T cell immune responses. Our multidisciplinary consortium of University of Pittsburgh investigators, together with our commercial partner, ImmunoSite, propose an innovative immunotherapeutic strategy by ex vivo engineering of DCs with virus derived from the same host (""""""""autologous"""""""" HIV-1). In Project 1, we propose to assess DCs loaded with SIV antigen encoded by adenovirus vectors for adjuvant effects in the rhesus macaque HAART model. In Project 2, we extend this concept to DCs transfected by autologous HIV-1 encoded by naked DNA plasmids in mice and in vitro human models, including various new strategies for polarization of Th1 responses by DCs. In project 3, we will advance our model of stimulation of CD8+ and CD4+ T cells by DCs loaded with autologous HIV-1 infected, apoptotic cells from preclinical work through a phase I clinical trial. These projects interact conceptually and operationally by collaborating on improving methods of DC activation and autologous antigen presentation to T cells. Vector core B will provide viral and cytokine expressing vectors for projects 1 and 2, and a new antigenic peptide derivation method for project 3. Imaging core C will provide state-of-the-art fluorescent microscopy for each project. ImmunoSite will lead DC core D by providing highly innovative, new technology for GMP-grade, ex vivo processing of DCs and T cells for preclinical studies in project 2, and the clinical trial in project 3. We believe that this novel immunotherapy strategy ideally fulfills the intent of the NIAID Integrated Preclinical/Clinical Program.
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