Principal Investigator/Program Director (Last, first, middle): Falo, Louis, D. RESEARCH &RELATED Other Project Information 1. * Are Human Subjects Involved? m Yes l No 1.a. If YES to Human Subjects Is the IRB review Pending? m Yes m No IRB Approval Date: Exemption Number: 1 2 3 4 5 6 Human Subject Assurance Number 2. * Are Vertebrate Animals Used? l Yes m No 2.a. If YES to Vertebrate Animals Is the IACUC review Pending? m Yes l No IACUC Approval Date: 05-17-2007 Animal Welfare Assurance Number A3187-01 3. * Is proprietary/privileged information m Yes l No included in the application? 4.a.* Does this project have an actual or potential impact on m Yes l No the environment? 4.b. If yes, please explain: 4.c. If this project has an actual or potential impact on the environment, has an exemption been authorized or an environmental assessment (EA) or environmental impact statement (EIS) been performed? m Yes m No 4.d. If yes, please explain: 5.a.* Does this project involve activities outside the U.S. or m Yes l No partnership with International Collaborators? 5.b. If yes, identify countries: 5.c. Optional Explanation: 6. * Project Summary/Abstract 9896-Abstract.pdf Mime Type: application/pdf 7. * Project Narrative 7711-Narrative.pdf Mime Type: application/pdf 8. Bibliography &References Cited 7473-07_FINAL_A2_HIV_R01_ReferencMesim.pedfType: application/pdf 9. Facilities &Other Resources 1948-07_REV_FINAL_A2_HIV_R01_ResMoiumrceeTsy.pdef: application/pdf 10. Equipment Tracking Number: Other Information Page 5 OMB Number: 4040-0001 Expiration Date: 04/30/2008 Principal Investigator/Program Director (Last, first, middle): Falo, Louis, D. The diversity of the HIV virus is a major obstacle to the development of an effective HIV immunotherapy. Several recent studies demonstrate an important role for cell-mediated immunity in both the prevention and control of HIV infection. Failure of HIV-specific immunity has been correlated with """"""""CTL escape"""""""" in both primate and human vaccination and immunotherapy studies. Establishment and maintenance of effective CTL- mediated immune responses generally depends on the presence of CD4+ T-cell help, and a Th1 type response is critical for induction and maintenance of cell-mediated immunity. Dendritic cells (DCs) play critical roles in the development and control of immunity. Besides being the most potent antigen-presenting cells (APC), they determine the nature and magnitude of immune responses and provide an essential link between innate and acquired immunity. The studies proposed here will build on our previous efforts utilizing DNA expression constructs encoding autologous patient-derived HIV antigens and novel DC transfection approaches to address major obstacles to effective HIV immunotherapy. Specifically, we propose to genetically engineer skin DCs in vivo to both efficiently present patient-specific Nef and Gag antigens, and express enhanced DC1 type polarized immune-stimulatory function essential for optimal activation of Th1 T- cells in HIV infected individuals. This proposal will develop novel in vivo antigen delivery systems based on the delivery of particulate and DNA formulations encoding HIV-1 antigens to: 1) drive the expression of transgenic (tg) antigens in DCs, 2) favor presentation of tg Ag peptides to CD8+ CTL and CD4+ Th cells and 3) elicit Th1 polarizing DC function. We will test the hypothesis that autologous dendritic cells, genetically engineered to present transgenic patient-derived HIV antigens in the context of Th1 skewing costimulatory function, will induce effective Th1 type patient-specific HIV immune responses. This will be accomplished using both murine models, and unique in situ human skin models we have developed to facilitate translation to clinical trials. In addition to testing this hypothesis, the studies we propose have the potential to overcome major limitations of existing HIV immunotherapies, and to define an immunization strategy capable of containing or eradicating infection in chronically infected patients. Importantly, the studies we propose include translational preclinical models designed as a direct prelude to human clinical trials. Project Description Page 6
