Despite considerable recent progress, an immunization strategy that is capable of inducing immune responses that can prevent or control HIV infection has not yet been achieved. By significantly reducing viral lode and inducing T-cell recovery, treatment of HIV infected individuals with highly active antiretroviral therapy (HAART) regimens may provide an opportunity of HIV-specific immunization. In this setting of recovery of T-lymphocyte function, HIV-specific immunizations may be effective. DNA-based immunization strategies can elicit both humoral and CTL- mediated antigen-specific immune responses and have significant potential for the treatment and prevention of HIV infection. The mechanisms by which genetic immunization induce immunity are unclear. The goal of this project is to elucidate key features of the mechanisms of DNA-based immunization, and to use this information for the rationale development of DNA-based immunization strategies against HIV. To accomplish this we will utilize murine and primate models to evaluate antigen expression, processing, and presentation, and to determine the role of professional antigen presenting cells in the initiation of the immune response induced by DNA-based immunization strategies. We will correlate variables effecting antigen expression and presentation with in vivo immunogenicity. Based on this analysis, the most effective immunization strategies will be evaluated as adjuvant immunotherapies to HAART regimens using an SIV infected simian model. These studies are designed to demonstrate feasibility and provide rationale for continuing development of DNA-based immunization as adjuvant therapy for HIV disease, including the initiation of human clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043916-02
Application #
2887865
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Bradac, James A
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Morelli, Adrian E; Larregina, Adriana T; Shufesky, William J et al. (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257-66
Morel, Penelope A; Falkner, Dewayne; Plowey, Jeffrey et al. (2004) DNA immunisation: altering the cellular localisation of expressed protein and the immunisation route allows manipulation of the immune response. Vaccine 22:447-56
Larregina, Adriana T; Morelli, Adrian E; Tkacheva, Olga et al. (2004) Highly efficient expression of transgenic proteins by naked DNA-transfected dendritic cells through terminal differentiation. Blood 103:811-9
Morelli, Adrian E; Larregina, Adriana T; Shufesky, William J et al. (2003) Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Blood 101:611-20
Dileo, John; Banerjee, Rajkumar; Whitmore, Mark et al. (2003) Lipid-protamine-DNA-mediated antigen delivery to antigen-presenting cells results in enhanced anti-tumor immune responses. Mol Ther 7:640-8
Zimmer, Michael I; Larregina, Adriana T; Castillo, Cielo M et al. (2002) Disrupted homeostasis of Langerhans cells and interdigitating dendritic cells in monkeys with AIDS. Blood 99:2859-68
Whitmore, M M; Li, S; Falo Jr, L et al. (2001) Systemic administration of LPD prepared with CpG oligonucleotides inhibits the growth of established pulmonary metastases by stimulating innate and acquired antitumor immune responses. Cancer Immunol Immunother 50:503-14
Wu, X; He, Y; Falo Jr, L D et al. (2001) Regression of human mammary adenocarcinoma by systemic administration of a recombinant gene encoding the hFlex-TRAIL fusion protein. Mol Ther 3:368-74
Larregina, A T; Morelli, A E; Spencer, L A et al. (2001) Dermal-resident CD14+ cells differentiate into Langerhans cells. Nat Immunol 2:1151-8
Larregina, A T; Falo Jr, L D (2000) Generating and regulating immune responses through cutaneous gene delivery. Hum Gene Ther 11:2301-5

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