A safe and successful vaccine against HIV will likely require the simultaneous priming of both cellular and humoral immune responses, and will preferentially involve the use of recombinant proteins. Targeting immunogens to Fc gamma receptor type I (FcgRI) on antigen presenting cells (APC) significantly enhances T cell activation in vitro, and antibody production in vivo. In addition, it can also lead to simultaneous priming of both cytotoxic and helper T cell responses. Furthermore, by combining the administration of antigen with cytokines, T cell activation can be further enhanced, and T cell subset development modulated. It has also been demonstrated that targeting antigen (Ag) to FcgRI on APC can eliminate the need for traditional adjuvant, easing difficulties associated with vaccine preparation and distribution. Therefore, developing a strategy which facilitates antigen targeting to APC, and the use of cytokines in vaccines, is likely to have a significant impact on current vaccine technology, in particular as it applies to HIV. We propose to utilize molecular techniques, and FcgRI-specific constructs, to create and test the ability of a prototype two component (modular) immune targeting system to stimulate enhanced humoral, CD4 helper T cell, and CD8 cytotoxic T cell responses in vitro and in vivo. Components will consist of a humanized divalent FcgRI-specific biotin-binding targeting element, and biotinylated functional elements including Hepatitis B Ag, gp120 Ag, and IL-2. The ability of the two component immunogens to modulate human CD4 and CD8 T cell responses in vitro, and murine B cell, CD4 T cell, and CD8 T cell responses in vivo, will be examined. In the latter instance, transgenic mice that express human FcgRI will be immunized with two component immunogens. Following immunization, CD4 and CD8 T cell responses, as well as the generation of Ag-specific antibody will be measured. These studies will provide a novel and safe approach for simultaneously priming humoral and cellular responses in vivo using recombinant proteins. This approach will not only provide an effective means for controlling the spread of HIV, but many other infectious organisms as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI046968-02
Application #
6374417
Study Section
Special Emphasis Panel (ZRG1-VACC (03))
Program Officer
Bradac, James A
Project Start
2000-08-01
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$232,500
Indirect Cost
Name
Albany Medical College
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
Jordan, Robert A; Preissler, Mark T; Banas, Jeffrey A et al. (2003) Production of genetically engineered biotinylated interleukin-2 and its application in a rapid nonradioactive assay for T-cell activation. Clin Diagn Lab Immunol 10:339-44
Walsh, Mary C; Banas, Jeffrey A; Mudzinski, Stanley P et al. (2003) A two-component modular approach for enhancing T-cell activation utilizing a unique anti-FcgammaRI-streptavidin construct and microspheres coated with biotinylated-antigen. Biomol Eng 20:21-33
Plitnick, L M; Jordan, R A; Banas, J A et al. (2001) Lipoteichoic acid inhibits interleukin-2 (IL-2) function by direct binding to IL-2. Clin Diagn Lab Immunol 8:972-9