Poonam, Poonam
(2009)
INDUCTION OF STRONG CELLULAR IMMUNE RESPONSES IN THE GUT MUCOSA AGAINST HIV-1 USING A COMBINATION VACCINE OF RECOMBINANT CLOSTRIDIUM PERFRINGENS AND HIV-1 VIRUS LIKE PARTICLES.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The gut mucosa is an important portal for HIV-1 transmission and infection. Therefore, a vaccine which can prevent virus transmission at mucosal surfaces would be an ideal HIV-1 vaccine candidate. Clostridium perfringens has been used as a vehicle to deliver SIV proteins in large quantity to the terminal ileum. A mucosal immunization strategy using C. perfringens should be able to induce potent mucosal immune responses against HIV-1. A recombinant C. perfringens expressing large amount of HIV-1 Gag protein (Cp-Gag) was constructed. Under in vitro conditions, Cp-Gag was found to induce bone marrow derived dendrite cell (BMDC) to mature and stimulate HIV-1 Gag specific T cell responses. Then in vivo experiments were performed in mice to demonstrate orally delivered Cp-Gag ability to prime gut mucosal T cell responses. Since oral tolerance is a major obstacle for orally delivered immunization approaches, a combination of mutated heat-labile enterotoxin of E. coli (mLT) and CpG containing oligodeoxynucleotides (CpG-ODN) were used as adjuvants for oral administration with Cp-Gag. Orally delivered Cp-Gag was tested for induction of HIV-1 Gag specific T cell responses in a prime-boost model with intranasal inoculation of HIV-1 virus like particles (VLP). HIV-1 specific cellular immune responses in both the effector (Lamina propria) and inductive sites (Peyer's patches) of the gastrointestinal (GI) tract were significantly higher in mice immunized using Cp-Gag and VLPs in prime-boost approaches compared to mice immunized with either Cp-Gag or VLPs alone. Such cellular immune response was found to be mediated by both CD8+ and CD4+ T cells. These groups of mice also seemed to have HIV-1 specific multifunctional T cells in PPs and LP of the GI tract. In summary, mucosal immunization of mice with a Cp-Gag and VLPs in a prime-boost mode led to strong HIV-1 Gag specific cellular immune responses in both mucosal and systemic immune compartments. Such strong mucosal immune response could be very important to control HIV-1 infection at mucosal surfaces. The proposed vaccine strategy has great public health significance for developing a practical vaccine against HIV due to its safety, low production cost and easy administration.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
28 September 2009 |
| Date Type: |
Completion |
| Defense Date: |
15 June 2009 |
| Approval Date: |
28 September 2009 |
| Submission Date: |
9 June 2009 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Clostridium perfringens; HIV-1; Mucosal Vaccine |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-06092009-125701/, etd-06092009-125701 |
| Date Deposited: |
10 Nov 2011 19:46 |
| Last Modified: |
15 Nov 2016 13:44 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8052 |
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