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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

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 (Unpublished)

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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
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Poonam, Poonampnm779@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee CoChairSalter, Russell Drds@pitt.eduRDS
Committee MemberRoss, Ted M.tmr15@pitt.eduTMR15
Committee MemberReinhart, Todd A.reinhar@pitt.eduREINHAR
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: Graduate 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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