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ENGINEERING VIRAL VECTORS FOR T-CELL IMMUNOTHERAPY AND HIV-1
VACCINE
by
Bingbing Dai
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MATERIALS SCIENCE)
May 2012
Copyright 201 Bingbing Dai
Object Description
| Title | Engineering viral vectors for T-cell immunotherapy and HIV-1 vaccine |
| Author | Dai, Bingbing |
| Author email | bingbingdai@gmail.com;bingbingdai@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Materials Science |
| School | Viterbi School of Engineering |
| Date defended/completed | 2011-11-04 |
| Date submitted | 2012-03-29 |
| Date approved | 2012-03-29 |
| Restricted until | 2012-03-29 |
| Date published | 2012-03-29 |
| Advisor (committee chair) | Wang, Pin |
| Advisor (committee member) |
Goo, Edward Arnold, Don |
| Abstract | T cell immunotherapy fell into two categories: passive (adoptive) transfer of in vitro expanded cells, and active expansion of antigen-specific T cells by in vivo immunization. I present three studies to promote T cell immunotherapy and T cell vaccine. In my first study, I described a method to generate autologous antigen-specific CD4⁺ helper T cells in vitro from easily accessible bone marrow cells. T lymphocytes are produced in thymus as the progeny of fetal liver (FL)- and bone marrow (BM)- derived precursors. A murine stromal cell line (OP9-DL1) expressing a notch ligand, Delta-like-1, has been shown to partially mimic the function of thymus and to drive the differentiation of both murine and human hematopoietic progenitors into T cells in vitro. Next, I attempt to develop a specific T-cell vaccine by in vivo gene delivery. Human immunodeficiency virus-1 (HIV-1) is one of the most catastrophic pandemics confronted by mankind with 33 million infections, and there is an urgent need for an effective vaccine. I choose lentiviral vector as the vaccine carrier as it is among the most efficient gene delivery machinery, and can infect both dividing and nondividing cells. In my second study, I evaluate in mice a dendritic cell (DC)-directed LV system encoding the Gag protein of human immunodeficiency virus (LV-Gag) as a potential vaccine for inducing an anti-HIV immune response. The DC-directed specificity is achieved through pseudotyping the vector with an engineered Sindbis virus glycoprotein capable of selectively binding to the DC-SIGN protein. To further optimize this T-cell vaccine system to achieve an increased immune response, in my third study, I attempt to break down the suppressive signaling pathways involved in T cell function. It was found that exhaustion of CD8⁺ T cells and upregulation of programmed death 1 (PD-1), a negative regulator of T cell activation, is a characteristic feature of individuals chronically infected with HIV-1. In this project, I demonstrate that blocking of the PD-1/PD-L1 inhibitory signal via an anti-PD-L1 antibody (αPD-L1) generated an enhanced HIV-1 Gag-specific CD8⁺ immune response following a both a single round of DC-targeting LV immunization and a homologous prime/boost regimen. |
| Keyword | gene delivery; HIV/AIDS vaccine; lentiviral vector engineering; stem cell development; PD1/PD1L pathway |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Dai, Bingbing |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume3/etd-DaiBingbin-560.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | ENGINEERING VIRAL VECTORS FOR T-CELL IMMUNOTHERAPY AND HIV-1 VACCINE by Bingbing Dai A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MATERIALS SCIENCE) May 2012 Copyright 201 Bingbing Dai |
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