More than 40 million people are living with human immunodeficiency virus-1 (HIV-1). A prophylactic vaccine inducing a 'sterilizing immunity' is desired to prevent further infections, but will require many years to develop. Moreover, prophylactic vaccines will not help the millions of people who are already infected with the virus, and who face life-long treatment with expensive and toxic antiretroviral therapy (ART). This dissertation is based on the proposal that the best strategy for these individuals is a therapeutic vaccine that will attack residual viral reservoirs by expanding HIV-1 specific, primary T cell responses to the persons's own, autologous virus.
Previously, this laboratory demonstrated that mature dendritic cells (DC) loaded with immunodominant HIV-1 peptides or HIV-1 infected apoptotic bodies can activate residual HIV-1 specific memory T cell responses. However, such memory T cells are only partially restored during ART. I hypothesized that targeting naive CD8⁺ T cells through a DC-based immunotherapy could elicit a robust and broad T cell response to HIV-1. Furthermore, most immunotherapy studies have used consensus strains of HIV-1 antigens that I believe inadequately represent the host's diverse pool of HIV-1 quasispecies. The current study has provided initial data that support that CD8⁺ T cells can be primed by in vitro engineered DC, even against autologous HIV-1 peptides representing immune escape variants. This study therefore supports the concept of using autologous virus as an antigen in immunotherapy and demonstrates that the use of autologous viral sequences expands both memory and primary T cell responses in vitro. Thus, a potential advantage is that future immunotherapies could use autologous virus representing a large repertoire of the host's diverse HIV-1 antigen pool. This could elicit primary immune responses specific for each patient's quasispecies of HIV-1, as well as activation of residual HIV-1 specific memory T cells, giving the broadest immune control of HIV-1 infection during ART. Such an approach has important public health implications by having a strong positive impact on, and improve the control of, HIV-1 infection in persons on ART. It also serves as an in vitro priming model for development of prophylactic vaccines against HIV-1 and other infectious agents.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08022007-200741 |
| Date | 27 September 2007 |
| Creators | Colleton, Bonnie A |
| Contributors | Phalguni Gupta, Charles R. Rinaldo, Russell Salter, Walter Storkus, Simon Barratt-Boyes |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08022007-200741/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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