Smith, Kellie
(2013)
Primary and recall cytotoxic T lymphocyte responses to autologous antigen in HIV-1-infected subjects.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human immunodeficiency virus type-1 (HIV-1) affects more than 30 million people worldwide and has accounted for over 30 million deaths. The advent of combination antiretroviral therapy (cART) resulted in a drastic decrease in AIDS-associated morbidity and mortality. Despite this, cART fails to completely eradicate the virus from infected patients, as cessation of treatment results in a rebound in viremia and a resumption of disease progression. Partial immune reconstitution is achieved under suppressive therapy, thus causing research efforts to begin development of curative strategies for HIV-1-infected patients. We believe the best method of HIV-1 eradication will be through cytotoxic T lymphocyte (CTL) elimination of the latently-infected reservoir, which may be difficult given the propensity of the virus to undergo mutations that evade CTL recognition. Dendritic cells, the most potent antigen-presenting cells, can reveal broad and robust HIV-1-specific T cell responses in subjects on cART and can prime CD8+ T cells specific for various HIV-1 antigens. We therefore believe the best method of inducing a potent anti-HIV-1 CTL response will be through the use of a DC-based immunotherapy targeting the patient’s own, unique (autologous) virus. It is unclear, however, if the naïve T cell repertoire and function has been sufficiently restored to respond to autologous virus containing multiple mutational variants. In the present study, we longitudinally evaluated autologous HIV-1 evolution and changes in T cell responses throughout untreated and treated HIV-1 infection in subjects from the Multicenter AIDS Cohort Study (MACS). We show that dendritic cells reveal autologous antigen-specific T cell responses at all stages of disease progression and are potent inducers of polyfunctional T cell responses after long-term suppressive cART. We developed and utilized an in vitro model of DC immunotherapy targeting naïve and memory CD8+ T cell subsets to show for the first time that naïve CD8+ T cells from subjects on cART can be primed to target the latent HIV-1 reservoir. Taken together, these findings shed new light on T cell responses to autologous HIV-1 viral variants and support the use of a DC immunotherapy in subjects on cART.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
16 December 2013 |
| Date Type: |
Publication |
| Defense Date: |
21 November 2013 |
| Approval Date: |
16 December 2013 |
| Submission Date: |
13 December 2013 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
283 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
dendritic cells, in vitro priming, T cells, HIV, immunotherapy |
| Date Deposited: |
16 Dec 2013 20:42 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20293 |
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