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Divergence in CD8+ T Cell Epitopes of HIV-1 as an Immune Escape Mechanism

Colleton, Bonnie A (2007) Divergence in CD8+ T Cell Epitopes of HIV-1 as an Immune Escape Mechanism. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Colleton, Bonnie Abacst45@pitt.edu, rinaldo@pitt.eduBACST45
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRinaldo, Charles Rrinaldo@pitt.eduRINALDO
Committee MemberGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberSalter, Russellrds@pitt.eduRDS
Committee MemberBarratt-Boyes, Simonsmbb@pitt.eduSMBB
Committee MemberStorkus, Walterstorkuswj@upmc.eduSTORKUSW
Date: 27 September 2007
Date Type: Completion
Defense Date: 17 August 2007
Approval Date: 27 September 2007
Submission Date: 2 August 2007
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
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: CTL; HIV-1; Immune escape
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08022007-200741/, etd-08022007-200741
Date Deposited: 10 Nov 2011 19:56
Last Modified: 19 Dec 2016 14:37
URI: http://d-scholarship.pitt.edu/id/eprint/8831

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