eprintid: 8831 rev_number: 9 userid: 6 dir: disk0/00/00/88/31 datestamp: 2011-11-10 19:56:28 lastmod: 2016-12-19 14:37:00 status_changed: 2011-11-10 19:56:28 type: thesis_degree metadata_visibility: show contact_email: bacst45@pitt.edu, rinaldo@pitt.edu item_issues_count: 0 eprint_status: archive creators_name: Colleton, Bonnie A creators_email: bacst45@pitt.edu, rinaldo@pitt.edu creators_id: BACST45 title: Divergence in CD8+ T Cell Epitopes of HIV-1 as an Immune Escape Mechanism ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: CTL; HIV-1; Immune escape 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. date: 2007-09-27 date_type: completed institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Rinaldo, Charles R etdcommittee_name: Gupta, Phalguni etdcommittee_name: Salter, Russell etdcommittee_name: Barratt-Boyes, Simon etdcommittee_name: Storkus, Walter etdcommittee_email: rinaldo@pitt.edu etdcommittee_email: pgupta1@pitt.edu etdcommittee_email: rds@pitt.edu etdcommittee_email: smbb@pitt.edu etdcommittee_email: storkuswj@upmc.edu etdcommittee_id: RINALDO etdcommittee_id: PGUPTA1 etdcommittee_id: RDS etdcommittee_id: SMBB etdcommittee_id: STORKUSW etd_defense_date: 2007-08-17 etd_approval_date: 2007-09-27 etd_submission_date: 2007-08-02 etd_access_restriction: 5_year etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2011.8831 thesis_type: dissertation degree: PhD committee: Charles R. Rinaldo (rinaldo@pitt.edu) - Committee Chair committee: Phalguni Gupta (pgupta1@pitt.edu) - Committee Member committee: Russell Salter (rds@pitt.edu) - Committee Member committee: Simon Barratt-Boyes (smbb@pitt.edu) - Committee Member committee: Walter Storkus (storkuswj@upmc.edu) - Committee Member etdurn: etd-08022007-200741 other_id: http://etd.library.pitt.edu/ETD/available/etd-08022007-200741/ other_id: etd-08022007-200741 citation: Colleton, Bonnie A (2007) Divergence in CD8+ T Cell Epitopes of HIV-1 as an Immune Escape Mechanism. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/8831/1/bonniecolleton2007.pdf