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CD8 T Lymphocyte Responses to Human Herpesvirus 8 Lytic and Latency Proteins

Lepone, Lauren M. (2013) CD8 T Lymphocyte Responses to Human Herpesvirus 8 Lytic and Latency Proteins. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Human herpesvirus 8 (HHV-8) is a lymphotropic gammaherpesvirus that causes Kaposi's sarcoma (KS), a vascular tumor of spindle-shaped endothelial cells. The importance of determining effective prevention and treatment for HHV-8 infection is evident in that KS continues to be the most common cancer among HIV-1 and AIDS patients. It is postulated that CD8+ T cell responses play an important role in controlling HHV-8 infection and preventing KS. However, there are minimal data supporting the role for T cell immunity in control of HHV-8 infection. Therefore, I investigated CD8+ T cell responses to HHV-8 lytic and latency proteins.
I used our dendritic cell-based system in an IFN-γ ELISPOT to identify novel epitopes in healthy, HHV-8 seropositive individuals, then further assessed new epitopes for immune mediators using polychromatic flow cytometry. I also used multimer complexes to directly detect HHV-8-specific CD8+ T cells in blood. I investigated the effect of regulatory T cells (Treg) on these anti-HHV-8 T cell responses by depleting samples of Treg. I then applied these assays to patients in the Multicenter AIDS Cohort Study to longitudinally investigate the role of these responses during the progression to KS.
Through these studies, I identified 10 novel HLA A*0201-restricted epitopes, which activated both monofunctional and polyfunctional CD8+ T cells producing various combinations of immune mediators. Responses were lower over many years prior to development of KS. Although CD8+ T cell IFN-γ responses were modest, a low but consistent percent of HHV-8-specific CD8+ T cells were present in blood, suggesting a functional down-regulation of this response. In support of this, removal of Treg enhanced CD8+ T cell responses to HHV-8 epitopes, and numbers of Treg increased prior to KS development.
Overall, these data support that T cell responses, in frequency, magnitude and quality, are essential for the control of HHV-8 infection to prevent disease development. They also indicate that these antiviral T cell responses are in part controlled by Treg. Involvement of CD8+ T cells and Treg in control of HHV-8 infection has public health significance through implications for understanding the immunopathogenesis of HHV-8 needed for prevention and treatment of KS.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lepone, Lauren M.lml33@pitt.eduLML33
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRinaldo, Charlesrinaldo@pitt.eduRINALDO
Committee MemberAyyavoo, Velpandivelpandi@pitt.eduVELPANDI
Committee MemberJenkins, Frankfjenkins@pitt.eduFJENKINS
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Date: 29 January 2013
Date Type: Publication
Defense Date: 29 November 2012
Approval Date: 29 January 2013
Submission Date: 15 November 2012
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 155
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: HHV-8, KSHV, CD8 T cell responses, Treg, Kaposi's sarcoma, CTL
Date Deposited: 29 Jan 2013 22:05
Last Modified: 19 Dec 2016 14:39
URI: http://d-scholarship.pitt.edu/id/eprint/16426

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