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(Unpublished)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