TY  - UNPB
ID  - pittir16426
UR  - http://d-scholarship-dev.library.pitt.edu/16426/
A1  - Lepone, Lauren M.
Y1  - 2013/01/29/
N2  - 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-? 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-? 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.
KW  - HHV-8
KW  -  KSHV
KW  -  CD8 T cell responses
KW  -  Treg
KW  -  Kaposi's sarcoma
KW  -  CTL
TI  - CD8 T Lymphocyte Responses to Human Herpesvirus 8 Lytic and Latency Proteins
EP  - 155
AV  - public
ER  -