Interaction of Kaposi’s Sarcoma-associated Herpesvirus with the Host Immune System Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Host, Kurtis
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent for three human malignancies; Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). KSHV-related diseases primarily manifest in immunocompromised hosts such as HIV positive patients, iatrogenic immune suppression, and geriatric populations. However, some subtypes of KS exist in the absence of obvious immune deficiency and remain poorly understood. KS is the leading cause of cancer in the sub-Saharan African nation of Malawi. Therefore, we sought to characterize the current clinical burden of KS in Lilongwe, Malawi, the capital city. We found that the majority of KS cases were associated with HIV. Interestingly, 9% of cases were in HIV naïve patients, suggesting a significant burden of the endemic subtype of KS. Our results suggest a needed emphasis for endemic KS research, a poorly understood subtype, as it represents a significant proportion of Malawi’s leading cancer. KSHV is recognized by the immune system, however, it encodes multiple mechanisms for thwarting effective immune responses. One mechanism implicated in escaping immune clearance is programmed death ligand 1 (PD-L1) overexpression. PD-L1 is a co-inhibitory molecule which interacts with the programmed death 1 (PD-1) receptor on T cells. PD-1:PD-L1 engagement blocks T cell receptor (TCR) signaling resulting in reduced T cell activation. Chronic PD-1:PD-L1 ligation results in T cell exhaustion. Tumor cells have been found to utilize PD-L1 to escape immune elimination. Current treatment targeting PD-L1 in certain cancer types is showing clinical efficacy. Therefore, we sought to determine if KSHV could increase PD-L1 expression. We found that KSHV is able to increase PD-L1 expression in human monocytes following infection. In addition, the cytokine profile showed a proinflammatory milieu. Our report is the first to show direct KSHV increase of PD-L1 expression and suggests that PD-L1 targeted therapeutics may have a role in KSHV mediated diseases.
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Advisor
  • Moody, Cary
  • Lemon, Stanley
  • Dittmer, Dirk
  • Su, Lishan
  • Damania, Blossom
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
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