Publication Date

2018-12-06

Availability

Open access

Embargo Period

2018-12-06

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2018-11-02

First Committee Member

Enrique A. Mesri

Second Committee Member

Ramiro Verdun

Third Committee Member

Kerry Burnstein

Fourth Committee Member

Wasif Khan

Fifth Committee Member

Jaime Merchán

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus that causes several AIDS-defining malignancies, including Kaposi's sarcoma (KS) and other lymphoproliferative disorders. These malignancies continue to burden AIDS patients, particularly one-seventh of the world’s population in sub-Saharan Africa, where highly active antiretroviral therapy (HAART) is poorly accessible. To successfully establish lifelong persistence within a host, KSHV employs several strategies, including mimicry of host cytokines, to modulate the immune response and usurp cellular signaling pathways. One crucial cytokine is vIL-6, a viral homolog to human IL-6 (hIL-6) and mouse IL-6 (mIL-6). Although the immune system plays a pivotal role in the pathogenesis of all KSHV-associated diseases, there is a paucity of information in regards to how primary or acute KSHV infection modulates the adaptive immune system. During the humoral immune response antigen-activated mature B cells generate antibodies (Abs) with varying biological effector functions via immunoglobulin heavy chain (IgH) class-switch recombination (CSR). CSR is initiated by the mutagenic DNA-editing enzyme, activation-induced cytidine deaminase (AID), which mediates DNA double-strand breaks (DSBs) in the IgH locus. This facilitates the reorganization and intramolecular recombination of IgH genes that is critical for consequent Ab functional diversification. We show that in the context of cytokine stimulation, CSR is enhanced in murine B cells exposed only to replication-competent KSHV in an environment of KSHV infection, which coincided with elevated AID transcripts. Using murine splenic B cells and the mouse lymphoma CH12F3-2 CSR system, we identified that vIL-6, but not murine IL-6, increased class-switching, which correlated with upregulated AID expression. Together, these data suggest a novel regulatory role for KSHV vIL-6 in functionally modulating B cell biology by enhancing CSR. Our data may provide a mechanistic explanation for how acute KSHV infection or recurrent lytic replication, in the context of certain cytokine and inflammatory environments, could affect humoral immunity in KSHV-associated diseases.

Keywords

class-switch recombination; KSHV; activation induced cytidine deaminase; viral IL-6; Kaposi's sarcoma; isotype

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