Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral IL-6 (vIL-6) Enhances Immunoglobulin Class-Switch Recombination.

Santas A Rosario,Gabriel E Santiago,Enrique A Mesri,Ramiro E Verdun

doi:10.3389/fmicb.2018.03119

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus that causes AIDS-associated Kaposi sarcoma (KS) and several lymphoproliferative disorders. During the humoral immune response antigen-activated mature B cells acquire functional diversification by immunoglobulin heavy chain (IgH) class-switch recombination (CSR). CSR is initiated by activation-induced cytidine deaminase (AID) which targets highly repetitive switch (S)-regions to mediate DNA double-stranded breaks (DSBs) in the IgH locus facilitating intramolecular recombination. Here 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 regulatory role for KSHV vIL-6 in functionally modulating B cell biology by promoting CSR, which may in part explain how KSHV infection influences humoral immunity and affect KSHV pathogenesis.

Highlights

Kaposi’s sarcoma-associated herpes virus (KSHV) is an oncogenic gamma-herpesvirus that is the underlying cause of Kaposi sarcoma (KS), an AIDS-associated angiogenic cancer of endothelial cell origin, and several lymphoproliferative malignancies namely, primary effusion lymphoma (PEL), multicentric Castleman Disease (MCD), and germinotropic lymphoproliferative disorder (GLD) (Du et al, 2002; Mesri et al, 2010; Bhavsar et al, 2017)
As activation-induced cytidine deaminase (AID) induces class-switch recombination (CSR), we investigated the functional consequence of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection on CSR
ISLK.219 cells are infected with a recombinant KSHV construct, rKSHV.219, which expresses GFP under the elongation factor-1 (EF-1) promoter upon latency establishment, and expresses RFP under the polyadenylated nuclear (PAN) promoter when the virus is reactivated with doxycycline (Myoung and Ganem, 2011b)

Summary

Introduction

Kaposi’s sarcoma-associated herpes virus (KSHV) is an oncogenic gamma-herpesvirus that is the underlying cause of Kaposi sarcoma (KS), an AIDS-associated angiogenic cancer of endothelial cell origin, and several lymphoproliferative malignancies namely, primary effusion lymphoma (PEL), multicentric Castleman Disease (MCD), and germinotropic lymphoproliferative disorder (GLD) (Du et al, 2002; Mesri et al, 2010; Bhavsar et al, 2017). KSHV passively replicates its episomal DNA and subverts immune detection by latently infecting the majority of cells (Mesri et al, 2010; Bekerman et al, 2013; Host et al, 2017). A small subset of cells within the population undergo lytic replication and produce various inflammatory, angiogenic and proliferative factors that activate their cognate receptors via paracrine signaling on latently and non-infected cells (Bais et al, 1998; Cesarman et al, 2000; Pati et al, 2001; Mesri et al, 2010). KSHV-related pathogenesis is a consequence of immune dysfunction, HIV co-infection, and perturbation of signaling mechanisms that are exploited by the dual phases of the KSHV life cycle

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