KSHV: pathways to tumorigenesis and persistent infection

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. These cancers often occur in the context of immunosuppression, which has made KSHV-associated malignancies an increasing global health concern with the persistence of the AIDS epidemic. KSHV has also been linked to several acute inflammatory diseases. KSHV exists between a lytic and latent lifecycle, which allows the virus to transition between active replication and quiescent infection. KSHV encodes a number of proteins and small RNAs that are thought to inadvertently transform host cells while performing their functions of helping the virus persist in the infected host. KSHV also has an arsenal of components that aid the virus in evading the host immune response, which help the virus establish a successful lifelong infection. In this comprehensive chapter, we will discuss the diseases associated with KSHV infection, the biology of latent and lytic infection, and individual proteins and microRNAs that are known to contribute to host cell transformation and immune evasion.

Keywords: HHV8; KSHV; Kaposi's sarcoma; Latency locus; Lytic replication; Multicentric Castleman's disease; Primary effusion lymphoma; Viral immune evasion; Viral oncogenes.

Figure 1. KSHV encodes a number of proteins that contribute to cell growth and transformation

A) K1 is a transmembrane protein with a constitutively active immunoreceptor tyrosine activation motif (ITAM) that activates signaling through SH2-containing proteins. K1 expression results in production of VEGF and pro-inflammatory cytokines. B) vGPCR is a constitutively active homolog of the IL8 receptor that results in activation of numerous cell signaling pathways and transcription factors to increase production of VEGF, VEGFR, and proinflammatory cytokines and chemokines. C) vIL6 is a functional homolog of human IL6 that can signal through shared IL6 pathways including JAK/STAT, MAPK, and PI3K. This results in activation of multiple IL6 response elements and production of human IL6 and VEGF. D) K15 is a transmembrane protein with several tyrosine residues and SH2 and SH3 domains and in its cytoplasmic tail that are critical for K15’s interaction with cellular TRAFs and signaling through the MAPK and NFκB pathways. K15 signaling results in activation of numerous transcription factors and expression of pro-inflammatory cytokines and chemokines and several human miRNAs that are involved in cell motility.

Figure 2. KSHV evasion of the host interferon response

KSHV encodes viral interferon regulatory factors (vIRF 1-3) that antagonize the function of cellular IRFs, p300, and NFκB to suppress production of type I IFN. ORF45, RTA, and KbZIP have also been shown to interfere with IRF signaling. K3 and K5 are able to degrade the IFN3γR1 to reduce antiviral IFNγ signaling through the JAK/STAT pathway. Viral infection and expression of vGPCR reduces TLR4 expression, and RTA can induce degradation of the TLR3 and TLR4 mediator TRIF. miR-K12-9 and 5 downregulate IRAK1 and MYD88 which are also components of TLR signaling pathways. Reduction of TLR signaling results in reduced expression of type I IFN. Finally, ORF64 is able to deubiquitinate RIG-I which suppresses RIG-I mediated production of IFNβ.