Kaposi sarcoma-associated herpesvirus: immunobiology, oncogenesis, and therapy

Abstract

Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8, is the etiologic agent underlying Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. This human gammaherpesvirus was discovered in 1994 by Drs. Yuan Chang and Patrick Moore. Today, there are over five thousand publications on KSHV and its associated malignancies. In this article, we review recent and ongoing developments in the KSHV field, including molecular mechanisms of KSHV pathogenesis, clinical aspects of KSHV-associated diseases, and current treatments for cancers associated with this virus.

Figure 1. Innate immune evasion by KSHV.

KSHV encodes multiple viral proteins that inhibit innate immune pathways. (i) KSHV-mediated activation of TLRs and RIG-I triggers interferon and IFN-β production following primary infection. (ii) KSHV Rta, ORF45, and vIRF1, -2, and -3 block cellular IRFs from activating interferon-responsive genes. (iii) KSHV LANA, ORF52, and vIRF1 block the cGAS-STING DNA-sensing pathway. (iv) KSHV ORF63 inhibits NLRP1 and NLRP3 inflammasome activation and KCP/ORF4 promotes KSHV pathogenesis by helping the virus to evade complement.

Figure 2. Epigenetic modifications to KSHV upon primary infection, latency, and reactivation.

DNA is shown as a single line (linear inside virion, circular as episomal plasmid). Depicted in the figure is the transition of primary infection towards long-term molecular latency as well as transition of latent infection to reactivation. L and R represent the LANA and Rta promoters, respectively. Active promoters are designated by black arrows, and inactive promoters are indicated by white arrows. Cylinders indicate chromatin marks (histones) of either repressive (orange) or active (green) nature. PRC, polycomb repressive complex; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; DNMT, DNA methyltransferase; TLK2, tousled-like kinase 2; JMJD, Jumonji domain–containing protein; UTX, ubiquitously transcribed tetratricopeptide repeat, X chromosome (lysine-specific demethylase).

Figure 3. KSHV vGPCR, K1, K15, and vIL-6 proteins impact the PI3K/AKT/mTOR signaling pathway.

Multiple KSHV viral proteins activate the PI3K/AKT/mTOR signaling pathway at different nodes in this pathway. Activation of this pathway ultimately results in cell survival and cell proliferation.