Kaposi's sarcoma-associated herpesvirus at 27

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) was discovered 27 years ago and its link to several pathologies - Kaposi's sarcoma, primary effusion lymphoma, and the B cell variant of Multicentric Castleman disease - is now well established. However, many questions remain about how KSHV causes tumors. Here, I will review studies from the last few years (primarily 2019-2021) that report new information about KSHV biology and tumorigenesis, including new results about KSHV proteins implicated in tumorigenesis, genetic and environmental variability in KSHV-related tumor development, and potential vulnerabilities of KSHV-caused tumors that could be novel therapeutic targets.

Keywords: HHV-8; KSHV; Kaposi's sarcoma; PEL; Viral oncogenesis.

Fig. 1

Current model of transformation by KSHV. After KSHV infects cells, they undergo a morphological, metabolic and gene expression change that turns them into “spindle cells”. Latently infected cells contribute to tumors through increased proliferation and survival, and angiogenesis. Lytically infected cells produce virus that contributes to reseeding and maintaining the latent pool of cells. They also secrete various cytokines, angiogenic factors and other signals that contribute to growth and transformation of the tumor. Latently infected cells also produce extracellular vesicles that can affect cellular phenotypes.

Fig. 2

Potential origins of spindle cells from endothelial and mesenchymal cells. KSHV infection may lead to de-differentiation of both endothelial and mesenchymal cells through endothelial-to-mesenchymal (EndMT) and mesenchymal-to-endothelial transition (MEndT), respectively. The infected cells thus because more motile, angiogenic and proliferative. Nonetheless, paracrine signals are likely needed for full transformation of the cells.