Kaposi's sarcoma-associated herpesvirus (KSHV), formally designated the human herpesvirus 8 (HHV-8), is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and is also associated with the plasmablastic variant of multicentric Castleman's disease (MCD). More recently, KSHV has been linked to another pathological condition with many features in common with MCD, named KSHV inflammatory cytokine syndrome (KICS). KSHV infection is highly prevalent in sub-Saharan Africa and among some Amerindian and Melanesian populations, and diffuse in the Mediterranean area, in some Middle Eastern countries, and in parts of South America. KSHV is less prevalent in Northern Europe, North America and most of Asia. KSHV is transmitted via nonsexual routes during childhood in regions with intermediate and high seroprevalence, and mainly via sexual contact during adulthood in countries with low seroprevalence. Saliva is an important reservoir of infectious virus and plays a central role in both sexual and nonsexual modalities of transmission. KSHV is equipped with unique and host-pirated gene products with oncogenic properties and ability to increase the survival and proliferation of infected cells, modulate cellular microRNAs, and induce genetic instability. KSHV encodes a set of microRNAs that provide alternative strategy to modulate host gene expression while avoiding recognition by the host immune system. In vitro studies, animal models and recombinant viruses have greatly increased our knowledge of the KSHV-driven pathogenic mechanisms. A distinctive characteristic of KSHV pathogenesis is that genes expressed during the lytic phase generate an inflammatory microenvironment that cooperates with latent genes and viral microRNAs in cell immortalization and transformation. Several aspects of KSHV-induced pathogenesis and many of the predisposing factors remain to be revealed, and only a small part of the new findings has been translated into an effective clinical practice. Globally useful or population-based prognostic and predictive biomarkers for KSHV-related disorders still need to be defined to guide physicians in the choice of therapeutic strategies and to selectively monitor patients at risk. In the future, new technological tools, such as digital PCR and next-generation sequencing, are expected to provide new diagnostic assays and to extend and refine our knowledge on KSHV.
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