Dual infection and recombination of Kaposi sarcoma herpesvirus revealed by whole-genome sequence analysis of effusion samples

Kaposi sarcoma herpesvirus (KSHV) is the etiological agent of three malignancies, Kaposi sarcoma, primary effusion lymphoma and KSHV-associated multicentric Castelman disease. KSHV infected patients may also have an interleukin six-related KSHV-associated inflammatory cytokine syndrome. KSHV-associated diseases occur in only a minority of chronically KSHV-infected individuals and often in the setting of immunosuppression. Mechanisms by which KSHV genomic variations and systemic co-infections may affect the pathogenic pathways potentially leading to these diseases have not been well characterized in vivo. To date, the majority of comparative genetic analyses of KSHV have been focused on a few regions scattered across the viral genome. We used next-generation sequencing techniques to investigate the taxonomic groupings of viruses from malignant effusion samples from fourteen participants with advanced KSHV-related malignancies, including twelve with primary effusion lymphoma and two with Kaposi sarcoma and elevated KSHV viral load in effusions. The genomic diversity and evolutionary characteristics of nine isolated, near full-length KSHV genomes revealed extensive evidence of mosaic patterns across all these genomes. Further, our comprehensive NGS analysis allowed the identification of two distinct KSHV genome sequences in one individual, consistent with a dual infection. Overall, our results provide significant evidence for the contribution of KSHV phylogenomics to the origin of KSHV subtypes. This report points to a wider scope of studies to establish genome-wide patterns of sequence diversity and define the possible pathogenic role of sequence variations in KSHV-infected individuals.