UNLABELLED

Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH), particularly in sub-Saharan Africa (SSA), where Kaposi sarcoma herpesvirus (KSHV or human herpesvirus 8 [HHV-8]) is endemic. In KSHV endemic areas, the overall survival of KS patients has changed little over the past 20 years. A phylogenetic analysis of available full-length viral genomes ( = 164) identified two different virus lineages that co-circulate in KSHV endemic regions today. Their sequences differ from the GenBank reference sequence and those of common laboratory strains, which originated in the 1990s in the US and Europe. Targeted short-read sequencing accuracy was validated by PacBio-based long-read sequencing to resolve repeats. This analysis identified over 1,000 single nucleotide variants (SNV) in a new 14-member sequence collection from tumor biopsies and blood in Malawi with 127 ± 32 (median ± SD) SNV per genome. Most were private, i.e., specific to one individual's virus. Within each of the two lineages, KSHV continues to evolve over time and across national borders by genetic drift and recombination. Analyses of shared SNVs by AlphaFold2 predicted some changes in the conformation of key viral proteins. These findings may help our understanding of herpesvirus evolution.

IMPORTANCE

To understand viruses, the field needs to know their genetic makeup. To develop mechanistic models, targeted therapies, and vaccines, we need comprehensive and up-to-date sequence information on the viral strains that circulate where the diseases appear today. Our knowledge of Kaposi sarcoma herpesvirus (KSHV) sequence distribution and evolution is behind that of other human herpesviruses and RNA viruses. Here, we add to community knowledge using new technologies and artificial intelligence.