Population Genetic Structure and Human Adaptation of Kaposi Sarcoma–Associated Herpesvirus

Background. Kaposi sarcoma–associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma, is human-specific and is thought to have emerged from primate-infecting gammaherpesviruses. KSHV seroprevalence shows geographic variation, being highest in sub-Saharan Africa, intermediate in the Mediterranean area, and low in most other locations. However, KSHV prevalence is also particularly high in specific regions such as the Miyako Islands (Japan). Methods. We retrieved KSHV genomes from public repositories and analyzed geographic patterns using principal component analysis and STRUCTURE. Adaptation to the human host was investigated by likelihood ratio tests for positive selection. Protein structures were derived from the HerpesFolds database. Results. Most non-African genomes are genetically separated by the African genomes, and the latter are divided into 2 main lineages. The African genomes received most of their ancestry from 2 populations showing limited drift, suggesting an African origin for circulating KSHV strains. Several non-African genomes instead have most of their ancestry covered by a highly drifted ancestral population. However, some non-African genomes show similar ancestry proportions to the African ones, including those from Miyako Islands and the variant F subtype sampled in France. Molecular analysis of adaptation to the human host identified core genes as the major selection targets, including 2 viral enzymes that counteract human immune defenses. Conclusions. We suggest that the genetic diversity of extant strains reflects relatively recent demographic events associated with viral lineage extinctions, which may have influenced KSHV epidemiology. Adaptation to the human host involved changes in core genes, possibly a strategy to optimize protein–protein interactions.