High Prevalence of Distinct Human Herpesvirus 8 Contributes to the High Incidence of Non-acquired Immune Deficiency Syndrome-Associated Kaposi’s Sarcoma in Isolated Japanese Islands

Background: Non-acquired immune deficiency syndrome (AIDS) Kaposi's sarcoma (KS) is extremely rare in Japan but highly endemic in Okinawa, especially in Miyako Islands. We aimed to elucidate the exact incidence and cause of this high prevalence. Methods: Non-AIDS KS cases in Okinawa Prefecture over the past 31 years were reviewed, and human herpesvirus 8 (HHV8) seroprevalence in Miyako Islands was determined. We examined whole-genome sequences of 3 HHV8 strains and performed whole-exome sequencing of 4 male patients from Miyako Islands. Results: Approximately half of the non-AIDS KS cases in Okinawa Prefecture were from Miyako Islands. The age-adjusted incidence rate was 0.87/105 per year for Miyako Islands and 0.056/105 per year for the rest of Okinawa. Human herpesvirus 8 seroprevalence was 15.4% in Miyako Islands. The 3 HHV8 genomes isolated from Miyako islanders formed a phylogenetically branch distinct from those of previously sequenced HHV8 strains and shared specific mutations in 9 proteins. These mutations were verified in Okinawan patients other than those from Miyako Islands. Whole-exome sequencing of the 4 male Miyako Islanders did not reveal shared pathogenic mutations. Conclusions: Miyako Islands are an endemic area of non-AIDS KS. The high rate of a distinct HHV8 may contribute to the high incidence of KS in the region.