JC virus (JCV) is a small DNA virus of the polyomavirus genus that is the agent of the subacute CNS demyelinating disease, progressive multifocal leukoencephalopathy (PML). The closely related human polyomavirus, BK virus, infects only the kidney, and has been implicated in kidney transplant failure. PML is the cause of death in approximately 5% of AIDS patients in the USA. JCV is excreted in the urine of healthy individuals and infects almost the entire population worldwide. Much of our effort in this project have been directed at characterizing the natural variation in the DNA sequence that occurs in both the regulatory region and the coding region of the viral genome, and determining the significance of these rearrangements and mutations for both the biology of the virus, and the pathogenesis of the CNS disease. As an added benefit, JCV has proved to be a useful marker of human populations as the virus evolved with the human species and remains strongly population associated. The regulatory region of virus excreted from the kidney is quite stable (archetypal) when circulating in the population, but rearranges extensively by unknown mechanisms before it attacks the brain of immunocompromised individuals. These brain adapted variants are each unique in their regulatory regions, and fortunately, appear not to be more readily transmissible from the urine. The concern is that with more PML present in the population, brain-adapted virus that also has a selective advantage in the kidney might begin to circulate in the population, putting infected individuals at higher risk of brain disease. Analysis of JC virus strains in Europe, Papua New Guinea and the South Pacific, as well as among Native Americans in North America and Misiones province of Argentina, and in Puerto Rico has helped to complete the picture of JC virus evolution in human populations, and thus of the movements and interactions of human populations over the past 100,000 years. A genotype in Europe (Type 4) is elevated in the Basque population, and we assign to it an origin in the Paleolithic prehistory of the European population. A genotype in Papua New Guinea and Melanesia (Type 8) may represent the earliest inhabitants of the region, whereas strains of more recent origin (Type 2E) may be associated with the Austronesian expansion into the South Pacific beginning 5,000 years ago. These Type 2E strains are most closely related to the Type 2A strains found in North Japan and Korea, and in the Native Americans of North and South America. The Native American strains are distinguished from those of Japan at only a few nucleotide positions, but do constitute a recognizable variant, Type 2A2. The relationship between Type 2A and Type 2E suggests a common ancestor in North Asia for a South Pacific population, Japanese founders, and Native Americans. In Puerto Rico JC virus strains representing Africa, Europe, and Native Americans have been identified. The later are predominant despite the disappearance there of the Taino Indians more than 200 years ago.
