About 40% of adults excrete JC virus (JCV), the causative agent of a fatal demyelinating disease in AIDS patients, progressive multifocal leukoencephalopathy (PML). Previously, a short DNA fragment was identified in the VP1 gene which defined five genotypes of JCV. We have now demonstrated that this simplified approach to JCV genotyping agrees well with virus phylogenetic relationships determined by sequencing the entire JCV genome. Sequences of 19 complete genomes reveal five (perhaps six) different genotypes. With the two sequences originally published by others (Mad1 and GS/B), JCV is now defined by a total of 21 complete genomes. Based on these complete genomes, a strain tentatively called Type 5 (strain #311) could be assigned to a subtype of Type 3 - Type 3B. Strain #X01 is a new candidate for Type 5, although its frequency and geographical origin are not known. The existence of subtypes of Types 1 and 2 were confirmed by the complete genome sequences. It was also confirmed that the sequence designated Type 4 is very closely related to Type 1, and could be considered as a new subtype of Types 1, Type 1C. The geographic origin of the major genotypes is evident (Type 1: European; Type 2: Asian; Types 3 and 6: African; and Type 4: USA). The geographic associations of subtypes is less clear, but Type 2A appears to be associated with northeast Asia, while Type 2B is a minor type found in Europe. Type 2 is of particular interest because it is over- represented in PML brains compared to control urines. We analyzed the Type 2 strains found in PML brains for subtype frequency, The increased in the proportion of Type 2 in PML brain is due to Type 2B (European subtype), rather than to Type 2A (Asian subtype). In contrast, the subtype proportion within Type 1 strains is not significantly different between virus excreted in urine and that found in PML brain. We conclude that a sequence difference in the coding region between JCV subtypes 2A and 2B may be crucial for the Type 2 effect. The significance of Type 2B for development of PML is two-fold. At the level of the individual, the risk of an AIDS patient developing PML is increased by a factor of about 3-fold. At the level of the population at risk, the incidence in a geographic area or ethnic group may be predictable from the proportion of different genotypes (e.g., Types 1, 2A, 2B, and 4) in the population. A notable amino acid change associated with Type2A occurs at position 301 of the T antigen where a Leu residue in Type 2A is changed to Gln in Type 2B the zinc finger motif. The zinc finger is found in many DNA- binding proteins. How a mutation there might affect the pathogenicity of JCV is under investigation.
