KSHV strains: the origins and global spread of the virus

Nucleotide sequence analysis at five distinct loci across the 140, 000 bp genomes of more than 60 KSHV samples from KS and PEL tumors from North America, Africa, the Middle East, Asia and the Pacific revealed that they cluster into four major subtypes (A, B, C and D) that have close associations with the geographic and ethnic background of the patients. In particular, the ORF-K1 protein subtypes encoded at the extreme LHS of the genome display up to 30% amino acid variability resulting from 85% non-synonymous nucleotide substitution rates. In addition, two alternative highly diverged forms of the complex spliced ORF-K15 gene (P or M) map at the extreme RHS of the genome and are essentially unlinked to the ORF-K1 genotypes. We conclude that: (1) KSHV is an ancient human virus with several major subtypes that reflect the migrationary divergence of modern human populations over the past 35,000-60,000 years; (2) the novel immunoglobulin receptor-like signal transducing protein ORF-K1 is subject to unusually strong biological selective pressures; and (3) a minority of KSHV genomes have undergone recombination events with a related virus producing two different alleles of the ORF-K15 latency membrane protein.