KSHV strains: the origins and global spread of the virus

Nucleotide sequence analysis at five distinct loci across the 140,000 bp ge nomes of more than 650 KSHV samples from KS and PEL tumors from North Ameri ca, Africa, the Middle East, Asia and the Pacific revealed that they cluste r into four major subtypes (A, B, C and D) that have close associations wit h 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 gen ome and are essentially unlinked to the ORF-K1 genotypes. We conclude that: (1) KSKV is an ancient human virus with several major subtypes that reflec t the migrationary divergence of modem human populations over the past 35,0 00-60,000 years; (2) the novel immunoglobulin receptor-like signal transduc ing protein ORF-K1 is subject to unusually strong biological selective pres sures; and (3) a minority of KSHV genomes have undergone recombination even ts with a related virus producing two different alles of the ORF-K15 latenc y membrane protein.