Nucleotide substitution at the highly polymorphic K1 locus of human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus)

The K1 locus is a highly polymorphic locus in the genome of human herpesvirus 8, the causative agent of Kaposi's sarcoma. Analysis of the pattern of nucleotide substitution among alleles at this locus supported the hypothesis that natural selection has acted to enhance amino acid diversity in the two hypervariable regions (VR1 and VR2) of the extracellular portion of the K1 protein. A phylogenetic analysis of 125 complete K1 sequences revealed two major clades, designated A/C and B. There was strong evidence against recombination between VR1 and VR2 among alleles belonging to different clades, and little support for frequent recombination within clades. The pattern of diversification of VR1 and VR2 within clades was similar to that between clades, but the immunoreceptor tyrosine-based activation motif (ITAM)-like sequence in the cytoplasmic region of K1 showed strong divergence between clades despite conservation within clades. The latter finding suggests that, while being subject to similar selection favoring diversity in the extracellular region, the two major clades of K1 alleles may be adapted for different types of interaction with host intracellular signal transduction mechanisms.