Evolution of CMV vCK Genes

To date, three vCK genes have been identified in the HCMV genome (Fig. 2), the CC chemokine-like gene UL128, and the CXC chemokine-like genes UL146 and UL147. To some extent, these genes are conserved among primate CMVs (Table 1). UL128-like genes are also present on the genomes of murine CMV (MCMV) and rat CMV (RCMV), as well as on the genome of human herpesvirus type 6 (HHV-6) (Table 1). The rodent CMV and HHV-6 species lack UL146- and UL147-like

Fig. 2 CMV chemokine and chemokine receptor homolog gene loci. The central line represents the HCMV Merlin strain genome (235,645 kb) derived from GenBank accession NC_006273. The black boxes on this line represent repetitive regions. The chemokine homolog gene loci are enlarged above the genomic line, the chemokine receptor homolog gene loci below the genomic line. The arrowheads indicate the sizes and directions of the coding content of the genes. The UL128 exon sizes and positions are analogous to those of the HCMV AD169 strain, as indicated in NC_006273. UL unique long, US unique short

Fig. 2 CMV chemokine and chemokine receptor homolog gene loci. The central line represents the HCMV Merlin strain genome (235,645 kb) derived from GenBank accession NC_006273. The black boxes on this line represent repetitive regions. The chemokine homolog gene loci are enlarged above the genomic line, the chemokine receptor homolog gene loci below the genomic line. The arrowheads indicate the sizes and directions of the coding content of the genes. The UL128 exon sizes and positions are analogous to those of the HCMV AD169 strain, as indicated in NC_006273. UL unique long, US unique short genes. Similar to the UL33- and UL78-like genes, the UL128-like chemokine genes are likely to have been acquired by betaherpesviruses at least 110 My ago. The conservation of this gene family suggests an essential role for these genes in the survival of betaherpesviruses in vivo. This notion is supported by the observation that the UL128 sequences from different clinical HCMV isolates are highly conserved (Baldanti et al. 2006). Paradoxically, the UL128 gene appears to be functional in laboratory strain HCMV AD169, whereas in the clinical, low-passage HCMV strains Toledo and Merlin, as well as in the chimpanzee CMV (CCMV) laboratory strain, the UL128-like genes are disrupted by inversions or frame shift mutations (Table 1). A UL128 counterpart was also identified on the HHV-6 genome, designated U83A. This gene was found to encode a potent CC chemokine (Derwin et al. 2006). Interestingly, the UL130 genes of the primate CMVs also contain chemokine-like sequences, including a CXC domain (Glass et al. 2003). However, the UL130-derived amino acid sequences lack other cysteine residues that are essential for classical chemokine folding (Glass et al. 2003). The MCMV and RCMV genome sequences available to date do not contain UL130-like CXC chemokine sequences. Nevertheless, within the genome of the Maastricht strain of RCMV, a second CC chemokine-like gene, r131, was identified adjacent to r129. These two genes may have originated from duplication of a common ancestor gene (Kaptein et al. 2004; Voigt et al. 2005). In contrast to the UL128-like genes, UL146 and UL147 appear to be restricted to the primate CMVs. Both the HCMV and CCMV UL146 genes encode a CXC vCK (Table 1). Rhesus macaque CMV (RhCMV) does not possess a UL146 homolog (Table 1). Both the HCMV and CCMV genomes contain a UL147 gene, whereas a UL147-like gene is present in

Table 1 Cytomegalovirus chemokine-like genes

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