The Virusan Evolutionary Perspective

With its 230-kb double-stranded DNA genome, wide tissue tropism, strict species specificity, and ability to establish latency, MCMV is a typical member of the betaherpes subfamily of the Herpesviridae [85] (Fig. 1a). Herpesviruses are considered an evolutionary success in terms of their occurrence in the animal kingdom because of their modest pathogenicity in the natural settings and their ability to establish latency. Part of this success can be attributed to the ability of herpesviruses to escape or modulate host immune responses through a complex array of virus-encoded mechanisms thought to result from an exquisite adaptation to their hosts. Many of these mechanisms are mediated by proteins encoded by families of related genes, which arose via gene duplication, and are localized in the extremities of the CMV genome [28, 85] (Fig. 1a). It appears that several of these viral genes have been captured from their host's genome during their evolution [73]. Betaherpesviruses are characterized by numerous and virus-specific mechanisms of immune evasion strategy [84], likely caused by their strict host tropism [73]. Although there is a substantial evolutionary divergence in the genomes of mouse and human CMV, infection of mice with MCMV has proven exceptionally useful for studying the complex host-pathogen interactions that occur during human CMV (HCMV) infection. This is in part because human and mouse CMV share 68 predicted proteins with significant amino acid identity [85] (Fig. 1a), as well as many similarities in their biological properties and clinical man-

Mcmv Genome

Fig. 1 a Schematic representation of MCMV genome. Rawlinson et al. (1996) predicted 170 open readingframes (ORF) in the MCMV genome representedby rectangles. White rectangles correspond to the predicted localization of 78 ORF with significant amino acid sequence similarity with ORF encoded in human CMV. We have indicated the localization of essential genes for origin-dependent replication, including DPAP (DNA polymerase accessory protein), DNApol (DNA polymerase), MDBP (single-stranded DNA binding protein), and the three components of the helicase complex (HP1, HP2, and Hel). Predicted ORF specific to MCMV are depicted in gray. The localization of the m02 and m145 gene at each of the extremities of the genomes is indicated. Vertical arrows point to the localization of ORF with predicted structural homology to mouse MHC class I. b Evasion molecules. Predicted structure of virus-encoded MHC class I-like molecules is characterized by the presence of three immunoglobin domains (a1-a3). m144 has been shown to bind host encoded p2-immunoglobulin (p2m) but not peptide

Fig. 1 a Schematic representation of MCMV genome. Rawlinson et al. (1996) predicted 170 open readingframes (ORF) in the MCMV genome representedby rectangles. White rectangles correspond to the predicted localization of 78 ORF with significant amino acid sequence similarity with ORF encoded in human CMV. We have indicated the localization of essential genes for origin-dependent replication, including DPAP (DNA polymerase accessory protein), DNApol (DNA polymerase), MDBP (single-stranded DNA binding protein), and the three components of the helicase complex (HP1, HP2, and Hel). Predicted ORF specific to MCMV are depicted in gray. The localization of the m02 and m145 gene at each of the extremities of the genomes is indicated. Vertical arrows point to the localization of ORF with predicted structural homology to mouse MHC class I. b Evasion molecules. Predicted structure of virus-encoded MHC class I-like molecules is characterized by the presence of three immunoglobin domains (a1-a3). m144 has been shown to bind host encoded p2-immunoglobulin (p2m) but not peptide ifestations [56]. Moreover, a common set of host responses are targeted by all CMVs, albeit through diverse mechanisms. As a result, it is frequently observed that evolutionarily distinct viral gene products have evolved to encode proteins with analogous activities and target similar pathways in a manner that suggests convergent evolution. Of note, nomenclature of animal CMV genes follows that set in place for HCMV, with uppercase letters (e.g., M44) for mouse MCMV genes that retain sequence similarity to HCMV and lowercase letters (m144) for those not conserved.

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