Evolution of the Sequence Composition of Flaviviruses

The adaption of pathogens to their host(s) is a major factor in the emergence of infectious disease and the persistent survival of many of the infectious diseases within the population. Since many of the smaller viral pathogens are entirely dependent upon host machinery, it has been postulated that they are under selection for a composition similar to that of their host. Analyses of sequence composition have been conducted for numerous small viral species including the Flavivirus genus. Examination of the species within this particular genus that infect vertebrate hosts revealed that sequence composition proclivities do not correspond with vector transmission as the evolutionary history of this species suggests. Recent sequencing efforts have generated complete genomes for many viral species including members of the Flavivirus genus. A thorough comparison of the sequence composition was conducted for all of the available Flaviviruses for which the complete genome is publicly available. This effort expands the work of previous studies to include new vector-borne species as well as members of the insect-specific group which previously have not been explored. Metrics, including mono-, di-, and trinucleotide abundances as well as NC values and codon usage preferences, were explored both for the entire polyprotein sequence as well as for each individual coding region. Preferences for compositions correspond to host-range rather than evolutionary history; species which infect vertebrate hosts exhibited particular preferences similar to each other as well as in correspondence with their host’s preferences. Flaviviruses which do not infect vertebrate hosts, however, did not show these proclivities, with the exception of the Kamiti River virus suggesting its recent (either past or present) infectivity of an unknown vertebrate host

Patterns of Evolution and Host Gene Mimicry in Influenza and Other RNA Viruses

It is well known that the dinucleotide CpG is under-represented in the genomic DNA of many vertebrates. This is commonly thought to be due to the methylation of cytosine residues in this dinucleotide and the corresponding high rate of deamination of 5-methycytosine, which lowers the frequency of this dinucleotide in DNA. Surprisingly, many single-stranded RNA viruses that replicate in these vertebrate hosts also have a very low presence of CpG dinucleotides in their genomes. Viruses are obligate intracellular parasites and the evolution of a virus is inexorably linked to the nature and fate of its host. One therefore expects that virus and host genomes should have common features. In this work, we compare evolutionary patterns in the genomes of ssRNA viruses and their hosts. In particular, we have analyzed dinucleotide patterns and found that the same patterns are pervasively over- or under-represented in many RNA viruses and their hosts suggesting that many RNA viruses evolve by mimicking some of the features of their host's genes (DNA) and likely also their corresponding mRNAs. When a virus crosses a species barrier into a different host, the pressure to replicate, survive and adapt, leaves a footprint in dinucleotide frequencies. For instance, since human genes seem to be under higher pressure to eliminate CpG dinucleotide motifs than avian genes, this pressure might be reflected in the genomes of human viruses (DNA and RNA viruses) when compared to those of the same viruses replicating in avian hosts. To test this idea we have analyzed the evolution of the influenza virus since 1918. We find that the influenza A virus, which originated from an avian reservoir and has been replicating in humans over many generations, evolves in a direction strongly selected to reduce the frequency of CpG dinucleotides in its genome. Consistent with this observation, we find that the influenza B virus, which has spent much more time in the human population, has adapted to its human host and exhibits an extremely low CpG dinucleotide content. We believe that these observations directly show that the evolution of RNA viral genomes can be shaped by pressures observed in the host genome. As a possible explanation, we suggest that the strong selection pressures acting on these RNA viruses are most likely related to the innate immune response and to nucleotide motifs in the host DNA and RNAs

Murine gammaherpesvirus 68 ORF75c contains ubiquitin E3 ligase activity and requires PML SUMOylation but not other known cellular PML regulators, CK2 and E6AP, to mediate PML degradation

AbstractAll gammaherpsviruses encode at least one gene related to the cellular formylglycinamide ribonucleotide amidotransferase (FGARAT) enzyme but their biological roles are relatively unknown. The murine gammaherpesvirus 68 (MHV68) vFGARAT, ORF75c, mediates a proteasome-dependent degradation of the antiviral promyelocytic leukemia (PML) protein by an unknown mechanism, which is addressed in this study. We found that ORF75c interacts weakly with PML and SUMO-modified forms of PML are important for its degradation by ORF75c. ORF75c-mediated PML degradation was not dependent on two known cellular regulators of PML stability, Casein kinase II (CK2) and human papilloma virus E6-associated protein (E6AP). Finally, ORF75c had self-ubiquitination activity in vitro and its expression increased levels of ubiquitinated PML in transfected cells. Taken together, the evidence accumulated in this study provides new insights into the function of a vFGARAT and is consistent with a model in which ORF75c could mediate direct ubiquitination of PML resulting in its degradation by the proteasome

Murine Gammaherpesvirus 68 Open Reading Frame 75c Tegument Protein Induces the Degradation of PML and Is Essential for Production of Infectious Virus▿

Promyelocytic Leukemia nuclear body (PML NB) proteins mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (γHV68) is emerging as a suitable model to study basic biological questions of virus-host interactions because it naturally infects mice. Therefore, we sought to determine whether γHV68 targets PML NBs as part of its natural life cycle. We found that γHV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, γHV68-mediated PML degradation was mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase enzyme. In addition, we show that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that γHV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo

Animal models of tumorigenic herpesviruses — an update

Any one model system, be it culture or animal, only recapitulates one aspect of the viral life cycle in the human host. By providing recent examples of animal models for Epstein Barr Virus and Kaposi Sarcoma-associated Herpesvirus, we would argue that multiple animal models are needed to gain a comprehensive understanding of the pathogenesis associated with human oncogenic herpesviruses. Transgenic mice, homologous animal herpesviruses, and tumorgraft and humanized mouse models all complement each other in the study of viral pathogenesis. The use of animal model systems facilitates the exploration of novel antiviral and anti-cancer treatment modalities for diseases associated with oncogenic herpesviruses