Cell-Derived Viral Genes Evolve under Stronger Purifying Selection in Rhadinoviruses.

Like many other large double-stranded DNA (dsDNA) viruses, herpesviruses are known to capture host genes to evade host defenses. Little is known about the detailed natural history of such genes, nor do we fully understand their evolutionary dynamics. A major obstacle is that they are often highly divergent, maintaining very low sequence similarity to host homologs. Here we use the herpesvirus genus Rhadinovirus as a model system to develop an analytical approach that combines complementary evolutionary and bioinformatic techniques, offering results that are both detailed and robust for a range of genes. Using a systematic phylogenetic strategy, we identify the original host lineage of viral genes with high confidence. We show that although host immunomodulatory genes evolve rapidly compared to other host genes, they undergo a clear increase in purifying selection once captured by a virus. To characterize this shift in detail, we developed a novel technique to identify changes in selection pressure that can be attributable to particular domains. These findings will inform us on how viruses develop strategies to evade the immune system, and our synthesis of techniques can be reapplied to other viruses or biological systems with similar analytical challenges.IMPORTANCE Viruses and hosts have been shown to capture genes from one another as part of the evolutionary arms race. Such genes offer a natural experiment on the effects of evolutionary pressure, since the same gene exists in vastly different selective environments. However, sequences of viral homologs often bear little similarity to the original sequence, complicating the reconstruction of their shared evolutionary history with host counterparts. In this study, we use a genus of herpesviruses as a model system to comprehensively investigate the evolution of host-derived viral genes, using a synthesis of genomics, phylogenetics, selection analysis, and nucleotide and amino acid modeling.

Sequence of the ateline alphaherpesvirus 1 (HVA1) genome.

Here, we report the genome sequence of a spider monkey alphaherpesvirus (ateline alphaherpesvirus 1, HVA1) and compare it with that of other primate alphaherpesviruses. The HVA1 genome is 147,346 bp long and contains 67 predicted ORFs. The genetic layout of the HVA1 genome is similar to that of the squirrel monkey alphaherpesvirus (saimirine alphaherpesvirus 1, HVS1) in that it lacks inverted repeat regions flanking the unique long region and homologues of the UL43, UL49.5, US8.5 and US10-12 genes. Unlike HVS1, HVA1 also lacks a homologue of the RL1 (γ34.5) gene and a replication origin near the end of the genome. Consistent with previous phylogenetic analyses, all predicted proteins of HVA1 are most closely related to those of HVS1.

Sodium taurocholate cotransporting polypeptide mediates woolly monkey hepatitis B virus infection of Tupaia hepatocytes.

Primary Tupaia hepatocytes (PTHs) are susceptible to woolly monkey hepatitis B virus (WMHBV) infection, but the identity of the cellular receptor(s) mediating WMHBV infection of PTHs remains unclear. Recently, sodium taurocholate cotransporting polypeptide (NTCP) was identified as a functional receptor for human hepatitis B virus (HBV) infection of primary human and Tupaia hepatocytes. In this study, a synthetic pre-S1 peptide from WMHBV was found to bind specifically to cells expressing Tupaia NTCP (tsNTCP) and it efficiently blocked WMHBV entry into PTHs; silencing of tsNTCP in PTHs significantly inhibited WMHBV infection. Ectopic expression of tsNTCP rendered HepG2 cells susceptible to WMHBV infection. These data demonstrate that tsNTCP is a functional receptor for WMHBV infection of PTHs. The result also indicates that NTCP's orthologs likely act as a common cellular receptor for all known primate hepadnaviruses.

Respiratory syncytial virus (RSV) pneumonia in a southern muriqui (Brachyteles arachnoides).

BACKGROUND: An adult male Brachyteles arachanoides, kept in captivity since 1990, was found dead without apparent clinical evidence. METHODS: Necropsy report, histopathology, immunohistochemistry, and ultrastructural examination were conducted. RESULTS: Pulmonary syncytial cells were positive for respiratory syncytial virus (RSV), and ultrastructural examination revealed viral particles inside macrophages compatible with the Paramyxoviridae family. CONCLUSIONS: Muriquis are susceptible to RSV pneumonia followed by respiratory distress syndrome and death.

Identification of novel inter-genotypic recombinants of human hepatitis B viruses by large-scale phylogenetic analysis.

Recombination plays an important role in the evolutionary history of Hepatitis B virus (HBV). We performed a phylogenetic analysis of 3403 full-length HBV genome sequences isolated from humans to define the genotype. The genome sequences were divided into 13 sub-datasets, each approximately 250 bp in length. Genotype designations obtained from the sub-datasets that differed from the genotype defined by the whole genome were assigned as putative recombinants. Our results showed that 3379 out of 3403 sequences belonged to the previously described and putative genotypes A to J respectively, with 315 sequences defined in this analysis. The remaining 24 viruses had sequence divergence of less than 8% with both genotypes B and C and were provisionally assigned genotype "BC". 1047 out of 3403 sequences were identified to be putative recombinants, of which 72 were identified to be novel recombinants. Notably, all viruses of the herein described genotype "BC" were identified to be B/C recombinants.

Species-specific inhibition of foamy viruses from South American monkeys by New World Monkey TRIM5{alpha} proteins.

Foamy virus evolution closely parallels that of the host species, indicating virus-host coadaptation. We studied simian foamy viruses (SFVs) from common marmosets, spider monkeys, and squirrel monkeys, New World monkey (NWM) species that share geographic ranges. The TRIM5alpha protein from each of these NWM species inhibited the replication of at least one of the SFVs associated with the other two species but did not affect the replication of its own SFV. Thus, TRIM5alpha has potentially shaped the evolution of SFVs in NWM hosts. Conversely, SFVs may have influenced the evolution of TRIM5 variants in New World primates.

Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein.

360 million people are chronically infected with the human hepatitis B virus (HBV) and are consequently prone to develop liver cirrhosis and hepatocellular carcinoma. As approved therapeutic regimens-which modulate patients' antiviral defenses or inhibit the viral reverse transcriptase-are generally noncurative, strategies interfering with other HBV replication steps are required. Expanding on our demonstration that acylated peptides derived from the large HBV envelope protein block virus entry in vitro, we show their applicability to prevent HBV or woolly monkey hepatitis B virus infection in vivo, using immunodeficient urokinase-type plasminogen activator (uPA) mice repopulated with primary human or Tupaia belangeri hepatocytes. Accumulation of the peptides in the liver, their extraordinary inhibitory potency and specific mode of action permit subcutaneous delivery at very low doses. Inhibition of hepadnavirus entry thus constitutes a therapeutic approach to prevent primary HBV infection, such as after liver transplantation, and might also restrain virus spread in chronically infected patients.

The complete nucleotide sequence of a New World simian foamy virus.

We determined the complete nucleotide sequence of the New World simian foamy virus (FV) from spider monkey (SFVspm). Starting from a conserved region in the integrase (IN) domain of the pol gene we cloned fragments of the genome up to the 5' end of the long terminal repeat (LTR) into plasmid vectors and elucidated their nucleotide sequence. The 3' end of the genome was determined by direct nucleotide sequencing of PCR products. Each nucleotide of the genome was determined at least two times from both strands. All protein motifs described to be conserved among primate FVs were found in SFVspm. At both the nucleotide and protein levels SFVspm is the most divergent primate FV described to date, reflecting the long-term phylogenetic separation between Old World and New World primate host species (Catarrhini and Platyrrhini, respectively). The molecular probes developed for SFVspm will allow the investigation of trans-species transmissions of this New World foamy virus to humans by serological assays.