Endogenous Foamy Viruses Research Articles

Discovery of an endogenous foamy virus in primitive ruminant chevrotains.

Foamy viruses (FVs) are a class of complex retroviruses that could lead to persistent infections in specific species. FVs have two evolutionary characteristics: the first is co-evolution with the host, and the second is difficulty going through the endogenization process. To date, in mammals, only a few species (aye-aye, sloths, and cape golden mole) have been found to have endogenous forms of FVs. In this study, we identified a novel endogenous FV named TraEFV in the genomes of two species of even-toed ungulate chevrotain (genus Tragulus, family Tragulidae) known as mouse-deer. Phylogenetic analysis clustered TraEFVs with an exogenous FV isolated from feline but not with those isolated from cow and horse, and such inconsistent virus-host relationships reflect their complex evolutionary history. Interestingly, TraEFVs could be divided into two lineages, suggesting that TraEFV invaded these hosts at least twice during ancient times. Finally, the molecular clock estimates that TraEFV is approximately 20 million years old, suggesting its ancient nature. Our findings enrich the host taxonomy of spumaretroviruses. IMPORTANCE Foamy viruses (FV) are complex retroviruses that generally codiverge with their hosts. We identified a novel endogenous FV in the genomes of two mouse-deer species, the first endogenous FV found in Artiodactyla. The phylogenetic inconsistency of viruses and hosts suggested that the viruses might have emerged from cross-species transmission in the past. These findings indicate that ancient FVs may have had a wider range of hosts that remain to be expanded.

Identification of Cartilaginous Fish Endogenous Foamy Virus Rooting to Vertebrate Counterparts.

Foamy viruses (FVs) are ideal models for studying the long-term evolutionary history between viruses and their hosts. Currently, FVs have been documented in nearly all major taxa of vertebrates, but evidence is lacking for true FV infiltration in cartilaginous fish, the most basal living vertebrates with jaws. Here, we screened 11 available genomes and 10 transcriptome sequence assemblies of cartilaginous fish and revealed a novel endogenous foamy virus, termed cartilaginous fish endogenous foamy virus (CFEFV), in the genomes of sharks and rays. Genomic analysis of CFEFVs revealed feature motifs that were retained among canonical FVs. Phylogenetic analysis using polymerase sequences revealed the rooting nature of CFEFVs to vertebrate FVs, indicating their deep origin. Interestingly, three viral lineages were found in a shark (Scyliorhinus torazame), one of which was clustered with ray-finned fish foamy-like viruses, indicating that multiple episodes of viral infiltrations had occurred in this species. These findings fill a major gap in the Spumaretrovirinae taxon and reveal the aquatic origin of FVs found in terrestrial vertebrates. IMPORTANCE Although foamy viruses (FVs) have been found in major branches of vertebrates, the presence of these viruses in cartilaginous fish, the most basal living vertebrates with jaws, remains to be explored. This study revealed a collection of cartilaginous endogenous FVs in sharks and rays through in silico genomic mining. These viruses were rooted in the polymerase (POL) phylogeny, indicating the ancient aquatic origin of FVs. However, their envelope (ENV) protein grouped with those of amphibian FVs, suggesting different evolutionary histories of different FV genes. Overall, we provide the last missing gap for the taxonomic investigation of Spumaretrovirinae and provide concrete support for the aquatic origin of FVs.

Avian and serpentine endogenous foamy viruses, and new insights into the macroevolutionary history of foamy viruses.

This study reports and characterises two novel distinct lineages of foamy viruses (FVs) in the forms of endogenous retroviruses (ERVs). Several closely related elements were found in the genome of oriental stork (Ciconia boyciana) and other was found in the genome of spine-bellied sea snake (Hydrophis hardwickii), designated ERV-Spuma.N-Cbo (where 'N' runs from one to thirteen) and ERV-Spuma.1-Hha, respectively. This discovery of avian and serpentine endogenous FVs adds snakes, and perhaps more crucially, birds to the list of currently known hosts of FVs, in addition to mammals, reptiles, amphibians, and fish. This indicates that FVs are, or at least were, capable of infecting all major lineages of vertebrates. Moreover, together with other FVs, phylogenetic analyses showed that both of them are most closely related to mammalian FVs. Further examination revealed that reptilian FVs form a deep paraphyletic group that is basal to mammalian and avian FVs, suggesting that there were multiple ancient FV cross-class transmissions among their hosts. Evolutionary timescales of various FV lineages were estimated in this study, in particular, the timescales of reptilian FVs and that of the clade of mammalian, avian, and serpentine FVs. This was accomplished by using the recently established time-dependent rate phenomenon models, inferred using mainly the knowledge of the co-speciation history between FVs and mammals. It was found that the estimated timescales matched very well with those of reptiles. Combined with the observed phylogenetic patterns, these results suggested that FVs likely co-speciated with ancient reptilian animals, but later jumped to a protomammal and/or a bird, which ultimately gave rise to mammalian and avian FVs. These results contribute to our understanding of FV emergence, specifically the emergence of mammalian and avian FVs, and provide new insights into how FVs co-evolved with their non-mammalian vertebrate hosts in the distant past.

The First Co-Opted Endogenous Foamy Viruses and the Evolutionary History of Reptilian Foamy Viruses.

A recent study reported the discovery of an endogenous reptilian foamy virus (FV), termed ERV-Spuma-Spu, found in the genome of tuatara. Here, we report two novel reptilian foamy viruses also identified as endogenous FVs (EFVs) in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel’s Japanese gecko (ERV-Spuma-Gja). Their presence indicates that FVs are capable of infecting reptiles in addition to mammals, amphibians, and fish. Numerous copies of full length ERV-Spuma-Spu elements were found in the tuatara genome littered with in-frame stop codons and transposable elements, suggesting that they are indeed endogenous and are not functional. ERV-Spuma-Ppi and ERV-Spuma-Gja, on the other hand, consist solely of a foamy virus-like env gene. Examination of host flanking sequences revealed that they are orthologous, and despite being more than 96 million years old, their env reading frames are fully coding competent with evidence for strong purifying selection to maintain expression and for them likely being transcriptionally active. These make them the oldest EFVs discovered thus far and the first documented EFVs that may have been co-opted for potential cellular functions. Phylogenetic analyses revealed a complex virus–host co-evolutionary history and cross-species transmission routes of ancient FVs.

Identification and evolution of avian endogenous foamy viruses.

A history of long-term co-divergence means that foamy viruses (family Retroviridae) provide an ideal framework to understanding virus-host evolution over extended time periods. Endogenous foamy viruses (EndFVs) are rare, and to date have only been described in a limited number of mammals, amphibians, reptiles and fish genomes. By screening 414 avian genomes we identified EndFVs in two bird species: the Maguari Stork (Ciconia maguari) and the Oriental Stork (Ciconia boyciana). Analyses of phylogenetic relationships, genome structures and flanking sequences revealed a single origin of EndFVs in Ciconia species. In addition, the marked incongruence between the virus and host phylogenies suggested that this integration event occurred independently in birds. In sum, by providing evidence that birds can be infected with foamy viruses, we fill the last major gap in the taxonomic distribution of foamy viruses and their animal hosts.

A reptilian endogenous foamy virus sheds light on the early evolution of retroviruses.

Endogenous retroviruses (ERVs) represent host genomic ‘fossils’ of ancient viruses. Foamy viruses, including those that form endogenous copies, provide strong evidence for virus-host co-divergence across the vertebrate phylogeny. Endogenous foamy viruses (EFVs) have previously been discovered in mammals, amphibians, and fish. Here we report a novel endogenous foamy virus, termed ERV-Spuma-Spu, in genome of the tuatara (Sphenodon punctatus), an endangered reptile species endemic to New Zealand. Phylogenetic analyses revealed that foamy viruses have likely co-diverged with their hosts over many millions of years. The discovery of ERV-Spuma-Spu fills a major gap in the fossil record of foamy viruses and provides important insights into the early evolution of retroviruses.

Tenth International Foamy Virus Conference 2014--achievements and perspectives.

For the past two decades, scientists from around the world, working on different aspects of foamy virus (FV) research, have gathered in different research institutions almost every two years to present their recent results in formal talks, to discuss their ongoing studies informally, and to initiate fruitful collaborations. In this report we review the 2014 anniversary conference to share the meeting summary with the virology community and hope to arouse interest by other researchers to join this exciting field. The topics covered included epidemiology, virus molecular biology, and immunology of FV infection in non-human primates, cattle, and humans with zoonotic FV infections, as well as recent findings on endogenous FVs. Several topics focused on virus replication and interactions between viral and cellular proteins. Use of FV in biomedical research was highlighted with presentations on using FV vectors for gene therapy and FV proteins as scaffold for vaccine antigen presentation. On behalf of the FV community, this report also includes a short tribute to commemorate Prof. Axel Rethwilm, one of the leading experts in the field of retrovirology and foamy viruses, who passed away 29 July 2014.

Endogenous Viral Sequences from the Cape Golden Mole (Chrysochloris asiatica) Reveal the Presence of Foamy Viruses in All Major Placental Mammal Clades

Endogenous retroviruses provide important insights into the deep history of this viral lineage. Endogenous foamy viruses are thought to be very rare and only a few cases have been identified to date. Here we report a novel endogenous foamy virus (CaEFV) within the genome of the Cape golden mole (Chrysochloris asiatica). The identification of CaEFV reveals the presence of foamy virus in the placental mammal superorder Afrotheria. Phylogenetic analyses place CaEFV basal to other foamy viruses of Eutherian origin, suggesting an ancient codivergence between foamy virus and placental mammals. These findings have implications for understanding the long-term evolution, diversity, and biology of retroviruses.

Evolution of Foamy Viruses: The Most Ancient of All Retroviruses

Recent evidence indicates that foamy viruses (FVs) are the oldest retroviruses (RVs) that we know and coevolved with their hosts for several hundred million years. This coevolution may have contributed to the non-pathogenicity of FVs, an important factor in development of foamy viral vectors in gene therapy. However, various questions on the molecular evolution of FVs remain still unanswered. The analysis of the spectrum of animal species infected by exogenous FVs or harboring endogenous FV elements in their genome is pivotal. Furthermore, animal studies might reveal important issues, such as the identification of the FV in vivo target cells, which than require a detailed characterization, to resolve the molecular basis of the accuracy with which FVs copy their genome. The issues of the extent of FV viremia and of the nature of the virion genome (RNA vs. DNA) also need to be experimentally addressed.

Essential domains and sequences of the foamy virus Bet protein involved in binding and counteracting APOBEC3 restriction factors

Background APOBEC3 (A3) cytidine deaminases restrict viral replication by efficiently editing viral genomes. To escape this restriction by lethal mutagenesis, lentiviruses have evolved the viral infectivity factor (Vif), which binds A3 proteins and targets them for proteolytic degradation. In contrast, foamy viruses (FVs) express high amounts of the accessory Bet protein allowing replication in the presence of A3, apparently by A3 binding/sequestration and thus preventing A3 packaging into virus particles. Due to virus-host coevolution, Bet can only counteract the activity of A3s from their cognate host species. FV bet genes appear to be ancient, since corresponding sequences are clearly present in endogenous FV sequences in different mammalian species.

An Endogenous Foamy Virus in the Aye-Aye (Daubentonia madagascariensis)

We report the discovery and analysis of an endogenous foamy virus (PSFVaye) within the genome of the aye-aye (Daubentonia madagascariensis), a strepsirrhine primate from Madagascar. Phylogenetic analyses indicate that PSFVaye is divergent from all known simian foamy viruses, suggesting an association between foamy viruses and primates since the haplorrhine-strepsirrhine split. The discovery of PSFVaye indicates that primate foamy virus might be more broadly distributed than previously thought.

Paleovirology reveals the macroevolution of complex retroviruses

Endogenous retroviruses (ERVs) result from permanent germline insertion of exogenous retroviruses within host genomes, and are abundant within mammalian genomes. The overwhelming majority of ERVs possess a relatively simple genomic organisation, lacking many of the accessory genes found in the more complex retroviruses. Furthermore, insertions prior to the radiation of mammalian orders lack closely related present day circulating exogenous counterparts. Foamy viruses (also termed Spumaviruses) are a superfamily of complex retroviruses that possess distinctive replication features, and are of great interest as both biological markers of zoonotic exposure risk and as candidate vectors for stem cell gene therapy. Despite a long evolutionary association with mammals, endogenous counterparts of infectious foamy viruses have been notably absent from mammalian genomes. We have discovered the first endogenous foamy virus (SloEFV) in the genomes of sloths (superorder: Xenarthra). SloEFV represents the first complex retrovirus to be described from the basal Xenarthran mammalian group. By determining the taxonomic distribution of related viruses in other Xenarthrans, and using bioinformatic approaches, we establish that SloEFV invaded sloth genomes prior to the colonization of continental South America by Boreoeutherian mammals. This observation, combined with exact congruence of branching order and statistically significant association of divergence between foamy virus and mammalian phylogenies, supports an extended cospeciation scenario under which foamy viruses remarkably similar to contemporary strains circulated in ancestral mammals >100 million years ago and diverged in concert with their hosts throughout the Cenozoic Era. Our discovery provides the first direct evidence for ancient and mammalian-wide origins of complex retroviruses, highlighting the role of evolutionary constraint in maintaining viral genome structure. We propose that the evolution of retroviral accessory genes and mammalian mechanisms of innate immunity are the products of a macroevolutionary conflict played out over a geological timescale. Furthermore, the extended coevolutionary relationship revealed by our analysis has implications for models of viral cross-species transmission and emergence.