Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; the... more Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:
A diverse range of DNA sequences derived from circoviruses (family ) have been identified in samp... more A diverse range of DNA sequences derived from circoviruses (family ) have been identified in samples obtained from humans and domestic animals, often in association with pathological conditions. In the majority of cases, however, little is known about the natural biology of the viruses from which these sequences are derived. Endogenous circoviral elements (CVe) are DNA sequences derived from circoviruses that occur in animal genomes and provide a useful source of information about circovirus-host relationships. In this study we screened genome assemblies of 675 animal species and identified numerous circovirus-related sequences, including the first examples of CVe derived from cycloviruses. We confirmed the presence of these CVe in the germline of the elongate twig ant (), thereby establishing that cycloviruses infect insects. We examined the evolutionary relationships between CVe and contemporary circoviruses, showing that CVe from ants and mites group relatively closely with cyclo...
Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads fr... more Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads from the viral RNA population revealing the viral genome diversity within a single host. A range of software tools and pipelines can transform raw deep sequencing reads into Sequence Alignment Mapping (SAM) files. We propose that interpretation tools should process these SAM files, directly translating individual reads to amino acids in order to extract statistics of interest such as the proportion of different amino acid residues at specific sites. This preserves per-read linkage between nucleotide variants at different positions within a codon location. The samReporter is a subsystem of the GLUE software toolkit which follows this direct read translation approach in its processing of SAM files. We test samReporter on a deep sequencing dataset obtained from a cohort of 241 UK HCV patients for whom prior treatment with direct-acting antivirals has failed; deep sequencing and resistance tes...
The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulati... more The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mamma...
The Deltaretrovirus genus of retroviruses (family Retroviridae) includes the human T cell leukemi... more The Deltaretrovirus genus of retroviruses (family Retroviridae) includes the human T cell leukemia viruses and bovine leukemia virus (BLV). Relatively little is known about the biology and evolution of these viruses, because only a few species have been identified and the genomic 'fossil record' is relatively sparse. Here, we report the discovery of multiple novel endogenous retroviruses (ERVs) derived from ancestral deltaretroviruses. These sequences-two of which contain complete or near complete internal coding regions-reside in genomes of several distinct mammalian orders, including bats, carnivores, cetaceans, and insectivores. We demonstrate that two of these ERVs contain unambiguous homologs of the tax gene, indicating that complex gene regulation has ancient origins within the Deltaretrovirus genus. ERVs demonstrate that the host range of the deltaretrovirus genus is much more extensive than suggested by the relatively small number of exogenous deltaretroviruses described so far, and allow the evolutionary timeline of deltaretrovirus-mammal interaction to be more accurately calibrated.
Background: Virus genome sequences, generated in ever-higher volumes, can provide new scientific ... more Background: Virus genome sequences, generated in ever-higher volumes, can provide new scientific insights and inform our responses to epidemics and outbreaks. To facilitate interpretation, such data must be organised and processed within scalable computing resources that encapsulate virology expertise. GLUE (Genes Linked by Underlying Evolution) is a data-centric bioinformatics environment for building such resources. The GLUE core data schema organises sequence data along evolutionary lines, capturing not only nucleotide data but associated items such as alignments, genotype definitions, genome annotations and motifs. Its flexible design emphasises applicability to different viruses and to diverse needs within research, clinical or public health contexts. Results: HCV-GLUE is a case study GLUE resource for hepatitis C virus (HCV). It includes an interactive public web application providing sequence analysis in the form of a maximum-likelihood-based genotyping method, antiviral resistance detection and graphical sequence visualisation. HCV sequence data from GenBank is categorised and stored in a large-scale sequence alignment which is accessible via web-based queries. Whereas this web resource provides a range of basic functionality, the underlying GLUE project can also be downloaded and extended by bioinformaticians addressing more advanced questions. Conclusion: GLUE can be used to rapidly develop virus sequence data resources with public health, research and clinical applications. This streamlined approach, with its focus on reuse, will help realise the full value of virus sequence data.
Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other fi... more Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filov...
Endogenous retroviral sequences provide a molecular fossil record of ancient infections whose ana... more Endogenous retroviral sequences provide a molecular fossil record of ancient infections whose analysis might illuminate mechanisms of viral extinction. A close relative of gammaretroviruses, HERV-T, circulated in primates for ~25 million years (MY) before apparent extinction within the past ~8 MY. Construction of a near-complete catalog of HERV-T fossils in primate genomes allowed us to estimate a ~32 MY old ancestral sequence and reconstruct a functional envelope protein (ancHTenv) that could support infection of a pseudotyped modern gammaretrovirus. Using ancHTenv, we identify monocarboxylate transporter-1 (MCT-1) as a receptor used by HERV-T for attachment and infection. A single HERV-T provirus in hominid genomes includes an env gene (hsaHTenv) that has been uniquely preserved. This apparently exapted HERV-T env could not support virion infection but could block ancHTenv mediated infection, by causing MCT-1 depletion from cell surfaces. Thus, hsaHTenv may have contributed to HERV-T extinction, and could also potentially regulate cellular metabolism.
The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulati... more The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the data-set. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response.
Transmission of drug-resistant HIV-1 is well recognized. However, the impact of such transmission... more Transmission of drug-resistant HIV-1 is well recognized. However, the impact of such transmission on natural history of infection remains unknown. Three hundred HIV-1-infected, antiretroviral-naive individuals, recruited between 1987 and 1993, and with resistance tests undertaken within 18 months of infection were assessed. We estimated the impact of transmitted drug resistance (TDR) on subsequent CD4 cell count decline in the absence of treatment. We also used Kaplan-Meier methods to assess the response to antiretroviral therapy based on the number of active drugs utilized (according to genotypic resistance results). Infection with any form of drug-resistant HIV-1 was associated with a steeper decline of CD4 cell count over the first year of infection. Estimated rates of decline in the first year were 5.0 [95% confidence interval (CI), 2.8-7.3] and 1.7 (95% CI, 0.8-2.6) radicalCD4 cells per year for TDR and no TDR, respectively (P = 0.005). For an individual at a CD4 cell count of 500 cells/microl at seroconversion, these rates correspond to a CD4 cell loss of 199 and 73 cells/microl, respectively, in the first year. Thereafter we found no evidence of a difference in the rate of CD4 cell decline (P = 0.32). Initiation of HAART after calendar year 2000, but not number of active drugs, was associated with improved responses. The impact of transmitted HIV-1 drug resistance on CD4 cell decline is time dependent, with greater rates of decline in the first year following infection. We found no evidence of a longer term effect of TDR on natural history of HIV-1 infection.
Bioinformatics were used to identify and characterise 39 pol, 34 gag and five env gammaretrovirus... more Bioinformatics were used to identify and characterise 39 pol, 34 gag and five env gammaretroviruses within the canine (Canis lupus familiaris) reference genome. These endogenous retroviruses are monophyletic to the Canidae, predate the divergence of dogs and foxes and are fixed in 20 canine breeds examined. They are transcribed in normal canine tissue but are unlikely to be replication competent in dogs.
The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruse... more The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events.
Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retrov... more Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retroviral genes as host alleles. For
other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral
elements (EVEs) derived from ten non-retroviral families by systematic in silico screening of animal genomes, including the
first endogenous representatives of double-stranded RNA, reverse-transcribing DNA, and segmented RNA viruses, and the
first endogenous DNA viruses in mammalian genomes. Phylogenetic and genomic analysis of EVEs across multiple host
species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the
elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate
lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all
known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of
paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than
has previously been recognized.
Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in... more Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in mammals, including humans. The emergence of pandemic HIV type-1 (HIV-1) infection during the late 20th century shaped a view of lentiviruses as 'modern' viruses. However, recent research has revealed an entirely different perspective, elucidating aspects of an evolutionary relationship with mammals that extends across many millions of years. Such deep evolutionary history is likely to be typical of many host-virus systems, fundamentally underpinning their interactions in the present day. For this reason, establishing the deep history of virus and host interaction is key to developing a fully informed approach to tackling viral diseases. Here, I use the example of lentiviruses to illustrate how paleovirological, geographic and genetic calibrations allow observations of virus and host interaction across a wide range of temporal and spatial scales to be integrated into a coherent ecological and evolutionary framework.
Retroviruses can leave a “fossil record” in their hosts’ genomes in the form of endogenous retrov... more Retroviruses can leave a “fossil record” in their hosts’ genomes in the form of endogenous retroviruses. Foamy viruses, complex retroviruses that infect mammals, have been notably absent from this record. We have found an endogenous foamy virus within the genomes of sloths and show that foamy viruses were infecting mammals more than 100 million years ago and codiverged with their hosts across an entire geological era. Our analysis highlights the role of evolutionary constraint in maintaining viral genome structure and indicates that accessory genes and mammalian mechanisms of innate immunity are the products of macroevolutionary conflict played out over a geological time scale.
The retroviral capacity for integration into the host genome can give rise to endogenous retrovir... more The retroviral capacity for integration into the host genome can give rise to endogenous retroviruses (ERVs): retroviral sequences that are transmitted vertically as part of the host germ line, within which they may continue to replicate and evolve. ERVs represent both a unique archive of ancient viral sequence information and a dynamic component of host genomes. As such they hold great potential as informative markers for studies of both virus evolution and host genome evolution. Numerous novel ERVs have been described in recent years, particularly as genome sequencing projects have advanced. This review discusses the evolution of ERV lineages, considering the processes by which ERV distribution and diversity is generated. The diversity of ERVs isolated so far is summarised in terms of both their distribution across host taxa, and their relationships to recognised retroviral genera. Finally the relevance of ERVs to studies of genome evolution, host disease and viral ecology is considered, and recent findings discussed.
Lentiviruses chronically infect a broad range of mammalian species and have been transmitted from... more Lentiviruses chronically infect a broad range of mammalian species and have been transmitted from primates to humans, giving rise to multiple outbreaks of HIV infection over the past century. Although the circumstances surrounding these recent zoonoses are becoming clearer, the nature and timescale of interaction between lentiviruses and primates remains unknown. Here, we report the discovery of an endogenous lentivirus in the genome of the gray mouse lemur (Microcebus murinus), a strepsirrhine primate from Madagascar, demonstrating that lentiviruses are capable of invading the primate germ line. Phylogenetic analysis places gray mouse lemur prosimian immunodeficiency virus (pSIVgml) basal to all known primate lentiviruses and, consistent with this, its genomic organization is intermediate between the nonprimate lentiviruses and their more derived primate counterparts. Thus, pSIVgml represents the first unambiguous example of a viral transitional form, revealing the acquisition and loss of genomic features during lentiviral evolution. Furthermore, because terrestrial mammal populations in Madagascar and Africa are likely to have been isolated from one another for at least 14 million years, the presence of pSIVgml in the gray mouse lemur genome indicates that lentiviruses must have been infecting primates for at least this period of time, or have been transmitted between Malagasy and African primate populations by a vector species capable of traversing the Mozambique channel. The discovery of pSIVgml illustrates the utility of endogenous sequences for the study of contemporary retroviruses and indicates that primate lentiviruses may be considerably older and more broadly distributed than previously thought.
The lentiviruses are associated with a wide range of chronic diseases in mammals. These include i... more The lentiviruses are associated with a wide range of chronic diseases in mammals. These include immunodeficiencies (such as HIV/AIDS in humans), malignancies, and lymphatic and neurological disorders in primates, felids, and a variety of wild and domesticated ungulates. Evolutionary analyses of the genomic sequences of modern-day lentiviruses have suggested a relatively recent date for their emergence, but the failure to identify any endogenous, vertically transmitted examples has meant that their longer term evolutionary history and origin remain unknown. Here we report the discovery and characterization of retroviral sequences belonging to a new lentiviral subgroup from the European rabbit (Oryctolagus cuniculus). These viruses, the first endogenous examples described, are >7 million years old and thus provide the first evidence for an ancient origin of the lentiviruses. Despite being ancient, this subgroup contains many of the features found in present-day lentiviruses, such as the presence of tat and rev genes, thus also indicating an ancient origin for the complex regulation of lentivirus gene expression. Although the virus we describe is defective, reconstruction of an infectious progenitor could provide novel insights into lentivirus biology and host interactions.
Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; the... more Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:
A diverse range of DNA sequences derived from circoviruses (family ) have been identified in samp... more A diverse range of DNA sequences derived from circoviruses (family ) have been identified in samples obtained from humans and domestic animals, often in association with pathological conditions. In the majority of cases, however, little is known about the natural biology of the viruses from which these sequences are derived. Endogenous circoviral elements (CVe) are DNA sequences derived from circoviruses that occur in animal genomes and provide a useful source of information about circovirus-host relationships. In this study we screened genome assemblies of 675 animal species and identified numerous circovirus-related sequences, including the first examples of CVe derived from cycloviruses. We confirmed the presence of these CVe in the germline of the elongate twig ant (), thereby establishing that cycloviruses infect insects. We examined the evolutionary relationships between CVe and contemporary circoviruses, showing that CVe from ants and mites group relatively closely with cyclo...
Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads fr... more Using deep sequencing technologies such as Illumina’s platform, it is possible to obtain reads from the viral RNA population revealing the viral genome diversity within a single host. A range of software tools and pipelines can transform raw deep sequencing reads into Sequence Alignment Mapping (SAM) files. We propose that interpretation tools should process these SAM files, directly translating individual reads to amino acids in order to extract statistics of interest such as the proportion of different amino acid residues at specific sites. This preserves per-read linkage between nucleotide variants at different positions within a codon location. The samReporter is a subsystem of the GLUE software toolkit which follows this direct read translation approach in its processing of SAM files. We test samReporter on a deep sequencing dataset obtained from a cohort of 241 UK HCV patients for whom prior treatment with direct-acting antivirals has failed; deep sequencing and resistance tes...
The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulati... more The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mamma...
The Deltaretrovirus genus of retroviruses (family Retroviridae) includes the human T cell leukemi... more The Deltaretrovirus genus of retroviruses (family Retroviridae) includes the human T cell leukemia viruses and bovine leukemia virus (BLV). Relatively little is known about the biology and evolution of these viruses, because only a few species have been identified and the genomic 'fossil record' is relatively sparse. Here, we report the discovery of multiple novel endogenous retroviruses (ERVs) derived from ancestral deltaretroviruses. These sequences-two of which contain complete or near complete internal coding regions-reside in genomes of several distinct mammalian orders, including bats, carnivores, cetaceans, and insectivores. We demonstrate that two of these ERVs contain unambiguous homologs of the tax gene, indicating that complex gene regulation has ancient origins within the Deltaretrovirus genus. ERVs demonstrate that the host range of the deltaretrovirus genus is much more extensive than suggested by the relatively small number of exogenous deltaretroviruses described so far, and allow the evolutionary timeline of deltaretrovirus-mammal interaction to be more accurately calibrated.
Background: Virus genome sequences, generated in ever-higher volumes, can provide new scientific ... more Background: Virus genome sequences, generated in ever-higher volumes, can provide new scientific insights and inform our responses to epidemics and outbreaks. To facilitate interpretation, such data must be organised and processed within scalable computing resources that encapsulate virology expertise. GLUE (Genes Linked by Underlying Evolution) is a data-centric bioinformatics environment for building such resources. The GLUE core data schema organises sequence data along evolutionary lines, capturing not only nucleotide data but associated items such as alignments, genotype definitions, genome annotations and motifs. Its flexible design emphasises applicability to different viruses and to diverse needs within research, clinical or public health contexts. Results: HCV-GLUE is a case study GLUE resource for hepatitis C virus (HCV). It includes an interactive public web application providing sequence analysis in the form of a maximum-likelihood-based genotyping method, antiviral resistance detection and graphical sequence visualisation. HCV sequence data from GenBank is categorised and stored in a large-scale sequence alignment which is accessible via web-based queries. Whereas this web resource provides a range of basic functionality, the underlying GLUE project can also be downloaded and extended by bioinformaticians addressing more advanced questions. Conclusion: GLUE can be used to rapidly develop virus sequence data resources with public health, research and clinical applications. This streamlined approach, with its focus on reuse, will help realise the full value of virus sequence data.
Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other fi... more Biological factors that influence the host range and spillover of Ebola virus (EBOV) and other filoviruses remain enigmatic. While filoviruses infect diverse mammalian cell lines, we report that cells from African straw-colored fruit bats (Eidolon helvum) are refractory to EBOV infection. This could be explained by a single amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 interaction. We found signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with the strongest signal at the same residue that controls EBOV infection in Eidolon helvum cells. Our work identifies NPC1 as a genetic determinant of filovirus susceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filovirus replication and virulence. A single viral mutation afforded escape from receptor control, revealing a pathway for compensatory viral evolution and a potential avenue for expansion of filov...
Endogenous retroviral sequences provide a molecular fossil record of ancient infections whose ana... more Endogenous retroviral sequences provide a molecular fossil record of ancient infections whose analysis might illuminate mechanisms of viral extinction. A close relative of gammaretroviruses, HERV-T, circulated in primates for ~25 million years (MY) before apparent extinction within the past ~8 MY. Construction of a near-complete catalog of HERV-T fossils in primate genomes allowed us to estimate a ~32 MY old ancestral sequence and reconstruct a functional envelope protein (ancHTenv) that could support infection of a pseudotyped modern gammaretrovirus. Using ancHTenv, we identify monocarboxylate transporter-1 (MCT-1) as a receptor used by HERV-T for attachment and infection. A single HERV-T provirus in hominid genomes includes an env gene (hsaHTenv) that has been uniquely preserved. This apparently exapted HERV-T env could not support virion infection but could block ancHTenv mediated infection, by causing MCT-1 depletion from cell surfaces. Thus, hsaHTenv may have contributed to HERV-T extinction, and could also potentially regulate cellular metabolism.
The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulati... more The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the data-set. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response.
Transmission of drug-resistant HIV-1 is well recognized. However, the impact of such transmission... more Transmission of drug-resistant HIV-1 is well recognized. However, the impact of such transmission on natural history of infection remains unknown. Three hundred HIV-1-infected, antiretroviral-naive individuals, recruited between 1987 and 1993, and with resistance tests undertaken within 18 months of infection were assessed. We estimated the impact of transmitted drug resistance (TDR) on subsequent CD4 cell count decline in the absence of treatment. We also used Kaplan-Meier methods to assess the response to antiretroviral therapy based on the number of active drugs utilized (according to genotypic resistance results). Infection with any form of drug-resistant HIV-1 was associated with a steeper decline of CD4 cell count over the first year of infection. Estimated rates of decline in the first year were 5.0 [95% confidence interval (CI), 2.8-7.3] and 1.7 (95% CI, 0.8-2.6) radicalCD4 cells per year for TDR and no TDR, respectively (P = 0.005). For an individual at a CD4 cell count of 500 cells/microl at seroconversion, these rates correspond to a CD4 cell loss of 199 and 73 cells/microl, respectively, in the first year. Thereafter we found no evidence of a difference in the rate of CD4 cell decline (P = 0.32). Initiation of HAART after calendar year 2000, but not number of active drugs, was associated with improved responses. The impact of transmitted HIV-1 drug resistance on CD4 cell decline is time dependent, with greater rates of decline in the first year following infection. We found no evidence of a longer term effect of TDR on natural history of HIV-1 infection.
Bioinformatics were used to identify and characterise 39 pol, 34 gag and five env gammaretrovirus... more Bioinformatics were used to identify and characterise 39 pol, 34 gag and five env gammaretroviruses within the canine (Canis lupus familiaris) reference genome. These endogenous retroviruses are monophyletic to the Canidae, predate the divergence of dogs and foxes and are fixed in 20 canine breeds examined. They are transcribed in normal canine tissue but are unlikely to be replication competent in dogs.
The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruse... more The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events.
Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retrov... more Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retroviral genes as host alleles. For
other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral
elements (EVEs) derived from ten non-retroviral families by systematic in silico screening of animal genomes, including the
first endogenous representatives of double-stranded RNA, reverse-transcribing DNA, and segmented RNA viruses, and the
first endogenous DNA viruses in mammalian genomes. Phylogenetic and genomic analysis of EVEs across multiple host
species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the
elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate
lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all
known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of
paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than
has previously been recognized.
Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in... more Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in mammals, including humans. The emergence of pandemic HIV type-1 (HIV-1) infection during the late 20th century shaped a view of lentiviruses as 'modern' viruses. However, recent research has revealed an entirely different perspective, elucidating aspects of an evolutionary relationship with mammals that extends across many millions of years. Such deep evolutionary history is likely to be typical of many host-virus systems, fundamentally underpinning their interactions in the present day. For this reason, establishing the deep history of virus and host interaction is key to developing a fully informed approach to tackling viral diseases. Here, I use the example of lentiviruses to illustrate how paleovirological, geographic and genetic calibrations allow observations of virus and host interaction across a wide range of temporal and spatial scales to be integrated into a coherent ecological and evolutionary framework.
Retroviruses can leave a “fossil record” in their hosts’ genomes in the form of endogenous retrov... more Retroviruses can leave a “fossil record” in their hosts’ genomes in the form of endogenous retroviruses. Foamy viruses, complex retroviruses that infect mammals, have been notably absent from this record. We have found an endogenous foamy virus within the genomes of sloths and show that foamy viruses were infecting mammals more than 100 million years ago and codiverged with their hosts across an entire geological era. Our analysis highlights the role of evolutionary constraint in maintaining viral genome structure and indicates that accessory genes and mammalian mechanisms of innate immunity are the products of macroevolutionary conflict played out over a geological time scale.
The retroviral capacity for integration into the host genome can give rise to endogenous retrovir... more The retroviral capacity for integration into the host genome can give rise to endogenous retroviruses (ERVs): retroviral sequences that are transmitted vertically as part of the host germ line, within which they may continue to replicate and evolve. ERVs represent both a unique archive of ancient viral sequence information and a dynamic component of host genomes. As such they hold great potential as informative markers for studies of both virus evolution and host genome evolution. Numerous novel ERVs have been described in recent years, particularly as genome sequencing projects have advanced. This review discusses the evolution of ERV lineages, considering the processes by which ERV distribution and diversity is generated. The diversity of ERVs isolated so far is summarised in terms of both their distribution across host taxa, and their relationships to recognised retroviral genera. Finally the relevance of ERVs to studies of genome evolution, host disease and viral ecology is considered, and recent findings discussed.
Lentiviruses chronically infect a broad range of mammalian species and have been transmitted from... more Lentiviruses chronically infect a broad range of mammalian species and have been transmitted from primates to humans, giving rise to multiple outbreaks of HIV infection over the past century. Although the circumstances surrounding these recent zoonoses are becoming clearer, the nature and timescale of interaction between lentiviruses and primates remains unknown. Here, we report the discovery of an endogenous lentivirus in the genome of the gray mouse lemur (Microcebus murinus), a strepsirrhine primate from Madagascar, demonstrating that lentiviruses are capable of invading the primate germ line. Phylogenetic analysis places gray mouse lemur prosimian immunodeficiency virus (pSIVgml) basal to all known primate lentiviruses and, consistent with this, its genomic organization is intermediate between the nonprimate lentiviruses and their more derived primate counterparts. Thus, pSIVgml represents the first unambiguous example of a viral transitional form, revealing the acquisition and loss of genomic features during lentiviral evolution. Furthermore, because terrestrial mammal populations in Madagascar and Africa are likely to have been isolated from one another for at least 14 million years, the presence of pSIVgml in the gray mouse lemur genome indicates that lentiviruses must have been infecting primates for at least this period of time, or have been transmitted between Malagasy and African primate populations by a vector species capable of traversing the Mozambique channel. The discovery of pSIVgml illustrates the utility of endogenous sequences for the study of contemporary retroviruses and indicates that primate lentiviruses may be considerably older and more broadly distributed than previously thought.
The lentiviruses are associated with a wide range of chronic diseases in mammals. These include i... more The lentiviruses are associated with a wide range of chronic diseases in mammals. These include immunodeficiencies (such as HIV/AIDS in humans), malignancies, and lymphatic and neurological disorders in primates, felids, and a variety of wild and domesticated ungulates. Evolutionary analyses of the genomic sequences of modern-day lentiviruses have suggested a relatively recent date for their emergence, but the failure to identify any endogenous, vertically transmitted examples has meant that their longer term evolutionary history and origin remain unknown. Here we report the discovery and characterization of retroviral sequences belonging to a new lentiviral subgroup from the European rabbit (Oryctolagus cuniculus). These viruses, the first endogenous examples described, are >7 million years old and thus provide the first evidence for an ancient origin of the lentiviruses. Despite being ancient, this subgroup contains many of the features found in present-day lentiviruses, such as the presence of tat and rev genes, thus also indicating an ancient origin for the complex regulation of lentivirus gene expression. Although the virus we describe is defective, reconstruction of an infectious progenitor could provide novel insights into lentivirus biology and host interactions.
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Papers by Robert Gifford
other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral
elements (EVEs) derived from ten non-retroviral families by systematic in silico screening of animal genomes, including the
first endogenous representatives of double-stranded RNA, reverse-transcribing DNA, and segmented RNA viruses, and the
first endogenous DNA viruses in mammalian genomes. Phylogenetic and genomic analysis of EVEs across multiple host
species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the
elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate
lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all
known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of
paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than
has previously been recognized.
other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral
elements (EVEs) derived from ten non-retroviral families by systematic in silico screening of animal genomes, including the
first endogenous representatives of double-stranded RNA, reverse-transcribing DNA, and segmented RNA viruses, and the
first endogenous DNA viruses in mammalian genomes. Phylogenetic and genomic analysis of EVEs across multiple host
species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the
elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate
lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all
known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of
paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than
has previously been recognized.