Predicting the effectiveness of hepatitis C virus neutralizing antibodies by bioinformatic analysis of conserved epitope residues using public sequence data

Hepatitis C virus (HCV) is a global health issue. Although direct-acting antivirals are available to target HCV, there is currently no vaccine. The diversity of the virus is a major obstacle to HCV vaccine development. One approach toward a vaccine is to utilize a strategy to elicit broadly neutralizing antibodies (bNAbs) that target highly-conserved epitopes. The conserved epitopes of bNAbs have been mapped almost exclusively to the E2 glycoprotein. In this study, we have used HCV-GLUE, a bioinformatics resource for HCV sequence data, to investigate the major epitopes targeted by well-characterized bNAbs. Here, we analyze the level of conservation of each epitope by genotype and subtype and consider the most promising bNAbs identified to date for further study as potential vaccine leads. For the most conserved epitopes, we also identify the most prevalent sequence variants in the circulating HCV population. We examine the distribution of E2 sequence data from across the globe and highlight regions with no coverage. Genotype 1 is the most prevalent genotype worldwide, but in many regions, it is not the dominant genotype. We find that the sequence conservation data is very encouraging; several bNAbs have a high level of conservation across all genotypes suggesting that it may be unnecessary to tailor vaccines according to the geographical distribution of genotypes

The evolution, distribution and diversity of endogenous circoviral elements in vertebrate genomes

Circoviruses (family Circoviridae) are small, non-enveloped viruses that have short, single-stranded DNA genomes. Circovirus sequences are frequently recovered in metagenomic investigations, indicating that these viruses are widespread, yet they remain relatively poorly understood. Endogenous circoviral elements (CVe) are DNA sequences derived from circoviruses that occur in vertebrate genomes. CVe are a useful source of information about the biology and evolution of circoviruses. In this study, we screened 362 vertebrate genome assemblies in silico to generate a catalog of CVe loci. We identified a total of 179 CVe sequences, most of which have not been reported previously. We show that these CVe loci reflect at least 19 distinct germline integration events. We determine the structure of CVe loci, identifying some that show evidence of potential functionalization. We also identify orthologous copies of CVe in snakes, fish, birds, and mammals, allowing us to add new calibrations to the timeline of circovirus evolution. Finally, we observed that some ancient CVe group robustly with contemporary circoviruses in phylogenies, with all sequences within these groups being derived from the same host class or order, implying a hitherto underappreciated stability in circovirus-host relationships. The openly available dataset constructed in this investigation provides new insights into circovirus evolution, and can be used to facilitate further studies of circoviruses and CVe

No evidence for distinct types in the evolution of SARS-CoV-2

A recent study by Tang et al. claimed that two major types of severe acute respiratory syndrome-coronavirus-2 (CoV-2) had evolved in the ongoing CoV disease-2019 pandemic and that one of these types was more ‘aggressive’ than the other. Given the repercussions of these claims and the intense media coverage of these types of articles, we have examined in detail the data presented by Tang et al., and show that the major conclusions of that paper cannot be substantiated. Using examples from other viral outbreaks, we discuss the difficulty in demonstrating the existence or nature of a functional effect of a viral mutation, and we advise against overinterpretation of genomic data during the pandemic

Hepatitis C and the absence of genomic data in low-income countries: a barrier on the road to elimination?

Following the development of highly effective direct acting antiviral (DAA) compounds for the treatment of the hepatitis C virus (HCV), WHO has set out plans for disease eradication by 2030. Many barriers must be surmounted before this can be achieved, including buy-in from governments and policy makers, reduced drug costs, and improved infrastructure for the pathway from diagnosis to treatment. A comprehensive set of guidelines was produced by WHO in 2014, updated in 2016, and they are due to be revised later this year

GLUE: a flexible software system for virus sequence data

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

Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses

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 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

Insights into circovirus host range from the genomic fossil record

A diverse range of DNA sequences derived from circoviruses (family Circoviridae) 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 (Pseudomyrmex gracilis), 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 cycloviruses in phylogenies. Furthermore, the relatively random interspersal of CVe from insect genomes with cyclovirus sequences recovered from vertebrate samples, suggested that contamination might be an important consideration in studies reporting these viruses. Our study demonstrates how endogenous viral sequences can inform metagenomics-based virus discovery. In addition, it raises doubts about the role of cycloviruses as pathogens of humans and other vertebrates

Convalescent plasma therapy for persistent hepatitis E virus infection

No abstract available

Natural selection in the evolution of SARS-CoV-2 in bats created a generalist virus and highly capable human pathogen

Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered “facilitating” intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human–human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus