Inhibition of hepatitis C virus RNA replication by ISG15 does not require its conjugation to protein substrates by the HERC5 E3 ligase

Chronic infection of the liver by hepatitis C virus (HCV) induces a range of host factors including IFN-stimulated genes such as ISG15. ISG15 functions as an antiviral factor that limits virus replication. Previous studies have suggested that ISG15 could influence HCV replication in both a positive and a negative manner. In this report, we determined the effect of ISG15 on HCV RNA replication in two independent cell lines that support viral genome synthesis by inhibiting ISG15 expression through small interfering RNA, short-hairpin RNA and CRISPR/Cas9 gene knockout approaches. Our results demonstrated that ISG15 impairs HCV RNA replication in both the presence and absence of IFN stimulation, consistent with an antiviral role for ISG15 during HCV infection. ISG15 conjugation to protein substrates typically requires the E3 ligase, HERC5. Our results showed that the inhibitory effect of ISG15 on HCV RNA replication does not require its conjugation to substrates by HERC5

Comparative host genomics: how has human evolution affected our immune defence against hepatitis C virus?

No abstract available

An interferon lambda 4-associated variant in the hepatitis C virus RNA polymerase affects viral replication in infected cells

Host IFNL4 haplotype status contributes to the development of chronic hepatitis C virus infection in individuals who are acutely infected with the virus. In silico studies revealed that specific amino acid variants at multiple sites on the HCV polyprotein correlate with functional single nucleotide polymorphisms (SNPs) in the IFNL4 locus. Thus, SNPs at the IFNL4 locus may select variants that influence virus replication and thereby outcome of infection. Here, we examine the most significantly IFNL4-associated amino acid variants that lie in the ‘Lambda (L) 2 loop’ of the HCV NS5B RNA polymerase. L2 loop variants were introduced into both sub-genomic replicon and full-length infectious clones of HCV and viral replication examined in the presence and absence of exogenous IFNλ4. Our data demonstrate that while mutation of NS5B L2 loop affects replication, individual IFNL4-associated variants have modest but consistent effects on replication both in the presence and absence of IFNλ4. Given the strong genetic association between these variants and IFNL4, these data suggest a nuanced effect of each individual position on viral replication, the combined effect of which might mediate resistance to the effects of IFNλ4

One future or many? November 14, 15, and 16, 2002

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's 2nd annual Conference that took place during November 14, 15, and 16, 2002.The conference brought together some 30 experts from various disciplines to discuss whether the trajectories of the future will be ‘global’ or ‘regional’ in nature. Different panels looks at the future trajectories for Europe, the Western Hemisphere, Central Asia and the Former Soviet Union, and on Asia and in each case the discussion looked at the relative importance of the regional and of global dynamics on teh forces shaping the future of these regions.Carnegie Council on Ethics and International Affair

Comparative analysis of genome-encoded viral sequences reveals the evolutionary history of flavivirids (family Flaviviridae)

The flavivirids (family Flaviviridae) are a group of positive-strand RNA viruses that pose serious risks to human and animal health on a global scale. Here we use flavivirid-derived DNA sequences, identified in animal genomes, to reconstruct the long-term evolutionary history of family Flaviviridae. We demonstrate that flavivirids are >100 million years old and show that this timing can be combined with dates inferred from co-phyletic analysis to produce a cohesive overview of their evolution, distribution and diversity wherein the main flavivirid subgroups originate in early animals and broadly co-diverge with major animal phyla. In addition, we reveal evidence that the ‘classical flaviviruses’ of vertebrates, most of which are transmitted via blood-feeding arthropod vectors, originally evolved in hematophagous arachnids and later acquired the capacity to be transmitted by insects. Our findings imply that the biological properties of flavivirids have been acquired gradually over the course of animal evolution. Thus, broad-scale comparative analysis will likely reveal fundamental insights into their biology. We therefore published our results via an open, extensible, database (Flavivirid-GLUE), which we constructed to facilitate the wider utilisation of genomic data and evolution-related domain knowledge in flavivirid research

Unusual, stable replicating viruses generated from mumps virus cDNA clones

The authors have acknowledged funding from a Wellcome Trust grant 101788/Z/13/Z to RER and funding from the respective universities for studentships, Queen’s University Belfast to CGB, and University of St Andrews to EWF.In reverse genetic experiments we have isolated recombinant mumps viruses (rMuV) that carry large numbers of mutations clustered in small parts of their genome, which are not caused by biased hyper-mutation. In two separate experiments we obtained such recombinant viruses: one virus had 11 mutations in the V/P region of the genome; the other, which also contained an extra transcription unit encoding green fluorescent protein (EGFP), had 32 mutations in the N gene. These specific sets of mutations have not been observed in naturally occurring MuV isolates. Unusually, the vast majority of the mutations (48/51) were synonymous. On passage in Vero cells and human B-LCL cells, a B lymphocyte-like cell line, these mutations appear stable as no reversion occurred to the original consensus sequence, although mutations in other parts of the genome occurred and changed in frequency during passage. Defective interfering RNAs accumulate in passage in Vero cells but not in B-LCL cells. Interestingly, in all passaged samples the level of variation in the EGFP gene is the same as in the viral genes, though it is unlikely that this gene is under any functionality constraint. What mechanism gave rise to these viruses with clustered mutations and their stability remains an open question, which is likely of interest to a wider field than mumps reverse genetics.Publisher PDFPeer reviewe

Wintertime overlaps between female Antarctic fur seals (Arctocephalus gazella) and the krill fishery at South Georgia, South Atlantic

The diet of Antarctic fur seals (Arctocephalus gazella) at South Georgia is dominated by Antarctic krill (Euphausia superba). During the breeding season, foraging trips by lactating female fur seals are constrained by their need to return to land to provision their pups. Post-breeding, seals disperse in order to feed and recover condition; estimates indicate c.70% of females remain near to South Georgia, whilst others head west towards the Patagonian Shelf or south to the ice-edge. The krill fishery at South Georgia operates only during the winter, providing the potential for fur seal: fishery interaction during these months. Here we use available winter (May to September) tracking data from Platform Terminal Transmitter (PTT) tags deployed on female fur seals at Bird Island, South Georgia. We develop habitat models describing their distribution during the winters of 1999 and 2003 with the aim of visualising and quantifying the degree of spatial overlap between female fur seals and krill harvesting in South Georgia waters. We show that spatial distribution of fur seals around South Georgia is extensive, and that the krill fishery overlaps with small, highly localised areas of available fur seal habitat. From these findings we discuss the implications for management, and future work

Trends in population structure of Patagonian toothfish over 25 years of fishery exploitation at South Georgia

Patagonian toothfish (Dissostichus eleginoides) supports valuable fisheries across the Southern Ocean under the management of the Commission for the Conservation of Antarctic Marine Living Resources. The fishery at South Georgia accounts for 26 % of the catch of this species in the Southern Ocean in the last 25 years. This study assesses the effects of exploitation and changes in management of the fishery on long-term trends in biological traits of Patagonian toothfish at South Georgia. Our results show variability in the size of fish, but no evidence of a systematic decline during the 25-year period. The mean size of fish was linked to recruitment, with pulses of recruitment associated with a reduction in mean size of the fishery. The years when recruitment was highest were in 2000–2010, with >50 % of toothfish of length classes < 90 cm. Management measures implemented over the last 25 years, including depth restrictions and benthic closed areas, have resulted in a gradual stabilization of the population structure. Catch per unit effort (CPUE) dropped from 1997 to 2010, gradually increased until 2017 and since 2018 has returned to values typical of the mid-2010s. Monthly changes in fish length, depth of capture and CPUE confirm that the spawning peak is in July. Size at maturity has remained stable over the last 25 years, suggesting the fishery has not had a major impact on population size structure. These results illustrate the role of management regulations in limiting the impacts of commercial exploitation on the population structure of a long-lived fish species. Given the bigger-deeper size pattern in Patagonian toothfish, there may be a case for increasing the minimum depth of the fishery (currently 700 m) when strong recruitment pulses are detected

A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages

As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNλ4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of all known extant coding variants of human IFNλ4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest ‘Pygmy’ hunter-gatherers. K154E greatly enhanced in vitro activity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genus Homo, including Neanderthals. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 correlates with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNλ4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNλ4 is conserved among humans and postulate that differences in IFNλ4 activity between species contribute to distinct host-specific responses to—and outcomes of—infection, such as HCV infection. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa

A polymorphic residue that attenuates the antiviral potential of interferon lambda 4 in hominid lineages

As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNλ4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of all known extant coding variants of human IFNλ4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest ‘Pygmy’ hunter-gatherers. K154E greatly enhanced in vitro activity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genus Homo, including Neanderthals. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 correlates with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNλ4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNλ4 is conserved among humans and postulate that differences in IFNλ4 activity between species contribute to distinct host-specific responses to—and outcomes of—infection, such as HCV infection. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa