Viruses of wild and domestic animals can infect humans in a process called zoonosis, and these events can give rise to explosive epidemics such as those caused by the HIV and Ebola viruses. While ...humans are constantly exposed to animal viruses, those that can successfully infect and transmit between humans are exceedingly rare. The key event in zoonosis is when an animal virus begins to replicate (one virion making many) in the first human subject. Only at this point will the animal virus first experience the selective environment of the human body, rendering possible viral adaptation and refinement for humans. In addition, appreciable viral titers in this first human may enable infection of a second, thus initiating selection for viral variants with increased capacity for spread. We assert that host genetics plays a critical role in defining which animal viruses in nature will achieve this key event of replication in a first human host. This is because animal viruses that pose the greatest risk to humans will have few (or no) genetic barriers to replicating themselves in human cells, thus requiring minimal mutations to make this jump. Only experimental virology provides a path to identifying animal viruses with the potential to replicate themselves in humans because this information will not be evident from viral sequencing data alone.
Within cells, motor and non-motor microtubule-associated proteins (MAPs) simultaneously converge on the microtubule. How the binding activities of non-motor MAPs are coordinated and how they ...contribute to the balance and distribution of motor transport is unknown. Here, we examine the relationship between MAP7 and tau owing to their antagonistic roles in vivo. We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. MAP7 promotes kinesin-based transport in vivo and strongly recruits kinesin-1 to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. Both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs differentially control distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of motor activity.
Tripartite Motif (TRIM) ubiquitin ligases act in the innate immune response against viruses. One of the best characterized members of this family, TRIM5α, serves as a potent retroviral restriction ...factor with activity against HIV. Here, we characterize what are likely to be the youngest TRIM genes in the human genome. For instance, we have identified 11 TRIM genes that are specific to humans and African apes (chimpanzees, bonobos, and gorillas) and another 7 that are human-specific. Many of these young genes have never been described, and their identification brings the total number of known human TRIM genes to approximately 100. These genes were acquired through segmental duplications, most of which originated from a single locus on chromosome 11. Another polymorphic duplication of this locus has resulted in these genes being copy number variable within the human population, with a Han Chinese woman identified as having 12 additional copies of these TRIM genes compared to other individuals screened in this study. Recently, this locus was annotated as one of 34 "hotspot" regions that are also copy number variable in the genomes of chimpanzees and rhesus macaques. Most of the young TRIM genes originating from this locus are expressed, spliced, and contain signatures of positive natural selection in regions known to determine virus recognition in TRIM5α. However, we find that they do not restrict the same retroviruses as TRIM5α, consistent with the high degree of divergence observed in the regions that control target specificity. We propose that this recombinationally volatile locus serves as a reservoir from which new TRIM genes arise through segmental duplication, allowing primates to continually acquire new antiviral genes that can be selected to target new and evolving pathogens.
Transferrin Receptor (TfR1) is the cell-surface receptor that regulates iron uptake into cells, a process that is fundamental to life. However, TfR1 also facilitates the cellular entry of multiple ...mammalian viruses. We use evolutionary and functional analyses of TfR1 in the rodent clade, where two families of viruses bind this receptor, to mechanistically dissect how essential housekeeping genes like TFR1 successfully balance the opposing selective pressures exerted by host and virus. We find that while the sequence of rodent TfR1 is generally conserved, a small set of TfR1 residue positions has evolved rapidly over the speciation of rodents. Remarkably, all of these residues correspond to the two virus binding surfaces of TfR1. We show that naturally occurring mutations at these positions block virus entry while simultaneously preserving iron-uptake functionalities, both in rodent and human TfR1. Thus, by constantly replacing the amino acids encoded at just a few residue positions, TFR1 divorces adaptation to ever-changing viruses from preservation of key cellular functions. These dynamics have driven genetic divergence at the TFR1 locus that now enforces species-specific barriers to virus transmission, limiting both the cross-species and zoonotic transmission of these viruses.
Background
Patients with moderate‐to‐severe psoriasis require long‐term treatment, yet few trials compare outcomes beyond a short‐term induction period. Quantitative comparisons of long‐term outcomes ...in patients with psoriasis are limited. To our knowledge, no network meta‐analysis (NMA) of such data has been performed.
Objective
To compare novel systemic therapies, both biologic and non‐biologic, approved for moderate‐to‐severe psoriasis by conducting a systematic review (SR) and NMA of Psoriasis Area and Severity Index (PASI) outcomes measured at or around 1 year.
Methods
An SR was conducted to identify studies reporting PASI 75, PASI 90 and PASI 100 responses. Feasibility of an NMA on maintenance phase endpoints was assessed and sources of heterogeneity considered. Data appropriate for analysis were modelled using a Bayesian multinomial likelihood model with probit link. Wherever possible, data corresponding to an intention‐to‐treat approach with non‐responder imputation were used.
Results
Twenty‐four studies reporting outcomes at 40–64 weeks were identified, but heterogeneity in study design allowed synthesis of only 17. Four 52‐week randomized controlled trials (RCTs) comprised the primary analysis, which found brodalumab was significantly more efficacious than secukinumab, ustekinumab and etanercept. Secukinumab was also more efficacious than ustekinumab and both outperformed etanercept. In a secondary analysis, evidence from 13 additional studies and 4 further therapies (adalimumab, apremilast, infliximab and ixekizumab) was included by comparing long‐term outcomes from active interventions to placebo outcomes extrapolated from induction. Results were consistent with the primary analysis: brodalumab was most effective, followed by ixekizumab and secukinumab, then ustekinumab, infliximab and adalimumab. Etanercept and apremilast had the lowest expected long‐term efficacy. Results were similar when studies with low prior exposure to biological therapies were excluded.
Conclusion
Results suggest that brodalumab is associated with a higher likelihood of sustained PASI response, including complete clearance, at week 52 than comparators. Further long‐term active‐comparator RCT data are required to better assess relative efficacy across therapies.
A major limitation of high-throughput DNA sequencing is the high rate of erroneous base calls produced. For instance, Illumina sequencing machines produce errors at a rate of ∼0.1–1 × 10−2 per base ...sequenced. These technologies typically produce billions of base calls per experiment, translating to millions of errors. We have developed a unique library preparation strategy, "circle sequencing," which allows for robust downstream computational correction of these errors. In this strategy, DNA templates are circularized, copied multiple times in tandem with a rolling circle polymerase, and then sequenced on any high-throughput sequencing machine. Each read produced is computationally processed to obtain a consensus sequence of all linked copies of the original molecule. Physically linking the copies ensures that each copy is independently derived from the original molecule and allows for efficient formation of consensus sequences. The circle-sequencing protocol precedes standard library preparations and is therefore suitable for a broad range of sequencing applications. We tested our method using the Illumina MiSeq platform and obtained errors in our processed sequencing reads at a rate as low as 7.6 × 10−6 per base sequenced, dramatically improving the error rate of Illumina sequencing and putting error on par with low-throughput, but highly accurate, Sanger sequencing. Circle sequencing also had substantially higher efficiency and lower cost than existing barcode-based schemes for correcting sequencing errors.
Herpes simplex virus 1 (HSV-1) establishes infections in humans and mice, but some non-human primates exhibit resistance via unknown mechanisms. Innate immune recognition pathways are highly ...conserved but are pivotal in determining susceptibility to DNA virus infections. We report that variation of a single amino acid residue in the innate immune sensor cGAS determines species-specific inactivation by HSV-1. The HSV-1 UL37 tegument protein deamidates human and mouse cGAS. Deamidation impairs the ability of cGAS to catalyze cGAMP synthesis, which activates innate immunity. HSV-1 with deamidase-deficient UL37 promotes robust antiviral responses and is attenuated in mice in a cGAS- and STING-dependent manner. Mutational analyses identified a single asparagine in human and mouse cGAS that is not conserved in many non-human primates. This residue underpins UL37-mediated cGAS deamidation and species permissiveness of HSV-1. Thus, HSV-1 mediates cGAS deamidation for immune evasion and exploits species sequence variation to disarm host defenses.
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•The HSV-1 UL37 tegument protein antagonizes the cGAS-STING pathway in mice•UL37 deamidates a critical Asn on cGAS of humans and mice but not many non-human primates•cGAS deamidation abolishes cGAMP synthesis and downstream innate immune activation•Variation of the cGAS UL37 deamidation site defines HSV-1 species-specific permissiveness
Natural sequence variations in immune factors may enable viral pathogens to evade or dismantle host defenses. Zhang et al. report that herpes simplex virus 1 exploits species-specific variation of a single amino acid residue in cGAS for deamidation, thereby inactivating innate defense in susceptible hosts.
Recent studies have identified ancient virus genomes preserved as fossils within diverse animal genomes. These fossils have led to the revelation that a broad range of mammalian virus families are ...older and more ubiquitous than previously appreciated. Long-term interactions between viruses and their hosts often develop into genetic arms races where both parties continually jockey for evolutionary dominance. It is difficult to imagine how mammalian hosts have kept pace in the evolutionary race against rapidly evolving viruses over large expanses of time, given their much slower evolutionary rates. However, recent data has begun to reveal the evolutionary strategy of slowly-evolving hosts. We review these data and suggest a modified arms race model where the evolutionary possibilities of viruses are relatively constrained. Such a model could allow more accurate forecasting of virus evolution.
TRIM25 is an E3 ubiquitin ligase that activates RIG-I to promote the antiviral interferon response. The NS1 protein from all strains of influenza A virus binds TRIM25, although not all virus strains ...block the interferon response, suggesting alternative mechanisms for TRIM25 action. Here we present a nuclear role for TRIM25 in specifically restricting influenza A virus replication. TRIM25 inhibits viral RNA synthesis through a direct mechanism that is independent of its ubiquitin ligase activity and the interferon pathway. This activity can be inhibited by the viral NS1 protein. TRIM25 inhibition of viral RNA synthesis results from its binding to viral ribonucleoproteins (vRNPs), the structures containing individual viral RNA segments, the viral polymerase, and multiple viral nucleoproteins. TRIM25 binding does not inhibit initiation of capped-RNA-primed viral mRNA synthesis by the viral polymerase. Rather, the onset of RNA chain elongation is inhibited because TRIM25 prohibits the movement of RNA into the polymerase complex.
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•TRIM25 binds to influenza ribonucleoproteins (vRNPs) in the nucleus•On vRNPs, TRIM25 acts as a clamp to inhibit viral RNA chain elongation•TRIM25 restriction of influenza RNA synthesis can be reconstituted in vitro•Influenza NS1 protein antagonizes this anti-influenza activity of TRIM25
Meyerson et al. identify an anti-influenza activity for TRIM25 in the nucleus. TRIM25 specifically targets influenza virus replication by binding viral-RNA-containing ribonucleoproteins (vRNPs). TRIM25 binds vRNPs in the nuclei of infected cells, acting as a molecular clamp that deprives the viral polymerase of its RNA template.
Schlafen11 (encoded by the SLFN11 gene) has been shown to inhibit the accumulation of HIV-1 proteins. We show that the SLFN11 gene is under positive selection in simian primates and is ...species-specific in its activity against HIV-1. The activity of human Schlafen11 is relatively weak compared to that of some other primate versions of this protein, with the versions encoded by chimpanzee, orangutan, gibbon, and marmoset being particularly potent inhibitors of HIV-1 protein production. Interestingly, we find that Schlafen11 is functional in the absence of infection and reduces protein production from certain non-viral (GFP) and even host (Vinculin and GAPDH) transcripts. This suggests that Schlafen11 may just generally block protein production from non-codon optimized transcripts. Because Schlafen11 is an interferon-stimulated gene with a broad ability to inhibit protein production from many host and viral transcripts, its role may be to create a general antiviral state in the cell. Interestingly, the strong inhibitors such as marmoset Schlafen11 consistently block protein production better than weak primate Schlafen11 proteins, regardless of the virus or host target being analyzed. Further, we show that the residues to which species-specific differences in Schlafen11 potency map are distinct from residues that have been targeted by positive selection. We speculate that the positive selection of SLFN11 could have been driven by a number of different factors, including interaction with one or more viral antagonists that have yet to be identified.
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