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.
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.
People with HIV (PWH) may have lower daily activity levels compared with persons without HIV. We sought to determine the impact of initiating a supervised exercise program on the daily step count of ...sedentary PWH and uninfected controls.
PWH and controls, aged 50-75, were enrolled in a 24-week supervised exercise program. All individuals were given a pedometer and instructed in regular use. A linear mixed model taking into account random effects was used to model daily step count.
Of 69 participants that began the study, 55 completed and 38 (21 PWH, 17 controls) had complete pedometer data. Baseline daily step count on nonsupervised exercise day was (estimated geometric mean, 95% confidence interval) 3543 (1306 to 9099) for PWH and 4182 (1632 to 10,187) for controls. Both groups increased daily steps on supervised 43% (20 to 69)%, P < 0.001 but not unsupervised exercise days -12% (-24 to 1)%, P = 0.071. Compared with controls, PWH had 26% (-47 to 4)%, P = 0.08 fewer daily steps on days with supervised exercise and 35% -53 to -10)%, P = 0.011 fewer daily steps on days without supervised exercise. Higher body mass index (per 1 unit) and smoking were associated with fewer daily steps -5% (-9 to -1)%; -49% (-67 to -23)%; P ≤ 0.012. Days with precipitation -8% (-13 to -3)%, P = 0.002 or below freezing -10% -15 to -4)%, P < 0.001 were associated with fewer steps.
Supervised exercise increased daily step counts in sedentary individuals, but at the expense of fewer steps on nonsupervised exercise days.
RNA viruses are a major source of emerging and re-emerging infectious diseases around the world. We developed a method to identify RNA viruses that is based on the fact that RNA viruses produce ...double-stranded RNA (dsRNA) while replicating. Purifying and sequencing dsRNA from the total RNA isolated from infected tissue allowed us to recover dsRNA virus sequences and replicated sequences from single-stranded RNA (ssRNA) viruses. We refer to this approach as dsRNA-Seq. By assembling dsRNA sequences into contigs we identified full length or partial RNA viral genomes of varying genome types infecting mammalian culture samples, identified a known viral disease agent in laboratory infected mice, and successfully detected naturally occurring RNA viral infections in reptiles. Here, we show that dsRNA-Seq is a preferable method for identifying viruses in organisms that don't have sequenced genomes and/or commercially available rRNA depletion reagents. In addition, a significant advantage of this method is the ability to identify replicated viral sequences of ssRNA viruses, which is useful for distinguishing infectious viral agents from potential noninfectious viral particles or contaminants.
Pandemic HIV-1 (group M) emerged following the cross-species transmission of a simian immunodeficiency virus from chimpanzees (SIVcpz) to humans. Primate lentiviruses (HIV/SIV) require the T cell ...receptor CD4 to enter into target cells. By surveying the sequence and function of CD4 in 50 chimpanzee individuals, we find that all chimpanzee CD4 alleles encode a fixed, chimpanzee-specific substitution (34T) that creates a glycosylation site on the virus binding surface of the CD4 receptor. Additionally, a single nucleotide polymorphism (SNP) has arisen in chimpanzee CD4 (68T) that creates a second glycosylation site on the same virus-binding interface. This substitution is not yet fixed, but instead alleles containing this SNP are still circulating within chimpanzee populations. Thus, all allelic versions of chimpanzee CD4 are singly glycosylated at the virus binding surface, and some allelic versions are doubly glycosylated. Doubly glycosylated forms of chimpanzee CD4 reduce HIV-1 and SIVcpz infection by as much as two orders of magnitude. Full restoration of virus infection in cells bearing chimpanzee CD4 requires reversion of both threonines at sites 34 and 68, destroying both of the glycosylation sites, suggesting that the effects of the glycans are additive. Differentially glycosylated CD4 receptors were biochemically purified and used in neutralization assays and microscale thermophoresis to show that the glycans on chimpanzee CD4 reduce binding affinity with the lentiviral surface glycoprotein, Env. These glycans create a shield that protects CD4 from being engaged by viruses, demonstrating a powerful form of host resistance against deadly primate lentiviruses.
Flaviviruses such as dengue encode a protease that is essential for viral replication. The protease functions by cleaving well-conserved positions in the viral polyprotein. In addition to the viral ...polyprotein, the dengue protease cleaves at least one host protein involved in immune response. This raises the question, what other host proteins are targeted and cleaved? Here we present a new computational method for identifying putative host protein targets of the dengue virus protease. Our method relies on biochemical and secondary structure features at the known cleavage sites in the viral polyprotein in a two-stage classification process to identify putative cleavage targets. The accuracy of our predictions scaled inversely with evolutionary distance when we applied it to the known cleavage sites of several other flaviviruses-a good indication of the validity of our predictions. Ultimately, our classifier identified 257 human protein sites possessing both a similar target motif and accessible local structure. These proteins are promising candidates for further investigation. As the number of viral sequences expands, our method could be adopted to predict host targets of other flaviviruses.
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