PubMed · 1279742
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Y Sokawa. 1992. [2',5'-A synthetase--gene, enzyme, function].. https://pubmed.ncbi.nlm.nih.gov/1279742/
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Among the many host genes induced by virus infection and interferon, the eIF2alpha protein kinase PKR and the 2'-5' oligoadenylate synthetase (OAS) are both activated by double-stranded RNA (dsRNA) produced in virus-infected cells. Furthermore, each is a critical component that independently acts to inhibit virus replication and thereby contributes to the establishment of an antiviral state. As part of their tactics to foil host defense mechanisms, some viruses prevent the induction of interferon-responsive genes at the level of transcription. Other viruses, such as herpes simplex virus type 1 (HSV-1), can additionally replicate in interferon-treated cells and must also evade the actions of host defense proteins such as PKR and OAS that have been previously synthesized and merely await detection of an activating signal. Whereas HSV-1 gene products gamma(1)34.5 and Us11 are required for viral replication in interferon-treated cells and both act in a temporally coordinated manner during infection to counteract PKR, HSV-1 functions that target OAS have not been described. Here, we demonstrate that HSV-1 infection inhibits 2'-5' oligoadenylate synthesis in interferon-stimulated primary human cells. The OAS-inhibiting activity is generated late in the virus' productive life cycle and requires the Us11 gene product. Moreover, we establish that the Us11 protein is sufficient to block OAS activation in extracts from uninfected, interferon-treated cells. Inhibition of OAS specifically requires the Us11 dsRNA-binding domain, suggesting a mechanism that, in part, relies on sequestering available dsRNA produced during infection. Thus, in addition to PKR and its protein activator, PACT, the HSV-1 Us11 gene product is able to counteract the activity of OAS, a third cellular protein critical for host defense.
Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (beta2mg) and 2-5 oligoadenylate synthetase (2-5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing-remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, beta2mg and 2-5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy.
Interferon (IFN)-alpha, -beta and -gamma have been shown to be only marginally effective against severe acute respiratory syndrome coronavirus (SARS-CoV) replication in Vero cell lines. We investigated the combination of type I IFNs (IFN-alpha or -beta) and IFN-gamma for antiviral activity and found that such combinations synergistically inhibited SARS-CoV replication in Vero cells, using yield reduction assay and the isobologram and combination index methods of Chou and Talalay for evaluation. The highly synergistic anti-SARS-CoV action of type I IFNs and IFN-gamma parallels the marked increase in 2'-5'-oligoadenylate synthetase and p56 mRNAs following exposure in Vero cells to either IFN-alpha or -beta and IFN-gamma compared with the transcriptional levels obtained after stimulation with either IFN alone. These results demonstrate that SARS-CoV, although only moderately sensitive to the antiviral action of the individual types of IFN, is highly sensitive to a combination of type I and II IFNs, which suggests that such combinations may have potential in the treatment of SARS-CoV infections.