Interferon antiviral state

The ability of interferons (especially type I interferons) to induce an antiviral state is unlikely to be solely dependent upon the enzymatic mechanisms discussed above. Furthermore the 2 -5 A synthetase and eIF-2a kinase systems may play important roles in mediating additional interferon actions. The ability of such systems to stall protein synthesis in cells may play a role in interferon-induced alterations of cellular differentiation or cell cycle progression. They may also be involved in mediating interferon-induced anti-proliferative effects on various transformed cells. 

The binding of interferons to their receptors induces a rapid increase in the transcription of particular genes and synthesis of corresponding proteins.196 202 One of the proteins induced is a double-stranded RNA-activated 2 -5 A synthase, which polymerizes ATP to a series of 2 -5 linked oligonucleotides containing triphosphates at the 5 termini.202-204 Double-stranded RNA is uncommon except in replicating viruses, and it is thought that the activation by dsRNA is related to establishment of an antiviral state. Another interferon-induced enzyme is the small subunit of eukaryotic protein synthesis initiation factor eIF-2. 

This is converted to an inactive phosphorylated form by a dsRNA-dependent protein kinase205 (Fig. 31-10). The protein kinase also appears to be an interferon-induced protein206 as is the oligo(2 -5 A)-activated RNAse indicated in Fig. 31-10.207 Interferons have effects other than inducing the antiviral state. Thus, human IFN-(32 is identical to a B-cell differentiation factor.208 Both IFN-a and IFN-(3 have antigrowth activity and are currently in use for treatment of some forms of cancer as well as for viral infections.209... 

Type II cytokines include IL-10, IL-19, IL-20, IL-22, and interferons (IFN-a, - 3, -e, -k, -co, -6, -x and -y). Functions of this group include induction of cellular antiviral states, modulation of inflammatory responses, inhibition or... 

On binding to surface receptors, interferon alfa results in activation of cytoplasmic enzymes affecting messenger RNA translation and protein synthesis (6). The antiviral state takes hours to develop but can persist... 

Figure 7-3 a The function of interferon. When a virus infects a host cell, the cell expresses interferon. Interferon activates natural killer cells, causing killing of the infected host cells and elimination of the reservoir of infection. At the same time, interferon induces an antiviral state in neighboring cells, effectively breaking the cycle of infection. 

Interferon-a (IFN-a) Leukocytes B cells proliferation and differentiation NK cells stimulates cytolytic activity Tc cells increases generation APCs increases MHC 1 and II expression Others increases MHC 1 and FcR expression induces antiviral state... 

Interferons (IFNs) are potent cytokines that possess antiviral, immunomodulating, and antiproliferative activities. These proteins are synthesized by host cells in response to various inducers and, in turn, canse biochemical changes leading to an antiviral state in cells. Three major classes of human interferons with significant antiviral activity cnrrently... 

The interferon-inducing ability of poly I C was first demonstrated in cell systems in 1968 [105] and this was shortly followed by details of its curative effects on a herpes virus infection of a rabbit s eye [106], and on various virus infections of animals [107]. Since then there have been a large numbo- of papers on its antiviral activity in vitro and in vivo. Human cell cultures appear to be protected against the common respiratory viruses at doses of poly I C (01-10 pg/ml) which are much lower than those required to induce detectable interferon (50 pg/ml) [108]. This and similar observations pose difficult questions as to the mode of action of poly I C. It has been suggested that small doses of the compound result in the synthesis of a pre-interferon which can produce an antiviral state without detectable free interferon. This pre-interferon can be converted to detectable interferon by antimetabolites, endotoxin or by larger doses of poly I C itself [109]. 

Biological Tests The polymers were tested as single. strands in eukaryotic and viral polymerase systems In base-paired complexes with their mate polynucleotides they were tested with regard to antiviral activities in establishing antiviral states, inducing and priming interferon. 

Figure 47. Establishment of antiviral states and interferon induction by partial (1) (C)n-simulations in a mouse L-cell system interferon induction by fC),i (1) —3.5 log PFU [c/co] for comparison. Other conditions of assaying like Figure 46 (62).

In conclusion, our results are indicative of a new pathway involving 2, 5 -oligo-adenylates in cell metabolism. In fact, such compounds can regulate ADP-ribosylation of proteins, which in turn may be crucial for the induction of the antiviral state of cells treated with interferon. 

Exposure of sensitive cells to purified interferon, from a compatible species, induces a series of biological effects, the best known among these being the antiviral state and the decrease in the rate of cell proliferation. At least one of interferon s antiviral effects is to inhibit viral protein synthesis (l-5) ... 

Treatment of cells with interferon leads to the development of an antiviral state. In a number of cases this inhibition of virus production appears to be due to an inhibition of viral protein synthesis but the exact nature of the defect is unknown. 

Taken together, these results provide additional evidence of the pleiotropic effect of interferon. Although interferon-treated cells exhibited the antiviral state when infected with each of the viruses used throughout this study, the cell responded in different ways to the infection, at least at the level of ribonuclease activity and of the exteni of phosphorylation of P67. In the case of mengo virus the enhanced ribonuclease activity and its location, triggered by the infection may explain the interferon action. The relationship between the expression of the antiviral state and the protein kinase system remains to be demonstrated. 

Exposure of animal cells to interferon results in the establishment of an antiviral state manifested by the inhibition of virus replication (l). In interferon-treated cells transcription and translation of viral templates are specifically inhibited by the activation of cellular defence mechanisms, the molecular basis of which is still unclear (2). 

The biochemical characteristics of extracts from interferon-treated cells have been compared with those of extracts from control cells in order to elucidate the molecular mechanisms underlying the antiviral state. Among the many differences reported between these extracts, the most significant appear to be (see chapter 12) 1) an enhanced inhibition of protein synthesis by double-stranded RUA (dsRHA) (5-4) ... 

An experiment conducted with mouse-monkey hybrid cells indicated that there were different genetic sites for the synthesis of interferon and the protein responsible for the antiviral state. This data is consistent with recent vitro experiments conducted with actlnomycin D. In these experiments cells were incubated with interferon for different time intervals, the interferon removed, and the cells incubated with actlnomycin for 3 hours and then challenged with vesicular stomatitis virus (VSV) and plaques counted. There was no antiviral state produced when actlnomycin was added prior to interferon, but the antiviral state was achieved and potentiated some 30-fold when actlnomycin was added at 4-5 hours and became maximal (100-fold) when actlnomycin was added at 5 1/2-6 hours. These data are consistent with the following scheme ... 

Similar experiments have also been carried out using poly IC. In further recent experiments a tissue antagonist of interferon was isolated which may be the control protein, because when it was added at 4-6 hours under the same experimental conditions described above, it decreased by 40 fold the antiviral state Induced by interferon. Its activity is blocked by actlnomycin D. The protection against MM virus afforded by MDV, statalon, endotoxin, pyran copolymer, poly IC or Interferon is also antagonized by estrone. 

CAIPANG CM, HIRONO I, AOKi T. Induction of antiviral state in fish cells by Japanese flounder, Paralichthys olivaceus, interferon regulatory factor-1. Fish Shellfish Immunol 2005,19,79-91. 

Drug therapy is used to suppress viral replication by immune mediating or antiviral effects. Interferon 2b lbN-fb1 lamivudine, telbivudine, ade-fovir entecavir, and pegylated IFN-a2a (PEG-IFN) are approved in the United States for first-line treatment of chronic HBV. 

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