Antiviral states

The antiviral state induced by different types of IFNs is mediated by various IFN-induced proteins. The best-known antiviral effectors produced as a result of IFN cascade induction are shown in Table 2. They include 2 -5 oligoadenylate synthetase (2 -5 OAS), double-stranded RNA activated protein kinase (PKR), and myxovirus (Mx) proteins. Additional effectors include RNA-specific adenosine deaminase 1 (ADARl), the 20-kDa ISG product (ISG20), ISG54 and ISG56, and IFN-stimulated micro RNAs (Pedersen et al. 2007). 

These intracellular enzymes remain in an inactive state after their initial induction. They are activated only when the cell comes under viral attack, and their activation can inhibit viral replication in that cell. The 2,5-A synthetase acts in concert with two additional enzymes, i.e. an endori-bonuclease and a phosphodiesterase, to promote and regulate the antiviral state (Figure 8.4). 

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. 

IFNs cannot be absorbed orally to be used therapeutically it) must be given intramuscularly or subcutaneously. The )H>lugical effects are quite long, so pharmacokinetic param-i (Ts are difficult to determine. The antiviral state in periph-.nalhlixxl mononuclear cells typically peaks 24 hours after tec of IFN-a and IFN-/3, then decrea.ses to baseline in 6 ia)s." Both recombinant and natural INF-a and INF-/3 are. qiioved for use in the United States for the treatment of (isul)toma acuminatum (venereal wans), chronic hepatitis... 

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... 

Tumor necrosis factor-a (TNF-a) Cachectin (TNF-a) Monocytes/macs Tumor cells cytotoxicity Others similar profile of activity of IL-1 promotes 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]. 

Thus poly I C is a toxic but efficient inducer of an antiviral state. It is effective in animal models against such serious human infections as rabies [117] and Japanese B encephalitis [118] and could possibly be used to treat such life-threatening infections in humans, but for general use in minor infections it appears at the present time to be far too toxic. 

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).

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