Interferon antiviral action

Interferons (IFN) are glycoproteins that, among other products, are released from virus-infected cells. In neighboring cells, interferon stimulates the production of "antiviral proteins." These inhibit the synthesis of viral proteins by (preferential) destruction of viral DNA or by suppressing its translation. Interferons are not directed against a specific virus, but have a broad spectrum of antiviral action that is, however, species-specific. Thus, interferon for use in humans must be obtained from cells of human origin, such as leukocytes (IFN-a), fibroblasts (IFN-P), or lymphocytes (IFN-y). Interferons are also used to treat certain malignancies and autoimmune disorders (e.g., IFN-a for chronic hepatitis C and hairy cell leukemia IFN-p for severe herpes virus infections and multiple sclerosis). 

Although interferon has been studied extensively for over a decade, the mechanism of its antiviral activity remains unclear. Considerable evidence exists to support the concept that interferon inhibits virus-specific protein synthesis, thus blocking viral replication in cells adjacent to the infected cell producing the interferon. There is no established reason to conclude, however, that interferon exerts antiviral action through a single mechanism. 

In this communication we extend our earlier observations, which primarily dealt with the antiviral action of mouse fibroblast interferon, to its antigrowth activity and to antiviral and antigrowth activities of mouse T-cell interferon. We will show that inhibition by common gangiiosides Is restricted to both activities of fibroblast interferon alone. T-cell interferon, although its biological activities are analogous to those of fibroblast Interferon, neither binds to nor Is inhibited by these glycol ipids. Furthermore we demonstrate that mouse leukemia L—1210 cells that were selected for resistance to fibroblast interferon (6), respond equally well to T-cell Interferon as the parent cells which are responsive to both Interferons. 

The basic sequence of events in the cellular production and antiviral action of interferons is illustrated in Figure 34—4. Virtually all of the body s cells are capable of producing interferons, and these substances serve as an early step in preventing the virus from infecting healthy cells.50 As illustrated in Figure 34—4, cells that have been infected by a virus produce interferons that are subsequently released from the infected cell. These... 

In addition to its antiviral actions, interferon has an antiproliferative effect and modifies the functions of macrophages and natural killer cells. Thymosin, a protein synthesized by the epithelioid component of the thymus, may be potentially valuable in patients with DiGeorge s syndrome or other T cell deficiency states. Levamisole augments T cell-mediated immunity and may be of value in the immunodeficiency associated with Hodgkin s disease. 

Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14 778-809. 

Thia-8-oxoguanosine 5-amino-3-p-D-ribofuranosylthiazolo[4,5- pyrimidine-2,7(3fJ,6.Ff)-dione, 59 [122970 40-5] synthesized by ICN Pharmaceuticals, (138) has shown broad-spectmm antiviral activity. 7-Thia-8-oxoguanosine, C10H12N4O6S, is highly active in mice and rats against Semliki Forest, San Angelo, benzi, rat corona, and encephalomyocarditis viruses when administered intraperitoneaUy before exposure to the vims (139). The compound was moderately effective in mice infected intraperitoneaUy with HSV-2 or intranasaUy with vesicular stomatitis vims. The mode of antiviral action of (59) in vivo may be due in part to the induction of interferon Ot (138). 

The triphosphates of 2 -5 -oligoadenylate trimers are implicated in at least one of the mechanisms of the antiviral action of interferon and bind to and activate a RNaseL resulting in the cleavage of viral mRNA and the inhibition of viral replication. In order to study the cellular function of oligoadenylate, the ... 

D) Increased activity of host cell phosphodiesterases that degrade tRNA is one of the antiviral actions of interferons... 

C. Interferons The interferons are endogenous glycoproteins with antineoplastic, immunosuppressive, and antiviral actions. Alpha-interferons (see Chapter 56) are effective against a number of neoplasms, including hairy cell leukemia, the early stage of chronic myelogenous leukemia, and T cell lymphomas. Toxic effects of the interferons include myelosuppression and neurologic dysfunction. 

Although interferons are mediators of immune response, different mechanisms for the antiviral action of interferon have been proposed. Interferon-a possesses broad-spectrum antiviral activity and acts on virus-infected cells by binding to specific cell surface receptors. It inhibits the transcription and translation of mRNA into viral nuoleic acid and protein. Studies in cell-free systems have shown that the addition of adenosine triphosphate and double-stranded RNA to extracts of interferon-treated cells activates cellular RNA proteins and a oellular endonuclease. This activation causes the formation of translation inhibitory protein, which terminates production of viral enzyme, nucleic acid, and structural proteins (28). Interferon also may act by blocking synthesis of a cleaving enzyme required for viral release. 

Sen, G.C. Ransohoff, R.M. Interferon-Induced Antiviral Actions and Their Regulation. In Advances in Virus Research , Maramorosch, K. Murphy, F.A. Shatkin, A.J. Eds. Academic Press, San Diego, London, 1993, 42, p 57-102. 

Kitajewski J, Schneider R, Safer B, Munemitsu S, Samuel C, Thimmappaya B, Shenk T (1986) Adenovirus VAI RNA antagonizes the antiviral action of interferon by preventing activation of the interferon-induced eIF-2 alpha kinase. Cell 45 195-200 Korner H, Burgert H-G (1994) Down-regulation of HLA antigens by the adenovirus type 2 E3/19K protein in a T-lymphoma cell line. J Virol 68 1442-1448 Korner H, Fritzsche U, Burgert H-G (1992) Tumor necrosis factor alpha stimulates expression of adenovirus early region 3 proteins implications for viral persistence. Proc Natl Acad Sci USA 89 11857-11861... 

The ribonuclease activity was found in a sedimentable fraction known to contain the replication complex where synthesis of virus-coded MA takes place. Therefore, the antiviral action of interferon may be explained in this particular system by the ability of such a nuclease to degrade viral mRNA. Although the nuclease is not only active on mengo virus ENA its location within the cell would limit its action to the virus-coded single stranded ENA, the final consequence being some discrimination between viral and host cell messengers. This finding does not exclude the possibility that the inhibition of protein synthesis also occurs by other mechanisms such as impaired initiation of translation. 

Interferon, first discovered in 1957 [12], is a substance of protein-like structure which is produced in the cells of vertebrates in response to viral infection, and possesses antiviral action. Today, it is generally accepted that interferons play an essential role in the formation of a host s nonspecific resistance to superinfection with a second virus [13]. Thus, the role of interferon in combating viral infections may be similar to that of antibodies toward bacterial infections. It is immediately apparent that a successful and readily available interferon inducer, such as the divinyl ether-maleic anhydride cyclocopolymer (DVE-MA) may be, could play an extremely significant role not only in aiding in recovery from a viral infection, but in its use in prior generation of interferon to prevent a viral attack. 

Interferons (IFNs) are an important class of broad spectrum antiviral cytokines found in higher animals, reptiles, fish, and birds. IFNs make up a large, still growing list of proteins, seven of which occur in humans. These are further divided into three classes types I, II, and III. Two important type I IFNs in human are IFNa and IFNy. There are at least 14 different alpha IFNs. These are produced by leukocytes and dendritic cells and are part of an innate immune response with antiviral action. IFNp, produced by fibroblasts and probably many other cells, is used in the treatment of multiple sclerosis. It inhibits viral replication and is the product of a single gene. Two synthetic... 

Carter, W. A., P. M. Pitha, W. W. Brockman, E. C. Borden, and L. W. Marshall Selective Inhibition of Viral Functions The Antiviral Action of Interferon and Strepto-varicin. Medicine 51, 181 (1972). 

Interferon-a2b has diverse mechanisms of action, including antiviral activity, impact on cellular metabolism and differentiation, and antitumor activity.42 The antitumor activity is due to a combination of direct antiproliferative effect on tumor cells and indirect immune-mediated effects.42 Interferon-a2b is currently approved by the Food and Drug Administration (FDA) as adjuvant therapy for patients who are free of disease after curative surgical resection but are at high risk of MM recurrence. This includes patients with bulky disease or regional lymph node involvement such as stage IIB, IIC, or III disease.43 It is controversial if interferon-a2b (IFN) should be offered as adjuvant therapy for every high-risk MM patient. The reason is because clinical trials with different doses of IFN have not proved definitively that IFN improves overall patient survival. 

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. 

Pharmacology Interferon beta-1 a and beta-lb have antiviral, antiproliferative, and immunoregulatory activities. The mechanisms by which they exert their actions in MS are not clearly understood. 

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