Antiviral interferon

The antiviral activity of polynucleotide interferon inducers is dependent upon many factors.53 in Poly I C the more stringent continuity and base pairing requirements of the poly I strand limit significant modifications to the poly C strand. The synthesis of guanidine or uridine "loops" in the poly C strand may be associated with more rapid hydrolysis, lessened toxicity, and preservation of the antiviral interferon-inducing activity. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

Interferons [alFN, piFN and ylFN]. Interferons are a family of glycosylated proteins and are cytokines which are produced a few hours after cells have been infected with a virus. Interferons protect cells from viral infections and have antiviral activities at very low concentrations ( 3 x 10 M, less than 50 molecules are apparently sufficient to protect a single cell). Double stranded RNA are very efficient inducers of IFNs. There are three main types of IFNs. The aIFNs are synthesised in lymphocytes and the piFNs are formed in infected fibroblasts. The a and P families are fairly similar consisting of ca 166 to 169 amino acids. Although ylFNs are also small glycosylated proteins (ca 146 amino acids), they are different because they are not synthesised after viral infections but are produced by lymphocytes when stimulated by mitogens (agents that induced cell division). 

Viral infections continue to be significant causes of morbidity and mortality and at the same time continue to be resistant to treatment by small molecules. Avridine (6) is an antiviral compound which has shown some activity in a variety of animal tests apparently based upon its ability to stimulate a number of cells to produce the high molecular weight endogenous antiviral substance interferon. Thus, the compound is believed to operate indirectly by stimulating the body s own natural defenses against viral penetration into host cells. Avridine is synthesized by... 

Interferon (IFN) differs from bona fide antiviral diugs since it is a natural defense protein of the host organism and does not directly interfere with the viral replication steps. Interferons are small glycoproteins inducing immune modulatory and antiviral activities. They are secreted by lymphocytes, leukocytes and fibroblasts in response to foreign nucleic acids (dsRNA). 

Interferon alfacon-1 (Inferax ), interferon alfa-2b (IntronA ), and interferon alfa-2a (Roferon -A) are applied in the treatment of chronic hepatitis B and C and some malignancies, especially hairy cell leukemia. IFN-a proteins induce the expression of antiviral, antiproliferative and immunomodulatory genes. 

Interferons (EFNs) are a family of multifunctional secreted proteins in vertebrates. Their most prominent functions are their antiviral properties on homologous cells against a wide range of viruses. It is important to note that prior exposure to EFN is required to render cells resistant to viral infection and replication. In contrast to antibodies, EFNs have no direct neutralizing effect on viruses. 

Pestka S (2003) A dance between interferon-alpha/beta andp53 demonstrates collaborations in tumor suppression and antiviral activities. Cancer Cell 4 85-87... 

Downing, J.F., Taylor, M.W., Wie, K.-M., Elizondo, R.S. (1987). In vivo hyperthermia enhances plasma antiviral activity and stimulates peripheral lymphocytes for increased synthesis of interferon gamma. J. Interferon Res. 7, 185-193. 

A major limitation in the development of anti-HCV compounds was the lack of a virus replication system. This was finally overcome with the development of a novel replicon system that directed persistent replication in a cell culture format (Lohmann et al. 1999). Using such a system, it was possible to demonstrate antiviral activity of an NS3/4A inhibitor in a cell culture assay, and demonstrate potency on par with treatment with interferon-a (Pause et al. 2003). 

Abstract In 2007, the world celebrated the 50th anniversary of the discovery of interferon (IFN) by Isaacs and Lindemnann. Subsequently, the IFN-a gene was cloned, fully sequenced and IFN-a was produced in recombinant form. Recombinant IFN-a is now used as the basis for treatment of chronic hepatitis C virus infection and can also be used to treat certain forms of chronic hepatitis B virus infections. IFNs have also been used in other viral infections, although with less success. The antiviral mechanisms of IFNs are reviewed in this chapter as well as the utility of IFNs in the treatment of persistent viral infections. 

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Ank N, West H, Bartholdy C, Eriksson K, Thomsen AR, Paludan SR (2006) Lambda interferon (IFN-lambda), a type III lEN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol 80 4501 509... 

Bain VG, Kaita KD, Yoshida EM, Swain MG, Heathcote EJ, Neumann AU, FisceUa M, Yu R, Osborn BE, Cronin PW, Ereimuth WW, McHutchison JG, Subramanian GM (2006) A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 44 671-678... 

Bain VG, Marotta P, Kaita K, Yoshida E, Swain MG, Bailey R, Neumann AU, Cronin PW, McHutchison JG, Pulkstenis E, Subramanian GM (2007) Comparable antiviral response rates with albumin interferon alpha-2b dosed at Q2W or Q4W intervals in naive subjects with genotype 2 or 3 chronic hepatitis C. J Hepatol 46 S7... 

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De Rosa EG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Veronese L, Raiteri R, CaUeri G, Di Perri G (2006) The early HCV RNA dynamics in patients with acute hepatitis C treated with pegylated interferon-alpha2b. Antivir Ther 11 165-171 Di Bisceglie A (1997) Hepatitis D virus. Marcel Dekker, NY... 

Dumoutier L, Tounsi A, Michiels T, Sommereyns C, Kotenko SV, Renauld JC (2004) Role of the interleukin (lL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of lL-29/interferon-lambda 1 similarities with type I interferon signaling. J Biol Chem 279 ... 

Fischl MA, Richman DD, Saag M, Meng TC, Squires KE, Holden-Wiltse J, Meehan PM (1997) Safety and antiviral activity of combination therapy with zidovudine, zalcitabine, and two doses of interferon-alpha2a in patients with HIV. J Acquit Immune Deflc Syndr Hum Retrovirol 16 247-253... 

Gunsar E, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, liter T, Batur Y (2005) Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther 10 721-726 Habersetzer E, Boyer N, MarceUin P, Badly F, Ahmed SN, Alam J, Benhamou JP, Trepo C (2000) A pdot study of recombinant interferon beta-la for the treatment of chronic hepatitis C. Liver 20 437 41... 

Osborn BL, Olsen HS, NardeUi B, Murray JH, Zhou JX, Garcia A, Moody G, Zaritskaya LS, Sung C (2002) Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys. J Pharmacol Exp Ther 303 540-548 Ozes ON, Reiter Z, Klein S, Blatt LM, Taylor MW (1992) A comparison of interferon-Conl with natural recombinant interferons-alpha antiviral, antiproliferative, and natural kiUer-inducing activities. J Interferon Res 12 55-59... 

Shiratori Y, Nakata R, Shimizu N, Katada H, Hisamitsu S, Yasuda E, Matsumura M, Narita T, Kawada K, Omata M (2000) High viral eradication with a daily 12-week natural interferon-beta treatment regimen in chronic hepatitis C patients with low viral load. Dig Dis Sci 45 2414-2421 Sidwell RW, Huffman JH, Khare GP, Allen LB, Witkowski JT, Robins RK (1972) Broad-spectrum antiviral activity of Virazole l-beta-D-ribofuranosyl-l,2,4-triazole-3-carboxamide. Science 177 705-706... 

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