Interferon antiviral activity

Anderson KP, Fennie EH (1987) Adenovirus early region 1A modulation of interferon antiviral activity. J Virol 61 787-795... 

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). 

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). 

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). 

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... 

Buckwold VE, Wei J, Huang Z, Huang C, Nalca A, Wells J, Russell J, Collins B, Ptak R, Lang W, Scribner C, Blanchett D, Alessi T, Langecker P (2007) Antiviral activity of CHO-SS cell-derived human omega interferon and other human interferons against HCV RNA repUcons and... 

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... 

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... 

HCV-796 is a non-nucleosidic NS5B polymerase inhibitor with potent antiviral activity in vitro. A phase lb study was performed to determine the antiviral activity, pharmacokinetics, and safety of HCV-796 in patients with chronic HCV infection. Maximum antiviral effects were achieved after 4 days of treatment with a mean reduction of HCV-RNA of 1.4 loglOIU/ml. Combination of HCV-796 with pegylated interferon-a led to a greater reduction of viral RNA load (3.3-3.5 loglO lU/ml) after a 14 days treatment interval. 

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. 

Interferons induce a wide range of biological effects. Generally, type I interferons induce similar effects, which are distinct from the effects induced by IFN-y. The most pronounced effect of type I interferons relates to their antiviral activity, as well as their anti-proliferative effect on various cell types, including certain tumour cell types. Anti-tumour effects are likely due not only to a direct anti-proliferative effect on the tumour cells themselves, but also due to the ability of type I interferons to increase NK and T-cytotoxic cell activity. These cells can recognize and destroy cancer cells. 

The molecular basis by which interferons promote their characteristic effects, in particular antiviral activity, is understood at least in part. Interferon stimulation of the JAK-STAT pathway induces synthesis of at least 30 different gene products, many of which cooperate to inhibit viral replication. These antiviral gene products are generally enzymes, the most important of which are 2 -5 oligoadenylate synthetase (2,5-A synthetase) and the eIF-2a protein kinase. 

Examples of the early application of recombinant DNA technology in medicine are the development of recombinant human growth hormone human insulin human interferons, thought to have anticancer activity in addition to antiviral activity interleukins (regulatory proteins from lymphocytes that are believed to be important in the treatment of immunodeficiency diseases and cancer) tumor necrosis factor epidermal and bone marrow progenitor cell growth factors and the production of vaccines (Table 12.1). 

Vandenbroeck et al.7 used an ELISA to determine the recovery of immu-noreactive porcine interferon-gamma (IFN-y) from E. coli inclusion bodies. The ELISA used a polyclonal coating antibody with detection by a MAb. The inclusion bodies were solubilized in diluted 6 M guanidine/HCl and IFN subsequently refolded by its removal. The antiviral activity of the interferon was measured with a bioassay using the cytopathic effect (CPE) of vesicular stomatitis virus (VSV) on bovine kidney cells. The results of this study showed that the immu-noreactivity measured by ELISA matched the biological activity measured by bioassay. 

High temperatures can break native S-S bonds and form new S-S bonds which can lock the protein into a denatured eonfiguration [89]. Low pH, sodium dodecyl sulfate. Tween 80, chaotropie salts, and exogenous proteins have been used to protect proteins from thermal inaetivation [90]. Ethylene glycol at 30-50% was used to protect the antiviral activity of P-interferon preparations [91]. Human serum albumin was used in recombinant human interferon-Psei-n which resulted in increased thermal stability [62]. Water-soluble polysaeeharides sueh as dextrans and amylose [92], as well as point-specific (site-directed) mutagenesis [93] have also been used to increase thermal stability of therapeutie proteins and peptides. 

Interferon-a2 concentrated solution is a solution of a protein that is produced according to the information coded by the o2 sub-species of interferon-a gene and that exerts non-specific antiviral activity, at least in homologous cells, through cellular metabolic processes involving synthesis of both ribonucleic acid and protein. Interferon-a2 concentrated solution also exerts antiproliferative activity. Different types of interferon a2, varying in the amino acid residue at position 23, are designated by a letter in lower case. 

Interferon. Any of a family of glycoproteins that exert virus-nonspecific but host-specific antiviral activity by inducing the transcription of cellular genes coding for antiviral proteins that selectively inhibit the synthesis of viral RNA and proteins. Interferons have immunoregulatory functions and can inhibit the growth of nonviral intracellular parasites. 

Anionic polyelectrolytes have been shown to enhance resistance to bacteria and fungi, enhance immune response, inhibit adjuvent arthritis and either depress or stimulate phagocytic activity of the reticuloendothelial system [458,459]. Carboxylic acid polymers have shown interferon induction, antiviral activity, and tumor growth inhibition [460]. The effects include inhibition of sarcoma, leukemia, polyoma and vesicular stomatitis virus. In one application, the cytotoxicity of bleomycin toward cultured mammalian cells was synergisti-cally enhanced by stirring in the presence of high molecular weight polyfacrylic acid) [461]. 

In addition, polyelectrolytes such as poly(acrylic acid-alt-maleic anhydride) (pyran) are reticuloendothelial stimulants, induce resistance to tumor growth [462,463] and show interferon-inducing ability and antiviral activity. The pyran activity may be dependent upon molecular weight. Low molecular weight materials of narrow polydispersity activate macrophages however antitumor activity does not appear to be molecular weight dependent [460]. 

Pish, E.N., K. Banerjee, and N. Stebbing, Human leukocyte interferon subtypes have different antiproliferative and antiviral activities on human cells. Biochem Biophys Res Commun, 1983.112(2) 537 6. 

Week, P.K., S. Apperson, L. May, and N. Stebbing, Comparison of the antiviral activities of various cloned human interferon-alpha subtypes in mammalian cell cultures. I Gen Virol, 1981.57(Pt 1) 233-7. 

Edwards, B.S., M.J. Hawkins, and E.C. Borden, Comparative in vivo and in vitro activation of human natural killer cells by two recombinant alpha-interferons differing in antiviral activity. Cancer Res, 1984. 44(7) 3135-9. 

As noted, Greenberg was the first to demonstrate the antiviral activity of a leukocyte-derived interferon against HBV infection [6]. Subsequent studies, using... 

Clinical pharmacology The mechanism by which interferon alfa-2a recombinant, or any other interferon, exerts antitumor or antiviral activity is not clearly... 

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. 

Effects of Glycolipids on Antiviral Activity of Fibroblast Interferon. 

Since interferons appear to be species-specific, we investigated whether the ganglioside fraction from mouse brain was more potent in inhibiting antiviral activity of mouse fibroblast interferon than that obtained from heterologous brain extracts. As seen in Figure 1 bovine brain gangliosides were almost as potent... 

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