Interferons antiviral effects

In addition, stndies evaluating interferon alpha/beta and interlenkin-16 expression have shown snbstantial antiviral effects against HlV-1 in vitro and in a humanized mouse model (Cremer et al. 2000 Lanret et al. 1994 Sanhadji et al. 1997 Zhou etal. 1997). 

Li XL, Blackford JA, Hassel BA (1998b) RNase L mediates the antiviral effect of interferon through a selective reduction in viral RNA during encephalomyocarditis virus infection. J Virol 72 2752-2759... 

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. 

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. 

Interferons a-2b (Intron-A), a-nl, and a-n3 (Alferon N) have both intrinsic antiviral effects and antiproliferative and immunomodulatory actions. These interferons are approved for intralesional therapy of refractory or recurrent condylomata (genital warts). Toxicities include flulike symptoms, nausea, depression of the white blood cell count, and mild diminution in hematocrit. 

The enhanced production of the cytokines called interferons is one of the body s earliest responses to a viral infection. These endogenous proteins exert potent antiviral, immunoregulatory, and antiproliferative effects and are classified according to the cell type from which they were initially derived. Interferon-a (type I, leukocyte) and interferon (3-(3 (type I, fibroblast) are synthesized by most types of cells in response to viral infection, certain cytokines, and double-stranded RNA. Interferon-y (type II, immune) is produced by natural killer (NK) cells and T lymphocytes in response to antigens, mitogens, and certain cytokines. Interferon-a and interferon-(3 exert the most potent antiviral effects interferon-y is antiviral and strongly immunomodulatory. 

Interferons are cellular glycoproteins produced by the host cells which exert complex antiviral, immunoregulatory and antiproliferative activities. After binding to interferon receptors it acts through cellular metabolic processes which involves synthesis of viral RNA and proteins. Interferon receptors are tyrosine protein kinase receptors which on activation phosphorylate cellular proteins. These then induce transcription of interferon induced proteins which exert antiviral effects. There are three type of interferons - alpha, beta and gamma. 

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... 

Mechanism of Action. Although the details are unclear, imiquimod enhances the local production of interferons, tumour necrosis factor-alpha, and possibly other cytokines that produce antiviral responses. Hence, this drug does not act directly on the virus, but instead modulates the host (human) immune responses that have antiviral effects. 

IFNs were originally discovered more than 40 years ago by Isaacs and Lindemann because of their antiviral effects.Today interferons are used mainly in the treatment of infectious viral hepatitis B and C. IFNs control genes involved in antiviral responses. Mice lacking the IFN-responsive transcriptional activator and transmitter, STAT 1, are defenceless against viral infections. Three antiviral pathways are induced by IFNs (Fig. 6.12). 

Ribavirin This guanosine analogue was first used experimentally by o. Reichard et al. (1991) and in chronic hepatitis C by J. Andersson et al. (1991). It is rapidly absorbed and distributed in the body, but is excreted slowly (half-life 79 hours). The bioavailability is 45-65%. As a monotherapy, it only leads to a decrease in transaminases and a slight improvement in histological activity. Ribavirin may not exhibit a direct antiviral effect, but can trigger a favourable response to interferon. When combined with IFN, ribavirin proved far more efficacious in chronic hepatitis C (immunomo-dulation ) without any increase in the typical side effects of IFN. (49, 51, 53) (s. p. 707)... 

Feray C, Samuel D, Gigou M, Paradis V, David MF, Lemonnier C, Reynes M, Bismuth H. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation antiviral effects and risk of rejection. Hepatology 1995 22(4 Pt l) 1084-9. 

Glycyrrhizin may exhibit antiviral effects. It has been shown to protect mice exposed to a lethal dose of influenza virus (Utsunomiya et al., 1997). This effect may be produced through the stimulation of interferon-y production by T cells (Abe et al., 1982 Utsinomiya et al., 1997). Glycyrrhizin also demonstrated an ability to inhibit the replication of varicella-zoster virus in human embryonic fibroblasts in vitro (Baba and Shigeta, 1987). 

Interferon has a direct antiviral effect by inhibiting viral protein synthesis. Class 1 major histocompatibility complex (MHC) antigen displayed on hepatocytes is enhanced, and it is thought to aid recognition of infected hepatocytes by the immune system. Other potentially beneficial effects include increased natural killer (NK) cell activity (196). 

In addition to antiviral effects, interferons have antitumor effects. The mechanisms of the antitumor effects are not well understood, but are probably likewise related to stimulation of specific gene expression by STAT proteins. Interferon-a, produced by recombinant DNA technology, has been used to treat patients such as Arlyn Foma who have certain types of nodular lymphomas and patients, such as Mannie Weitzels, who have chronic myelogenous leukemia. 

Tazulakhova EB, Novokhatsky AS, Yershov FI. Interferon induction by, and antiviral effect of, poly(rl)-poly (rC) in experimental viral infection. Acta Virol. 1973 17 487-492. 

The interferons (IFNs) are potent stimulators of MHC expression and antigen presentation. Type I IFNs (IFN-ot/p) induce MHC class I expression, whereas type II IFNs (IFN-y) induce MHC class I and class II expression as well as components of the antigen processing machinery (Boss 1997 Glimcher and Kara 1992 Ting and Baldwin 1993). Moreover, IFNs mediate direct antiviral effects through several distinct effector molecules that block viral infection or replication (Kimura et al. 1994, 1996 Samuel 1991). 

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