The Good the Bad and the Promising

IFN in the Treatment of Viral Infections

IFNa/p has a long history of clinical use for the treatment of viral infections. Our understanding of the molecular mechanisms by which IFN exerts its remarkably pleiotropic effects is constantly being refined, from the intricate cascade of phosphorylations, which characterize its signaling pathways, to the identification of an ever-growing array of antiviral ISGs. The greater understanding of their virus-specific antiviral functions may provide a new approach to antiviral therapy.

In hepatocytes, hepatitis C virus (HCV) triggers the induction of IRF-3 and NF-k B, via the signaling cascade initiated by HCV genomic RNA. It has been shown that TLR7 confers immunity against HCV via IFN-dependent and -independent pathways. Thus TLR7 agonists might present an alternative to IFN in the treatment of chronic HCV infection (Lee et al. 2006). Clinically, polyethylene glycol-modified IFNa 2a in addition to ribavirin is currently the treatment of choice for chronic HCV infection, which leads to cirrhosis and hepatocellular carcinoma. IFNa has been shown to suppress HCV replication. In most patients, a sustained inhibition of HCV genotype 2 and 3 replication is achieved after 24 weeks of treatment (Dalgard and Mangia 2006).

In spite of the efficacy with which IFN inhibits HCV, chronic infection can be established in the liver, mainly because HCV has been remarkably successful in evolving mechanisms to evade these defenses. The HCV-encoded NS3/4A protease is an effective antagonist of both the RIG-I and TLR3 signaling pathways that are induced by dsRNA regions of secondary structure in the ssRNA HCV genome. Not only does NS3/4A inhibit direct signaling for IFN secretion, but it also prevents IFN amplification via the autocrine and paracrine loops (Foy et al. 2003). HCV core protein induces in vitro expression of suppressor of cytokine signaling (SOC) proteins, which downregulate the JAK-STAT pathway (Bode et al. 2003). Lastly, because the HCV polymerase lacks a proofreading function, a number of viral variants can be generated during the course of a persistent infection, thus affording a great deal of viral complexity and variable sensitivity to IFN (Gale and Foy 2005). The understanding of the molecular strategies employed by the virus to evade immune surveillance will provide novel targets for therapeutic control of HCV (see the chapter by Loo and Gale, this volume).

IFNa was shown to inhibit angiogenesis in Kaposi sarcoma and reactivation of KSHV in primary effusion lymphoma cells (Albini et al. 2000; Marchisone et al. 1999) and, in combination with antiviral therapy, it was used in patients with AIDS-associated Kaposi sarcoma (KS) (Krown et al. 2006).

Another viral infection where IFN has been used therapeutically is respiratory papillomatosis associated with human papilloma virus (HPV) infection (Gerein et al. 2005). Interferon inducer imiquimod has also been used topically (Aldara cream) for treatment of genital warts caused by HPV (Slade et al. 1998).

However, the use of the recombinant IFN at therapeutically effective doses is generally associated with side effects and toxicity and thus a novel method of delivery or use of interferon analogs with higher specific activity that would allow a lower well-tolerated dose are being developed.

Role of IFN in Autoimmune Diseases

Constitutive production of IFN has been associated with the pathogenesis of some autoimmune diseases, whereas while in others, IFN treatment seems to be beneficiary. There is a preponderance of evidence for an association of IFN with the pathogenesis of systemic lupus erythematosus (SLE) and that of insulin-dependent diabetes mellitus (IDDM). In both diseases, serum levels of IFN are increased, but no initial inducer, be it endogenous or exogenous, has been identified so far. In addition, either disease may appear as an unintended consequence of IFN treatment for an unrelated condition (Devendra and Eisenbarth 2004).

The role of IFN on IDDM appears to be dependent on the stage of the disease. Initially, IFN might be responsible for an aberrant autoimmune response to a viral inducer with pancreatic tropism. As mentioned earlier, no such inducer has been identified to date, but pro-inflammatory products of damaged cells and secretion of other cytokines may induce local IFN secretion and

IFN-mediated pancreatic tissue damage. In later stages of IDDM, proliferation and survival of reactive T cells appears to be suppressed by IFN. Type 1 diabetes has been reported in association with IFN treatment of unrelated disorders, such as cancer and chronic hepatitis (Fabris et al. 2003) and in association with elevated IFN levels during coxsackievirus B infection (Chehadeh et al. 2000). In mice, transgenic expression of type I IFN in beta cells of the pancreas resulted in the destruction of the beta cells (Stewart et al. 1993). However, in NOD mice IFN had a beneficial effect (Sobel and Ahvazi 1998).

I n spite of the conspicuous absence of a known inducer, a model has been proposed whereby SLE is the result of sustained activation of myeloid dendritic cells at the instigation of IFN secreted by pDCs in a predisposed background. It remains unclear whether a predisposing background is due to hypersensitivity to stimuli, a greater number of IFN-producing cells, or the existence of a particularly effective inducer (Theofilopoulos et al. 2005). Recently, global gene expression profiling of PBMCs from SLE patients has shown induction of ISG as a hallmark of SLE (Bennett et al. 2003). Moreover, two novel autoantigens have been identified in CD1 lupus mice and found to be IFNa-inducible (Hueber et al. 2004) (see the chapter by Crow, this volume).

The use of IFNP in the treatment of multiple sclerosis (MS) is well established, although its mechanism of its action is mostly unknown. The beneficial effects of IFNP in preventing relapsing episodes may be due to a combination of anti-inflammatory, antiproliferative, and pro-apoptotic responses (Hafler 2004). Both experimental rheumatoid arthritis and myasthenia gravis also appear to benefit from treatment with IFN (Deng et al. 1996).

Given its pleiotropic effect in both innate and adaptive immunity, it is not surprising that IFN would play a pivotal role in the pathogenesis of autoimmunity as well. By the same token, IFN provides both a privileged and vulnerable target for therapeutic intervention.

Type I IFN has been shown to have both positive and negative modulatory effects on autoimmune diseases, yet what needs to be established is the nature of the inducer in distinct autoimmune disease and which of the IFNa variants subtypes are induced.

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