The Use of Interferon-α in Virus Infections

Abstract

The interferons (IFN) act too slowly to arrest acute viral infections, but interferon-alpha (IFN alpha) preparations have proved useful in some chronic infections and will clearly be used increasingly in these in the future. In the preparations derived from human leucocytes or cultured B lymphoblastoid cells, which are in routine clinical use, mixtures of a number of distinct subtypes of human IFN alpha have been identified. There are also 3 slightly different versions of the same single subtype, IFN alpha-2, made by recombinant DNA procedures in bacteria. IFN alpha preparations are injected intramuscularly or subcutaneously. Dose-related side effects are common but usually tolerable, but prolonged treatment may cause increasing fatigue and depression. Some patients form neutralising antibodies which block the effects of the IFN; these appear to be relatively more common after recombinant IFN alpha-2 than after IFN derived from human cells. Given intranasally, IFN alpha can prevent a subsequent experimental rhinovirus infection, or the spread of natural colds within a family. Repeated administration progressively damages the nasal mucosa, so that long term prophylaxis is not possible. IFN alpha has proved useful in patients with papillomavirus warts of the larynx, ano-genital region (condyloma acuminata) and skin (common warts). Treatment regimens remain to be optimised and are likely to include surgery or other treatments. IFN alpha and zidovudine (azidothymidine) synergistically inhibit the growth of HIV in vitro, and combination are on trial in patients with early AIDS. Very large doses of IFN alpha are effective against Kaposi's sarcoma in some AIDS patients. In chronic hepatitis B, continuing virus replication may lead to cirrhosis or primary liver cancer. Earlier clinical trials with IFN alpha gave inconclusive results, but recent large studies have confirmed that 25 to 40% of patients obtain benefit; this probably results from both the antiviral and the immunomodulatory effects of IFN alpha. In patients with chronic hepatitis C, the biochemical markers usually improve rapidly during IFN alpha administration, but relapse if treatment is stopped after only a few months; to increase the chances of sustained cure, the treatment period is now being prolonged.

Intranasal Administration of Alpha Interferon Reduces Seasonal Influenza A Virus Morbidity in Ferrets

“…Today, IFN-␣ is established as an essential component of hepatitis B and C treatment regimens (9,17,31). Even though clinical studies demonstrated that intranansal IFN-␣ treatment can also prevent rhinovirus infection and spread (6,14,15), side effects such as irritation of the nasal mucosa and occasional nose bleeding after long-time and repeated administration prevented further in-depth evaluation of the potential therapeutic use of IFN-␣ to combat respiratory diseases such as influenza. The current interest in drugs against influenza is fueled by the threat that circulating avian H5N1 viruses or another subtype may adapt to humans and cause a devastating pandemic.…”

“…The human MxA protein also inhibits the replication of influenza viruses (30,53). In spite of promising initial clinical studies with IFN-␣ for the treatment of respiratory diseases, side effects such as irritation of the nasal mucosa and occasional nose bleeding have prevented the in-depth evaluation of IFN-␣ as a treatment for these diseases (6,15,19,25). If intranasally applied IFN were effective against influenza A viruses, the benefit would in many cases outweigh the reported mild side effects of the treatment.…”

Innate STAT1-Dependent Genomic Response of Neurons to the Antiviral Cytokine Alpha Interferon

“…Initially identified as antiviral proteins, IFNs-␣/␤ are now known to be pleiotropic and plurifunctional molecules with antiproliferative and immune-regulatory properties (32,41), which has led to their widespread therapeutic use in patients with certain viral infections (16), various cancers (21), and autoimmune disorders (11,38). The binding of IFNs to their common receptor, named the IFN-␣/␤ receptor (IFNAR), activates a signaling cascade involving the Janus kinase /signal transducer and activator of transcription (STAT) pathway (41).…”

Understanding Interferon Subtype Therapy for Viral Infections: Harnessing the Power of the Innate Immune System.

“…Such treatments with these limited subtypes overlook the possible therapeutic potential of the other natural IFN subtypes with divergent biological functions. Furthermore, although most IFNs are biologically active in the picomolar range, conventional IFN treatment uses systemic administration of extraordinary high doses, often associated with severe side effects including neurological toxicity limiting treatment efficacy [7,33,34]. Alternative treatment regimes using low dose IFN application, directed to the mucosal immune system, have shown improved clinical efficacy against virus infection in an experimental setting [34][35][36][37].…”