Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

Experiments done with inactivated influenza virus in embryonated chicken eggs have provided some of the clearest early data relating to the interference phenomenon. From results generated by multiple groups, it became clear that interference can be caused by either inactivated virus particles or live virus grown under specific conditions, such as repeated passage with large inocula or repeated freeze-thawing. It also became apparent that the method of inactivation was highly important for the degree of interference, with UV inactivation being far superior to heat or formalin treatment. The length of UV treatment corresponded to an increase in interfering ability until a peak was reached and decreased with further exposure (Ziegler et al. 1944) . Furthermore, the replication ability of a virus was much more sensitive to UV treatment than the interfering ability. Based on these early observations, many proposals as to the mechanism of interference were made, including the conclusion that this phenomenon was caused by a cellular product resulting from primary viral infection (Henle 1950) . Further support for this hypothesis came from the now famous work of Isaacs and Lindenmann who coined the term 'interferon' and described it as a 'nonhemagglutinating macromolecular particle which has many different properties from those of heated influenza virus' (Isaacs and Lindenmann 1957) . Over the next 30 years, type I interferon (IFN) was characterized in detail and identified as a family of cytokines encoded by the IFN-b gene and multiple IFN-a genes. After an arduous struggle, human IFN was purified to homogeneity and characterized for its biochemical properties by three individual groups, which identified its acid-stability and amino acid composition (Rubinstein et al. 1978 (Rubinstein et al. , 1979 Tan et al. 1979; Zoon et al. 1979) . Consequently, the availability of purified IFN and subsequent cloning and expression of the IFN-b gene product from E. coli allowed much more detailed analysis of its antiviral action (Nagata et al. 1980) . Today, IFN is known as a key component of the innate immune system responsible not only for broad cellular antimicrobial activity in response to primary infection, but also for its role in linking innate and adaptive immune responses (Biron 2001 ).