Investigation of anti-alphavirus activities induced by interferon.

摘要

Members of the Alphavirus genus of the family Togaviridae are small mosquito-vectored RNA viruses that can be classified into Old World (e.g., Sindbis virus [SINV]) or New World (e.g., Venezuelan equine encephalitis virus [VEEV]) groups based upon areas of endemicity and human and veterinary disease characteristics. Alphavirus diseases can range from rash and arthritis to severe, sometimes fatal, encephalitis. Unfortunately, the biology of these viruses is poorly understood and currently there are no available therapeutics or licensed vaccines for protection of humans.;Interestingly, the translation-inhibiting activity blocked the IFN-alpha/beta-sensitive alphavirus SINV, to a degree similar to that of the IFN-alpha/beta-resistant alphavirus VEEV, implying that VEEV is resistant to other aspects of the IFN-alpha/beta-induced antiviral state. Consistent with this idea, we found that IFN-alpha/beta treatment of cells also induced an antiviral activity that inhibited the production of the RNA anti-genome, the initial step in virus RNA synthesis, and that VEEV replication was more resistant to this activity than that of SINV.;Together, these studies have identified two stages of virus replication, initial translation and synthesis of the virus anti-genome that are specifically targeted by IFN-alpha/beta-induced antiviral effectors. In addition, we have identified the route of introduction of an mRNA into the translation initiation process as a major mechanism through which host cells distinguish self from non-self during the innate immune response. Additional studies that more fully characterize these activities may lead to design of antiviral therapeutic strategies.;Interferon-alpha/beta (IFN-alpha/beta) is an important component of the host innate immune system providing a rapid, nonspecific response against infection with many viruses, including alphaviruses. We have begun identifying IFN-alpha/beta-induced effectors involved in host defense against alphaviruses and comparing the capacity of each to inhibit different alphaviruses. We show here that IFN-alpha/beta priming induces a PKR-independent activity that inhibits m7G cap-dependent translation initiation. Remarkably, the activity targets mRNAs, such as those of RNA viruses, that enter across the cytoplasmic membrane but nucleus-transcribed RNAs are relatively unaffected. These data suggest a mechanism for inhibition of invading viruses that preserves essential host activities, including the expression of antiviral and stress-responsive genes.