The innate immune system forms the first line of defence against invading micro-organisms such as viruses. It dampens initial virus replication and ensures survival of the host until specialized adaptive responses are developed. Type I interferons (IFNs) are secreted key cytokines on the innate immune axis that protect uninfected cells and stimulate leukocytes residing at the interface of innate and adaptive immunity, such as macrophages and dendritic cells. These cells prod the adaptive immune system to mount a full, specialized response against the invading microbe.
The ability to outrun innate immunity before adaptive immune responses are mounted is crucial for the survival of virtually all the mammalian viruses, regardless of their genome type and complexity. Relatively simple viruses such as RNA viruses from the Picornavirus family, as well as DNA viruses with large genomes, such as members from the Poxvirus family, have been shown to inhibit the IFN system. This review covers the latest insights into how virus-encoded antagonists sidetrack the IFN machinery and how this knowledge is currently used to generate second generation live vaccines and antiviral compounds.
Viral tricks to grid-lock the type I interferon system. Curr Opin Microbiol. Jun 9 2010
Type I interferons (IFNs) play a crucial role in the innate immune avant-garde against viral infections. Virtually all viruses have developed means to counteract the induction, signaling, or antiviral actions of the IFN circuit. Over 170 different virus-encoded IFN antagonists from 93 distinct viruses have been described up to now, indicating that most viruses interfere with multiple stages of the IFN response. Although every viral IFN antagonist is unique in its own right, four main mechanisms are employed to circumvent innate immune responses: (i) general inhibition of cellular gene expression, (ii) sequestration of molecules in the IFN circuit, (iii) proteolytic cleavage, and (iv) proteasomal degradation of key components of the IFN system. The increasing understanding of how different viral IFN antagonists function has been translated to the generation of viruses with mutant IFN antagonists as potential live vaccine candidates. Moreover, IFN antagonists are attractive targets for inhibition by small-molecule compounds.
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