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Influenza epidemics and pandemics are constant threats to human health. The application of antiviral drugs provides an immediate and direct control of influenza virus infection. At present, the major strategy for managing patients with influenza is through targeting conserved viral proteins critical for viral replication. Two classes of conventional antiviral drugs, the M2 ion channel blockers and the neuraminidase inhibitors, are frequently used. In recent years, increasing levels of resistance to both drug classes has become a major public health concern, highlighting the urgent need for the development of alternative treatments. Novel classes of antiviral compounds or biomolecules targeting viral replication mechanism are under development, using approaches including high-throughput small-molecule screening platforms and structure-based designs. In response to influenza virus infection, host cellular mechanisms are triggered to defend against the invaders. At the same time, viruses as obligate intracellular pathogens have evolved to exploit cellular responses in support of their efficient replication, including antagonizing the host type I interferon response as well as activation of specific cellular pathways at different stages of the replication cycle. Numerous studies have highlighted the possibility of targeting virus-host interactions and host cellular mechanisms to develop new treatment regimens. This review aims to give an overview of current and novel concepts targeting the virus and the host for managing influenza., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Type I interferons (IFNs) function as the first line of defense against viral infections by modulating cell growth, establishing an antiviral state and influencing the activation of various immune cells. Viruses such as influenza have developed mechanisms to evade this defense mechanism and during infection with influenza A viruses, the non-structural protein 1 (NS1) encoded by the virus genome suppresses induction of IFNs-α/β. Here we show that expression of avian H5N1 NS1 in HeLa cells leads to a block in IFN signaling. H5N1 NS1 reduces IFN-inducible tyrosine phosphorylation of STAT1, STAT2 and STAT3 and inhibits the nuclear translocation of phospho-STAT2 and the formation of IFN-inducible STAT1:1-, STAT1:3- and STAT3:3- DNA complexes. Inhibition of IFN-inducible STAT signaling by NS1 in HeLa cells is, in part, a consequence of NS1-mediated inhibition of expression of the IFN receptor subunit, IFNAR1. In support of this NS1-mediated inhibition, we observed a reduction in expression of ifnar1 in ex vivo human non-tumor lung tissues infected with H5N1 and H1N1 viruses. Moreover, H1N1 and H5N1 virus infection of human monocyte-derived macrophages led to inhibition of both ifnar1 and ifnar2 expression. In addition, NS1 expression induces up-regulation of the JAK/STAT inhibitors, SOCS1 and SOCS3. By contrast, treatment of ex vivo human lung tissues with IFN-α results in the up-regulation of a number of IFN-stimulated genes and inhibits both H5N1 and H1N1 virus replication. The data suggest that NS1 can directly interfere with IFN signaling to enhance viral replication, but that treatment with IFN can nevertheless override these inhibitory effects to block H5N1 and H1N1 virus infections.