Review
Emerging cellular targets for influenza antiviral agents

https://doi.org/10.1016/j.tips.2011.10.004Get rights and content

At the global level, influenza A virus (IAV) is considered a major health threat because it causes significant morbidity. Different treatment and prevention options have been developed; however, these are insufficient in the face of recent IAV outbreaks. In particular, available antiviral agents have limited effectiveness owing to IAV resistance to these virus-directed drugs. Recent advances in understanding of IAV replication have revealed a number of cellular drug targets that counteract viral drug resistance. This review summarizes current knowledge on IAV replication with a focus on emerging cellular drug targets. Interestingly, for many of these targets, compounds for which safety testing has been carried out in humans are available. It is possible that some of these compounds, such as inhibitors of heat shock protein 90, proteasome, importin α5 or protein kinase C, will be used for treatment of IAV infections after careful evaluation in human primary cells and severely ill flu patients.

Section snippets

The influenza A virus

Influenza viruses belong to the Orthomyxoviridae family and include A, B and C types, which differ in host range and pathogenicity. Influenza type A viruses (IAV) are further classified into subtypes based on the distinct antigenic properties of two viral surface proteins, hemagglutinin (HA) and neuraminidase (NA). IAV subtypes H1N1, H2N2 and H3N2 have caused four major pandemics during the past 100 years, and it is highly probable that a novel IAV subtype will cause the next global pandemic 1,

Cellular factors in IAV replication

IAV replication mainly takes place in epithelial cells of the respiratory tract, alveolar macrophages and dendritic cells, and it depends on dozens of host factors. Many of these host factors have been identified only recently using genome-wide siRNA screening, genomic, proteomic and bioinformatic approaches 9, 10, 11, 12, 13, 14, 15. Figure 1 depicts cellular factors in the virus replication cycle, and Figure 2 provides a close-up view of cellular factors in viral RNA and protein synthesis.

Cellular antiviral targets

In contrast to viral proteins, cellular factors are less susceptible to mutations. Some host factors are essential for viral replication but are not crucial for cell growth, and thus represent excellent targets for therapeutic intervention. Table 1 lists cellular factors and their inhibitors that halt progression of the IAV replication cycle in cells at non-cytotoxic concentrations. For example, recombinant sialidases abolish virus attachment by removing SAs from the cell surface [99].

Discovery of novel cellular antiviral targets

The discovery of novel cellular antiviral targets could also result in better treatment of IAV infections. In particular, screening of chemical compound libraries is becoming a valuable source of novel antiviral targets (http://www.ncbi.nlm.nih.gov/pcassay [107]). For example, a recent high-throughput screen of 200 000 synthetic compounds identified REDD1 as a host anti-IAV factor and mTORC1 as potential antiviral target [55]. In contrast to in vitro efforts, in silico chemical library screening

Concluding remarks

IAVs cheat the host adaptive immunity by constantly modifying the structure of viral surface proteins. IAVs have also evolved mechanisms to disconcert the host innate immunity and secure viral replication, and to redirect basic cellular processes, such as transcription and translation, for efficient production of viral building blocks. However, there are host mechanisms that limit virus replication and, in the majority of cases, protect humans against the development of severe and lethal

Acknowledgements

We thank Sergey Shiryaev, Alun Parsons, Minttu Kaloinen and Oxana Denisova for critical reading of the manuscript, and Fonds National de la Recherche Luxembourg, the Center for International Mobility (CIMO), the Academy of Finland and the Jane and Aatos Erkko Foundation for financial support.

References (145)

  • K. Martin et al.

    Nuclear transport of influenza virus ribonucleoproteins: the viral matrix protein (M1) promotes export and inhibits import

    Cell

    (1991)
  • J.S. Rossman et al.

    Influenza virus assembly and budding

    Virology

    (2011)
  • I. Tato

    Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling

    J. Biol. Chem.

    (2011)
  • V. Deretic et al.

    Autophagy, immunity, and microbial adaptations

    Cell Host Microbe

    (2009)
  • G.J. Smith

    Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic

    Nature

    (2009)
  • G.J. Nabel

    Vaccinate for the next H2N2 pandemic now

    Nature

    (2011)
  • N. Singh

    Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target

    Expert Rev. Mol. Med.

    (2010)
  • D. Vijaykrishna

    Long-term evolution and transmission dynamics of swine influenza A virus

    Nature

    (2011)
  • G.J. Smith

    Dating the emergence of pandemic influenza viruses

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • T. Han et al.

    Structural basis of influenza virus neutralization

    Ann. N. Y. Acad. Sci.

    (2011)
  • T.G. Sheu

    Dual resistance to adamantanes and oseltamivir among seasonal influenza A (H1N1) viruses: 2008-2010

    J. Infect. Dis.

    (2011)
  • D.L. Chao

    The global spread of drug-resistant influenza

    J. R. Soc. Interface

    (2011)
  • B.G. Bradel-Tretheway

    Comprehensive proteomic analysis of influenza virus polymerase complex reveals a novel association with mitochondrial proteins and RNA polymerase accessory factors

    J. Virol.

    (2011)
  • A. Karlas

    Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication

    Nature

    (2010)
  • R. König

    Human host factors required for influenza virus replication

    Nature

    (2010)
  • S. Lin

    GC/MS-based metabolomics reveals fatty acid biosynthesis and cholesterol metabolism in cell lines infected with influenza A virus

    Talanta

    (2011)
  • L. Josset

    Gene expression signature-based screening identifies new broadly effective influenza A antivirals

    PLoS ONE

    (2010)
  • N. Lietzen

    Quantitative subcellular proteome and secretome profiling of influenza A virus-infected human primary macrophages

    PLoS Pathog.

    (2011)
  • M. Matrosovich

    Influenza receptors, polymerase and host range

    Rev. Sci. Tech.

    (2009)
  • C. Chen et al.

    Epsin 1 is a cargo-specific adaptor for the clathrin-mediated endocytosis of the influenza virus

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • T. Eierhoff

    The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells

    PLoS Pathog.

    (2010)
  • H. Marjuki

    Influenza A virus-induced early activation of ERK and PI3K mediates V-ATPase-dependent intracellular pH change required for fusion

    Cell. Microbiol.

    (2011)
  • E. de Vries

    Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway

    PLoS Pathog.

    (2011)
  • S.B. Sieczkarski

    Role of protein kinase C betaII in influenza virus entry via late endosomes

    J. Virol.

    (2003)
  • S.B. Sieczkarski et al.

    Differential requirements of Rab5 and Rab7 for endocytosis of influenza and other enveloped viruses

    Traffic

    (2003)
  • S. Bertram

    Novel insights into proteolytic cleavage of influenza virus hemagglutinin

    Rev. Med. Virol.

    (2010)
  • M. Sharma

    Insight into the mechanism of the influenza A proton channel from a structure in a lipid bilayer

    Science

    (2010)
  • E. Vanderlinden

    Novel inhibitors of influenza virus fusion: structure–activity relationship and interaction with the viral hemagglutinin

    J. Virol.

    (2010)
  • C.Y. Wu

    The SUMOylation of matrix protein M1 modulates the assembly and morphogenesis of influenza A virus

    J. Virol.

    (2011)
  • I. Widjaja

    Inhibition of the ubiquitin–proteasome system affects influenza A virus infection at a postfusion step

    J. Virol.

    (2010)
  • S.E. Dudek

    The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza A virus and vesicular stomatitis virus propagation by establishing an antiviral state

    J. Virol.

    (2010)
  • G. Gabriel

    Differential use of importin-alpha isoforms governs cell tropism and host adaptation of influenza virus

    Nat. Commun.

    (2011)
  • W.W. Wu et al.

    The directionality of the nuclear transport of the influenza A genome is driven by selective exposure of nuclear localization sequences on nucleoprotein

    Virol. J.

    (2009)
  • A. Dias

    The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit

    Nature

    (2009)
  • D. Guilligay

    The structural basis for cap binding by influenza virus polymerase subunit PB2

    Nat. Struct. Mol. Biol.

    (2008)
  • J. Zhang

    Cyclin T1/CDK9 interacts with influenza A virus polymerase and facilitates its association with cellular RNA polymerase II

    J. Virol.

    (2010)
  • L.L. Poon

    The RNA polymerase of influenza virus, bound to the 5′ end of virion RNA, acts in cis to polyadenylate mRNA

    J. Virol.

    (1998)
  • N. Satterly

    Influenza virus targets the mRNA export machinery and the nuclear pore complex

    Proc. Natl. Acad. Sci. U.S.A.

    (2007)
  • J.C. Kash

    Selective translation of eukaryotic mRNAs: functional molecular analysis of GRSF-1, a positive regulator of influenza virus protein synthesis

    J. Virol.

    (2002)
  • K. Sharma

    Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation

    PLoS ONE

    (2011)

    • Cited by (0)

    View full text
    Copyright © 2011 Elsevier Ltd. Published by Elsevier Ltd. All rights reserved.