Editors' ChoiceInfluenza

Targeting the Host to Curb the Flu

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Science Translational Medicine  07 Jan 2015:
Vol. 7, Issue 269, pp. 269ec6
DOI: 10.1126/scitranslmed.aaa3466

Influenza virus can cause substantial morbidity and mortality in high-risk populations such as the young, the elderly, and the immunosuppressed. One reason for the evolutionary success of this virus is that it has developed clever mechanisms to promote its own replication, evade the immune system, and avoid destruction by antiviral drugs. Currently there are only two antiviral drugs available to treat flu in the clinic—one targets the M2 ion channel and the other targets the NA neuraminidase viral protein. However, influenza strains resistant to these drugs are already emerging because of the high mutation rate of the virus. Thus, understanding how the virus relies on the relatively immutable host for its own survival may lead to new strategies to prevent and treat the infection.

Watanabe and colleagues attempted to do just that, using a human cell line permissive for the replication of a bona fide and clinically relevant influenza virus. Their stepwise systematic approach identified ~1300 host proteins that co-immunoprecipitated with at least one of 11 tagged influenza viral proteins. These proteins were identified through mass spectrometry and then silenced with siRNA to determine whether the host protein affected influenza viral replication and cell viability. The group identified 91 promising host cell targets that when reduced by siRNA were able to decrease viral replication without causing substantial cell death. They then performed mechanistic studies to assess the selected 91 host factors for their role in the viral life cycle, viral genome replication, viral protein trafficking, virus-like protein formation, and viral RNP incorporation into mature virions.

Taking advantage of existing drug databases, they searched for drugs that targeted the host factors identified and selected 11 drugs for in vitro testing. The investigators were able to identify two surprising drug targets that would have never been thought to have anti-viral properties: Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) and Janus kinase 1 (JAK1). The beauty of this approach is that by a better focus on the role of the host on viral survival, novel drug targets were identified that can curb the viral infection. In addition, the approach takes advantage of already existing drugs that can be repurposed as antiviral therapeutics.

T. Watanabe et al., Influenza virus-host interactome screen as a platform for antiviral drug development. Cell Host Microbe 16, 795–805 (2014). [Abstract]

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