r help with the cell cycle analysis, and Sarah Dickerson for help preparing the manuscript. This work was supported by National Institutes of Health grant P01 CA022443. Antiviral drug development is currently based on two approaches: SKI-606 SRC inhibitor i the conventional approach of inhibiting the activity of a viral enzyme SKI-606 SRC inhibitor which often leads to the emergence of drug resistant viruses due to viral genomic variability and ii the more recent approach of targeting cellular factors that are required for viral replication. Indeed, coding for a limited number of proteins, viruses hijack the cellular machinery and rely on many host proteins for their replication.
The major recognized advantage of targeting a host factor is therefore to limit the development of resistance as the virus cannot replace a missing cellular protein.
Such an approach has been used in antiretroviral therapy with the development of a CCR5 antagonist showing promise as an anti CP-690550 CP-690550 HIV drug. We have also demonstrated that this strategy is efficient at inhibiting the replication of herpes viruses resistant to conventional antivirals. In influenza research, the effective in vitro and in vivo inhibition of two different cellular pathways without inducing resistance has been reported, and both are currently undergoing preclinical trials.
Targeting cellular proteins may provide another crucial advantage: if a cellular pathway is critical to the viral cycle, agents that target such a pathway should represent potential broad spectrum antivirals. The influenza virus represents a constant threat to public health due to the emergence of new viral strains and is therefore an ideal model on which to test this hypothesis.
Belonging to the orthomyxoviridae family, influenza viruses have genomes composed of single stranded RNA and are classified into three types: A, B and C according to their internal protein sequences. The influenza A viruses are further subtyped based on the antigenicity of the two envelope glycoproteins hemagglutinin and neuraminidase . All influenza A subtypes are endemic in aquatic birds but only two, H1N1 and H3N2, are presently circulating among humans.
Since the influenza genome is segmented, two different viral strains infecting the same cell are able to reassort their genomic segments. Variability can also be due to the low fidelity of the viral RNA polymerase, which causes yearly epidemics owing to an antigenic drift in glycoproteins.
Novel pathogenic strains of the influenza virus have also emerged with antigenically different HA and/or NA and have caused three pandemics in the 20th century: the Spanish influenza in 1918, responsible for approximately 50 million deaths, the Asian influenza in 1957 during which about 2 4 million people died, and the Hong Kong influenza in 1968 responsible for 1 2 million deaths. Considering this pandemic potential and with up to 500,000 annual deaths worldwide during usual winter outbreaks, influenza A viruses represent a major public health concern. Prevention relies on vaccination which has several major limitations including the lag time for vaccine preparation and the low vaccination coverage rate. Once a patient becomes infected, the current etiologic treatment of flu relies on M2 channel blockers or NA inhibitors. However, these existing therapie