Abstract
BackgroundThe threat of recurring influenza pandemics caused by new viral strains and the occurrence of escape mutants necessitate the search for potent therapeutic targets. The dependence of viruses on cellular factors provides a weak-spot in the viral multiplication strategy and a means to interfere with viral multiplication.ResultsUsing a motif-based search strategy for antiviral targets we identified caveolin-1 (Cav-1) as a putative cellular interaction partner of human influenza A viruses, including the pandemic influenza A virus (H1N1) strains of swine origin circulating from spring 2009 on. The influence of Cav-1 on human influenza A/PR/8/34 (H1N1) virus replication was determined in inhibition and competition experiments. RNAi-mediated Cav-1 knock-down as well as transfection of a dominant-negative Cav-1 mutant results in a decrease in virus titre in infected Madin-Darby canine kidney cells (MDCK), a cell line commonly used in basic influenza research as well as in virus vaccine production. To understand the molecular basis of the phenomenon we focussed on the putative caveolin-1 binding domain (CBD) located in the lumenal, juxtamembranal portion of the M2 matrix protein which has been identified in the motif-based search. Pull-down assays and co-immunoprecipitation experiments showed that caveolin-1 binds to M2. The data suggest, that Cav-1 modulates influenza virus A replication presumably based on M2/Cav-1 interaction.ConclusionAs Cav-1 is involved in the human influenza A virus life cycle, the multifunctional protein and its interaction with M2 protein of human influenza A viruses represent a promising starting point for the search for antiviral agents.
Highlights
The threat of recurring influenza pandemics caused by new viral strains and the occurrence of escape mutants necessitate the search for potent therapeutic targets
In a recent investigation of the enveloped γ-retroviruses budding from lipid rafts we showed that caveolin-1 (Cav-1) interacts with the MLV retroviral matrix protein in the Gag precursor, suggesting that Cav-1 serves in positioning the Gag precursor at lipid rafts [13]
Influenza A virus titres are affected in Madin-Darby canine kidney cells (MDCK) Cav-1 knockdown cells We used MDCK (ATCC CCL-34), a canine kidney cell line commonly used in basic influenza virus research and vaccine production [16,17,18,19]
Summary
The threat of recurring influenza pandemics caused by new viral strains and the occurrence of escape mutants necessitate the search for potent therapeutic targets. In the last few years the interaction of viral matrix proteins or precursors with cellular proteins has attracted much attention in the field of medical virology due to the increase in the understanding of their interplay in late viral processes like protein transport, virus assembly and budding. Viral matrix proteins establish the link between outer shell and capsid core of enveloped viruses and bring together these parts in the virus assembly step. In influenza A viruses two M proteins are located on RNA7 of the negative-stranded, segmented RNA virus. The M1 protein functions as a typical matrix protein, while M2 exerts multiple tasks in the early and late phase of virus infection. M2 tetramers form an ion channel and in the early phase of virus infection
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