Page 79 - CIBERES2016-ENG

Highlights
During year 2016 we have studied the interactions between the influenza virus polymerase and the infected cell, modulation of viral replication by antiviral agents and the epigenetic changes induced by influenza virus infection. In addition, we have continued with the structural, antigenic and immunogenic characterization of Pneumoviridae fusion proteins with the aim of designing a universal vaccine for this family of viruses.
• Cellular proteins that interact with influenza virus polymerase proteins
We have characterized the interaction of two transcription-related proteins with influenza virus polymerase. One is hCLE, a positive modulator of the RNAP II, and the other is CHD1, a chromatin remodeler. Both, positively modulate influenza virus replication and moreover, hCLE is incorporated into influenza virus particles.
• Modulation of influenza virus replication by antiviral agents
We have used DNA aptamers that impair the interaction between influenza virus polymerase with components of the cellular translation machinery. Their use decreases viral replication and can be useful tools as potential antiviral compounds.
We have shown that influenza virus downregulates the unfolded protein response mediated by the PERK sensor, while Montelukast, a drug used to treat asthma in humans, specifically stimulates this response and downregulates viral protein synthesis and multiplication. Hence, our studies suggest that modulation of the PERK-mediated unfolded protein response is a target for influenza virus inhibition.
• Effect of influenza virus infection on chromatin remodelers and epigenetic changes induced in the infected cell.
We have studied the epigenetic changes of the cellular chromatin that take place during infection. DNA methylation is not modified, but histone modifications are altered. A general decrease in histone acetylation is observed and an increase in H3K79 methylation. Inhibiting the specific methylase of this residue we have observed that it controls the antiviral response and therefore influenza virus replication.
• generation and characterization of respiratory syncytial virus (RSv) and metapneumovirus (MPv) chimeric fusion proteins.
Based on previous structural studies of both RSV and MPV F glycoproteins, chimeric molecules were designed in which antigenic sites were swapped between the two molecules. Thus, soluble forms of postfusion MPV F with RSV antigenic site II and prefusion RSV F with MPV antigenic site IV were made and expressed from vaccinia recombinant viruses. The purified chimeric proteins showed the expected antigenic properties, as probed with monoclonal antibodies, and were capable of inducing cross- reactive and cross-neutralizing antibodies in mice. These results represent a proof of concept for a human Pneumoviridae universal vaccine.
RES
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