DENGUE VIRUS CAPSID

The role of lipid membranes in dengue virus assembly

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 Obiettivo del progetto (Objective)

'Viral hemorrhagic fever is a serious health threat mostly caused by the Dengue Virus (DV), which infects 50 to 100 million people worldwide yearly. Aedes spp. mosquitoes, the disease vectors endemic to tropical and subtropical regions, are spreading to temperate regions. A. aegypti, the main vector, is now found in Madeira, Portugal, and A. albopictus, a less frequent albeit potential vector, is present in several European countries. Conditions for a possible dengue outbreak in Europe are now set, only being necessary the mosquitoes to enter in contact with human viral carriers, as recently occurred in the A. albopictus promoted Chikungunya fever 2007 outbreak in Italy. DV infection is therefore a potential clinical problem for Europe, as stated in the EU FP7 Emerging Epidemics program (http://ec.europa.eu/research/health/). Once infected, no specific treatment is available, partially due to the lack of detailed information on the molecular mechanisms of viral assembly. The project intends to fill that gap by studying the viral assembly capsid protein, in biologically relevant conditions, using lipid bilayers mimicking biological membranes and intracellular lipid droplets isolated from hepatic cell lines. The project gathers the complementary expertise of two teams, each having a distinct yet synergistic role. Prof. Da Poian, from the Medical Biochemistry Institute, Federal University of Rio de Janeiro, Brazil, has expertise in cell and molecular biology, NMR and calorimetry studies applied to DV proteins. Prof. Santos, from the Institute of Molecular Medicine, Lisbon, Portugal, is skilled in light scattering spectroscopy and atomic force microscopy applied to lipid bilayers interaction with viral proteins. Thus the project assembles an eclectic gathering of complementary expertise to study the role of lipid membranes in dengue viral assembly. Following this approach, it is expected to open a gateway to the future development of capsid assembly-targeted therapies.'

Introduzione (Teaser)

The dengue virus, a major cause of viral hemorrhagic fever, has traditionally been localised in tropical and subtropical regions. However, the threat of infection now presents a potential medical problem for Europe.

Descrizione progetto (Article)

No specific treatment is available for dengue virus infection. This is mainly due to a lack of knowledge of the molecular mechanisms involved in the development of the dengue virus capsid protein (DVCP). The 'The role of lipid membranes in dengue virus assembly' (Dengue virus capsid) project is working to fill this gap by studying the role of lipid membranes in dengue viral assembly.

It is known that lipids play a role in DVCP-mediated viral RNA assembly and encapsidation, and that this probably occurs via interaction with intracellular lipid droplets. A capsid is the coating of a protein that has enclosed the nucleic acid core of a virus and encapsidation the process whereby this enclosing takes place. Lipid droplets are cellular subunits generated and used by viruses for replication.

So far, work has been focused on characterisation of the molecular details of the interaction between the DVCP and lipids, using lipid droplets directly isolated from hepatic cell lines. Biophysical techniques such as nuclear magnetic resonance (NMR) were used for the studies.

Main results show that on DVCP interaction with lipid droplets, there is a minor drop in alpha-helical content. An alpha-helix is a secondary protein structure that is spiral in form. As NMR results indicate, this decrease is consistent with interactions in alpha-helical regions. Based on a simulation of binding of the DVCP protein to model membranes, the project has been able to identify two possible sites where interaction is initiated. Following this 'activation', conformational rearrangements take place, likely prompting the viral RNA to bind the protein. Researchers believe this leads the dengue virus assembly and encapsidation process further.

Having identified the DVCP lipid droplets interaction sites as putative targets for drug or vaccine development, the Dengue virus capsid project expects to show that by blocking this interaction, the viral assembly and encapsidation process can be halted and the viral load reduced within the organism.