Question

Summarize your understanding in computational approaches on virology. Your summary must not be more than 3000 words and less than 1000 words.

Answer 1

We apply an array of computational methods to study various aspects of viruses.This includes (i) virus discovery from deep sequencing data to broaden our understanding of the diversity of viruses affecting humans and other organisms, (ii) phylogenetics to reconstruct the origin and evolution of different virus families, (iii) virus classification to group our complex knowledge about viruses into usable units, and (iv) virus-host interactions to analyze the interplay between viruses and the immune system and to explore whether certain viral infections can be linked to unexplained diseases like some types of human cancer. In most of these studies we follow an interdisciplinary approach through collaborations with virologists from Germany and abroad.

Ultimately, we envision to combine our insights on viruses and certain methodical aspects of these studies with those of our other projects related to different human cancers. We hope that this will promote synergy and amplify output and impact of these two lines of research.

Viruses typically pack their genetic material within a protein capsid. Enveloped viruses also have an outer membrane made up of a lipid bilayer and membrane spanning glycoproteins. X-ray diffraction and cryoelectron microscopy provide high resolution static views of viral structure.

Molecular dynamics (MD) simulations may be used to provide dynamic insights into the structures of viruses and their components. There have been a number of simulations of viral capsids and (in some cases) of the inner core of RNA or DNA packaged within them. These simulations have generally focussed on the structural integrity and stability of the capsid and/or on the influence of the nucleic acid core on capsid stability.

More recently there have been a number of simulation studies of enveloped viruses, including HIV-1, influenza A, and dengue virus. These have addressed the dynamic behaviour of the capsid, the matrix, and/or of the outer envelope. Analysis of the dynamics of the lipid bilayer components of the envelopes of influenza A and of dengue virus reveals a degree of biophysical robustness, which may contribute to the stability of virus particles in different environments.

Significant computational challenges need to be addressed to aid simulation of complex viruses and their membranes, including the need to integrate structural data from a range of sources to enable us to move towards simulations of intact virions.This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov.

Viruses cause a plethora of human illnesses, resulting in > 1.5 million annual deaths worldwide (WHO Fact sheet 310). Viruses also indirectly regulate the carbon flux of our planet, they are used to attack cancer cells (oncolytic viruses; reviewed elsewhere), and are leveraged for a number of biotechnology applications (e.g. virus-like particles, VLPs, decorated with tumour-associated carbohydrate antigens as anti-cancer vaccines; and the packaging of enzymes within VLPs). At a more fundamental level they help us to probe many aspects of the biology of cells, including the organization and dynamics of cell membranes.

There has been considerable progress over the past two decades in the structural biology of viruses, employing X-ray crystallography, and cryoelectron microscopy and tomography. Viruses may be classified as non-enveloped (in which case the genome is surrounded by a protein capsid) and enveloped (in which case the capsid or nucleoprotein core is surrounded by a viral membrane envelope, containing both proteins and lipids). Structural studies have provided many high resolution structures of capsids, and also structures of envelopes, the latter often determined by cryoelectron microscopy and tomography. Viral envelopes are derived from the membranes of the host cell. Thus, studies of the organization of viral envelopes may also provide insights into the organization and dynamics of cell membranes.

Treatment of HIV infection is based on combinations of antiviral drugs.To identify the optimal drug combination for each patient, develop computational methods based on the genetic composition of the virus population of the patient.Predict the probability that the virus will develop escape mutations that would result in drug resistance and eventually in treatment failure.This personalized medicine approach allows for defining drug combinations that are optimized for each individual patient.In order to estimate the genetic composition of an intra-​​host virus population, we have developed several computational approaches for the analysis of ultra-​​deep sequencing data. This challenging task, known as the viral quasispecies assembly problem, involves the assembly of all sequencing reads into an unknown number of unknown viral haplotype sequences.In order to make ultra-​deep sequencing of virus populations accessible to a broad range of biomedical users, we develop and actively maintain V-​pipe, a bioinformatics pipeline for the analysis of viral high-​throughput sequencing data. V-​pipe supports the reproducible analysis of genomic diversity in intra-​host virus populations, which is involved in viral pathogenesis and virulence, and enables diagnostic applications.