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Computer Simulations Offering New Insights Into Drug-Resistant Viruses

NS5B.jpg

Joshua Hollett

GTP molecule and Sofosbuvir complexed with RNA-dependent RNA-polymerase of hepatitis C virus, NS5B.

Spotlight On:

Joshua Hollett
The University of Winnipeg
Department of Chemistry

Every year, more than 1.5 million deaths globally result from two viruses: human immunodeficiency virus (HIV)-related causes and Hepatitis C Virus (HCV) infections. While cures for these two viruses remain elusive, key research into potential HIV and HCV vaccines and drug development has the potential to impact the treatment of other viruses as well.

At The University of Winnipeg, Joshua Hollett, an Assistant Professor in the Department of Chemistry, is leveraging Compute Canada’s advanced research computing resources to better understand the role of viral mutation in the treatment of HIV and HCV. His research team’s ultimate goal is to develop an efficient tool for the prediction of viral drug resistance.

“The development of treatments for devastating diseases such as AIDS and hepatitis C is deeply rooted in understanding the complex interactions between viruses and the immune system,” says Hollett. “Much can be learned about these interactions by studying viruses such as HIV and HCV and cells of the immune system at the molecular level. The proteins involved in virus replication, T-cell recognition, and drug interactions can all be modeled computationally to shed light on this important biological problem.”

For example, past research has shown the effectiveness of HIV relies substantially on its ability to enter and exit the host T-cell. Therefore, it is expected that significant advances in HIV treatment can be made by focusing on the interaction of the viral envelope with the T-cell co-receptor. This interaction is dominated by the interaction between the CD4 protein of the T-cell and the gp120 envelope protein of HIV. Recent studies have shown that mutation of the CD4 sequence leads to increased susceptibility to HIV infection.

Hollett’s research uses computationally-intensive molecular dynamics (MD) simulations to understand the key interactions of CD4/gp120 binding and determine the influence (if any) of the reported CD4 mutation. Knowledge gained concerning the structure of these proteins and their interaction will provide insight for both vaccine development and small molecule treatment of the virus.

HCV has also shown itself to be particularly prone to genetic mutation. In fact, the emergence of drug resistant mutations during treatment is a significant challenge to the development of new drugs against HCV. In this case, MD simulations are used to determine the relative binding energies of natural substrates and small molecule inhibitors of a hepatitis C viral enzyme.

These kinds of studies require massive computing power, often parallel computations using 35-150 processors at once, along with large amounts of memory. This is where access to WestGrid and Compute Canada resources is essential for Hollett.

“As a research group at smaller Canadian university, the independent creation and maintenance of the facilities required for our work is just not feasible,” says Hollett. “Hence, the resources provided by WestGrid and Compute Canada are vital to our research.”

Through Compute Canada’s Resource Allocation Competition, Hollett and his team have been using WestGrid’s Jasper and Lattice systems to complete much of his simulation work.

“Our work entails the use of a wide range of molecular modelling techniques,” says Hollett. “The ultimate goal is to develop a predictive tool to guide experimental development and drug treatments.”

While Hollett’s current work is focused mainly on HIV and HCV, he says results from his studies could prove invaluable for the development of drugs against any virus.