September 2013

New Molecular Insights into how Hepatitis B Virus Marches Through the Human Cell

Tue, 10 September 13 06:08

Congratulations to Dr Neil Ferguson, who has had papers published in Nature Chemical Biology and in Proceedings of the National Academy of Sciences USA. Dr Ferguson’s team reported key molecular details of how the Hepatitis B virus recruits a human cell to replicate itself and establish, or maintain, viral infections.

Why is this important? Knowing the finer nuts and bolts of the viral machinery could provide the route towards new or more effective interventions.

Hepatitis B is a global problem, explains Ferguson, who was himself surprised at its extent when he started working in the area. “Around one-third of the planet has already had a Hepatitis B virus infection already in their life,” he says. “Normally you get an acute infection and, through poorly understood mechanisms, your immune system kicks in and you develop antibodies and lifelong immunity. However in 5 to 10 per cent of adults, and in 90 per cent of infants, chronic hepatitis B virus infections develop.”

Serious, chronic infections are linked with cancer, and treatment often requires a liver transplant. “There are some therapies available but they work only for a limited number of patients, have adverse side effects and cause viral resistance,” says Dr Ferguson, who is a Science Foundation Ireland Senior Stokes Lecturer and a Senior Lecturer in structural biology at UCD School of Medicine & Medical Science. “And what is hampering the discovery of new therapies is that is it hard to work out the molecular structure of the viral proteins, so it’s difficult to find new targets or optimise existing drugs to work better.”

To get a better handle on the key molecular events that drive the march of the Hepatitis B virus through the human cell, Dr Ferguson’s lab is taking its life cycle apart in stages. That includes looking at how the virus forms a structure called the capsid, which is like an outer protein shell around its genetic material. A pliable and deformable structure, the capsid is built from a single protein called HBc, and its shape plays an important role in determining how the capsid forms and ultimately how the virus matures within the cell.

"Until now we have not had enough structural information to understand how the capsids form," says Dr Ferguson. “But we worked out the HBc protein folding mechanism and found that it folds in pieces - it goes from unstructured to partially structured and then folded and then it can form capsids.”

Working with colleagues in the UK, his lab also worked out how point mutations, or changes in the sequence of the protein, can stop the normal process of capsid formation, as reported in PNAS. The capsid’s structural dynamics and assembly mechanism represent an ‘Achilles’ heel’ in the virus that could be exploited and blocked, according to Dr Ferguson. “If you target HBc functions, you hit lots of important virus functions all at once,” he says.

But he also has another protein in his sights. Once the capsid forms and the virus genome is mature, the virus typically adds on an outer ‘coat’ or envelope as the final stage prior to leaving human cells, and a key protein here is preS1. “It is a vital, multifunctional virus protein, and a key component of the viral envelope, and yet no marketed therapies exist that target its various molecular interactions,” says Dr Ferguson.

Together with colleagues in the UK and Trinity College Dublin, his lab analysed the preS1 protein. They mapped its interaction with a human protein - the first time this has been done at atomic resolution, according to Dr Ferguson - and found that the viral protein had areas that imperfectly mimicked human protein sequences.

“The viral preS1 domain seems to be copying human sequences in a way that allows it to do its job, to use the human machinery in the cell to build an outer envelope for the virus,” says Dr Ferguson of the results, which were reported in Nature Chemical Biology.

It’s a delicate balance, because if the virus were to completely hijack the human machinery and turn it over to viral replication, it would kill the host cell outright, he explains. And this is where Nature may have thrown us a bone. “The virus is mimicking the human proteins but it is not the same, thus you should be able to specifically target the virus protein interaction(s) and not the human one,” says Dr Ferguson.

His lab is now continuing to tease out the structural biology of the Hepatitis B virus life cycle, and he anticipates that having this deeper understanding at the molecular level will enable new and smarter approaches to therapies. 

“The value of what we are doing is potentially very high,” he says. “And while we already interact with a number of companies on developing novel methodologies to look at - or perturb - important molecular interactions, the logical next step would be to spin out a company from the lab to help accelerate our discoveries towards having a clinical impact.”

In conversation with Claire O'Connell