Suzanne Lazaroo
29 July 2024: Their sights set on defeating the deadly chronic viral infection, the PÕ¾ÊÓƵ’s Associate Professor Xiaonan Zhang and his team have created an assessment model to solve some of the mysteries of Hepatitis B – and help them develop novel therapies in the search for a cure.
Hepatitis B carries with it a huge burden of disease – 300 million people worldwide are chronically infected with the Hepatitis B virus (HBV) which causes inflammation of the liver, and one million people die from it every year.
It’s particularly dangerous because people infected with Hepatitis B can be unaware of it for years, and spread it via infected blood and sexual transmission.
“One of the things we don’t understand yet is why some people get an acute Hepatitis B infection – which their immune system then clears, so that they recover – while others suffer from the chronic variety,” Professor Zhang said.
Professor Zhang was a molecular biologist working on the molecular underpinnings of HBV persistence at Fudan University in Shanghai, China; in 2021, he moved here to join the University's Faculty of Science and Technology.
His move to Canberra sparked a corresponding shift in perspective – Professor Zhang’s focus is now on immunobiology, as he works to understand how a host’s immune system can overcome viral persistence.
His work is funded by a Discovery Translation Fund (DTF) supported by the University; along with funding from the Australian Centre for HIV and Hepatitis Virology Research (ACH4) and National Health and Medical Research Council (NHMRC).
“The ability of a host’s immune system to overcome the persistence of the virus depends on whether the immune system can be reinvigorated,” Professor Zhang said.
“This is a choking point in HBV research – current drugs and therapies fall short because we still lack a fundamental understanding of why some patients get chronic infections, and others are able to recover.
“We need to understand the key molecular switches at work. Without that understanding, searching for a cure is like going into a dark room blindfolded, and feeling around blindly for the switches.”
The lack of a small animal model that can accurately replicate both chronic infection and recovery scenarios has been the main impediment to this understanding.
“HBV has a very strict tropism [the ability to infect an organism] and can’t naturally infect lab mice,” Professor Zhang says.
His answer has been to come up with a surrogate model, generating a recombinant adeno-associated virus engineered to encode the HBV genome – a virus vector that works like a Trojan horse.
“It’s very reliable, robust and consistently repeatable, and importantly, enables us to model the two different outcomes – life-long persistence, and infections which can be cleared within three weeks,” he said. In this way, the team can assess what is driving these outcomes – and answer key scientific questions, like how and why the immune system allows a chronic infection to persist.
“And why some patients mount an immune defence and overcome the virus, while others don’t,” Professor Zhang said.
In the last year, Professor Zhang and his team used the adeno-associated virus system with different HBV strains, and have come upon unique variants of the virus that have generated strikingly different traits.
“These outcomes have been rigorous enough to address some of the most important questions, and while we build this understanding we will then be able to work on and assess novel therapies for the disease … and develop a cure,” he said.
But why look for a cure, when there is an existing vaccine?
Epidemiological projections have shown that while the prophylactic vaccine helps, it isn’t enough, says Professor Zhang – because it generates a variable antibody response, it won’t work for everybody.
Plus, vertical transmissions occur from mother to child at birth – these can be mitigated by medical interventions, but under lower socioeconomic conditions in certain countries, this isn’t always possible. And HBV infection for a baby generally leads to a persistent lifelong infection.
“This model is the missing piece of the puzzle, which will allow us to simultaneously work on contributing to a fundamental understanding of HBV infection and the applied work of designing novel therapeutic vaccines,” Professor Zhang said.