Researchers Identify Mechanism That May Lead to Age Disparity in Chronic HBV

Jody L. Baron, MD, PhD

A new study has identified a key pathway that may help explain why one’s ability to clear a hepatitis B virus (HBV) infection appears to improve with age.

A team of researchers led by scientists at the University of California, San Francisco (UCSF), collaborated to try and unpack the process of HBV clearance and distinguish the mechanisms that lead to the age disparity, using mouse models and samples from humans.

The research led them to the costimulatory molecule OX40, which regulates the activation of T cells. They found the expression of the OX40 ligand (OX40L) occurs at higher rates in older patients. The team found that treating infected cells with OX40 agonists led to better clearance of HBV antigens.

Jody L. Baron, MD, PhD, an associate professor of medicine at UCSF, told Contagion^® she and her team have been working for a long time to figure out what it is within the body’s immune response that determines whether a patient is able to clear HBV before it becomes a chronic problem.

“Our previous work using our mouse model of HBV clearance and persistence, and supported by our correlative studies in humans, demonstrated that immune priming to HBV occurs in the liver,” she said, “and strongly implicated the competency of immune priming within the hepatic microenvironment as a pivotal factor that guides HBV-specific T cell diversity, HBsAb seroconversion and HBsAg clearance.”

This work suggested that hepatic immune priming is less effective in younger mice and humans, the same groups that seem to have more difficulty clearing the virus.

“For this reason, we embarked on studies to identify molecules on hepatic antigen presenting cells that are expressed in an age-dependent manner, that might contribute to effective immune priming to HBV,” she said. “OX40L expression came out of this analysis.”

The findings should help guide researchers working to develop treatments for HBV, the chronic form of which can lead to cirrhosis and cancer.

“The greatest clinical need right now is new effective therapies for the 350 million people current chronically infected with HBV,” she said. “The patient population is largely derived from individuals who were infected as infants and children. Thus the ineffective immune response primed at the time of infection is likely still present in these chronically infected adults.”

Baron said the focus of her research now is to try to find ways to “effectively tilt immune responses either towards viral clearance or away from immune-mediated liver injury in chronically infected adults.”

This new study suggested that manipulating OX40/OX40L expression on CD4+ T cells might allow for clearance of the virus, even in patients who contracted the virus before immune priming.

“We are working on ways to target the OX40/OX40L pathway in chronic HBV, and testing its therapeutic potential both alone and in conjunction with modulation of other immune pathways that we and others have identified to be important in developing effective HBV immunity,” she said.