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HBV: seroconversion does not improve T cell responses

The research group led by Matteo Iannacone, head of the Dynamics of Immune Responses Unit at IRCCS Ospedale San Raffaele, in collaboration with Luca Guidotti and Gilead Sciences, showed for the first time that HBV antigen clearance does not improve T cells responses in an experimental model of chronic hepatitis B.

Since patients who undergo seroconversion – defined as the antibody-mediated clearance of hepatitis B surface antigen from blood circulation – are the ones with better outcomes, scientists thought the event may be able to trigger T cells responsiveness to the virus.

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Unfortunately, the results just published in the Journal of Experimental Medicine suggests that seroconversion alone – either spontaneous or mediated by antibody therapy – has minimal effects on T cell responses.

The study could have significant clinical implications, since monoclonal antibodies for chronic HBV infection are currently being tested in humans in phase I clinical trials.

 

The role of circulating antigens in HBV infection

Hepatitis B surface antigen, besides being present on the surface of the virion, is found in the circulation in the form of noninfectious spheres and filaments in exceptional quantities.

Detectable antigen in the blood is a hallmark of persistent HBV infection and, conversely, sustained serum antigen loss (seroconversion) is a widely accepted marker of therapeutic success.

In fact, for the virus, producing circulating antigens could serve as a way of keeping neutralizing antibodies occupied, away from the actual virions within the liver. Moreover, circulating antigens are thought not only to have a negative impact on B cell responses, but also to delete or functionally impair T cells.

 

Correlation, not causation

This hypothesis is supported by the observation that seroconversion is associated with an increase in the quality and vigor of HBV-specific T cell responses.

“But whether these T cell responses are actively unleashed by the antigen loss or whether antigen loss is simply a consequence of such responses is currently unknown. A causative link between antigen level and the impairment of the immune system has not been established,” explains Matteo Iannacone. “That's why we simulated what happens during seroconversion in an experimental model of the disease”

The researchers addressed this issue by using HBV replication-competent transgenic mice that are depleted of circulating HBV surface antigen via either spontaneous seroconversion or therapeutic monoclonal antibodies.

“Surprisingly, we found that serum clearance of the antigen has only a minimal effect on the expansion of HBV-specific T cells. Therefore, in our experiment, seroconversion does not produce an immune response capable of exerting a therapeutic effect” concludes Iannacone.

It is therefore still unclear why the immune response is activated during the seroconversion process and further studies are needed. But the results obtained so far should inform clinical studies on monoclonal antibodies against HBV surface antigen: they could be less effective than previously thought. However, Iannacone maintains that such monoclonal antibodies “might still have the benefit of preventing the infection of new hepatocytes, significantly reducing viral load”.