Potency of Hepatitis B Virus Traced to ‘Grappling Hooks’ Virus Acquires as It Matures
A discovery of the process by which the hepatitis B virus matures inside the body helps to explain why the virus is much more potent that others in causing infection, and how it so effectively targets the liver.
The findings, published in the journal Cell Host & Microbe, also provide new avenues for drug development approaches that target the process — offering hope to chronic hepatitis patients.
Scientists have long known that the hepatitis B virus infects only liver cells, despite the fact that the molecule — heparan sulfate proteoglycans, or HSPG — needed for the virus to dock to cells is present on virtually all cell types.
“For a virus which has to reach a target organ in far distance from the transmission site, HSPG seemed to be the most disadvantageous attachment receptors one could imagine,” the study’s lead author, Dr. Stefan Seitz, said in a press release. The virus’ virulence — it is much more effective in causing infections than most other animal viruses —and its selective docking receptors have long confused scientists.
A clue to solving this mystery came in earlier studies showing that the virus is present in two forms in the body, with rather different looks. Also, a protein present in the viral envelope — the structure encapsulating a virus — can adopt two different 3-D structures. In one structure, the part of the protein needed for binding to the HSPG receptor is pointing inward; in the other, it is exposed on the outside.
Linking the two findings, Dr. Seitz and his colleagues at the German Cancer Research Center and Heidelberg University Hospital hypothesized that the virus can be present in two different states, which determine its ability to cause disease.
Researchers developed a method, described in the study “A Slow Maturation Process Renders Hepatitis B Virus Infectious,” capable of distinguishing between the viral particles able to bind to HSPG, which they referred to as the B-type, and those too immature to bind, which they called the N-type.
Tracking its life cycle, the team discovered that the virus is released from cells as N-type particles. Over time, these viral particles mature into the B-type by turning their binding protein outward, so it is exposed on each particle’s surface.
The team also reported that mice injected with low numbers of virus particles, mostly B-types, rarely developed infection because the mature particles were essentially more sticky, binding to cell types other than those of the liver. But the N-type viruses effectively caused liver infection. Scientists believe that slow virus maturation is a key step in making the virus so infectious.
“In the immature N-type state, the viral particles are inert and hence can cycle in the bloodstream continuously until they once reach the liver where they finally will be trapped. Conversion into mature particles afterward will lead to a productive infection,” Professor Ralf Bartenschlager, the study’s senior author, said.
“It is a novel and highly elegant paradigm for a viral maturation mechanism that differs fundamentally from all previously described viral maturation mechanisms,” he added. “Our study also shows that hepatitis B virus particles are not stiff and static objects, but highly dynamic nanomachines with a precisely running stochastic clockwork. Literally, they are little ticking time bombs which suddenly shoot out molecular grappling hooks.”
More importantly, the findings might open up for new ways of treating hepatitis B infection. “It offers the possibility to develop inhibitors of the maturation mechanism that lead to a “lock-in” or “freezing” of hepatitis B particles in the immature, non-infectious state. Such inhibitors could be used to support therapy of chronic hepatitis B which is still incurable and represents a leading cause of cancer in mankind,” said Dr. Seitz.
Exploring the exact mechanism controlling this viral switch, as well as searching for drugs that might block it, is what the research group is now focusing on. “Obviously, breaking chronicity of hepatitis B infection and eradicating the virus would reduce the risk of infected individuals to develop hepatocellular carcinoma,” Dr. Bartenschlager concluded.