INSERM: An international collaboration led by Professor Thomas
Baumert (Inserm/University of Strasbourg Joint Research Unit 1110,
“Institute for Viral and Liver Disease”) has shown that a monoclonal
antibody directed specifically against claudin-1, a liver protein
essential for infection by the hepatitis C virus (HCV), enables the
prevention and treatment of chronic infection by this virus in an animal
model. It turns out that this antibody, which was known to inhibit HCV
entry and thereby prevent the initiation of infection, can also
eliminate infected cells. This discovery, published in a letter in the
Nature Biotechnology
issue of 23 March 2015, opens the way to developing an approach to
hepatitis C that is not only preventive, but therapeutic as well.
Infection with hepatitis C virus (HCV) leads to
cirrhosis of the liver and liver cancer,
the second leading cause of cancer death in the world. These
complications are major indications for liver transplantation, but HCV
reinfection of the transplant is a challenge.
To date there is no vaccine,
and the new treatments developed recently can be accessed by only a
minority of patients worldwide because of their high cost. The
development of new preventive and therapeutic strategies therefore
continues.
The team directed by Prof. Thomas Baumert (Inserm/University of
Strasbourg Joint Research Unit 1110, “Institute for Viral and Liver
Disease”), in collaboration with international teams, decided to target a
liver protein essential for viral infection instead of targeting the
virus. They chose claudin-1, a molecule that is important in the initial
steps of HCV infection, and involved in cell-cell contacts.
Using mouse models with humanised liver, the researchers show that a
monoclonal antibody directed against claudin-1 can prevent HCV infection
by blocking the entry of the virus into liver cells. Surprisingly, the
researchers also observed that this antibody enables the treatment of
chronic HCV infection by inhibiting the activation of intracellular
signalling pathways needed by the virus for survival. As a result, the
infected cells disappear and are gradually replaced by uninfected cells.
The advantage of this strategy is that it does not need to be combined with an antiviral agent.
Moreover,
by using different viral strains, the researchers show that it is
difficult for the virus to escape from this antibody and develop
resistance.
“Claudin-1” is a protein that is usually localised in the tight
junctions that are the points of contact between adjacent cells. It is
interesting to note that tight junction proteins constitute receptors
for other pathogens, such as dengue virus and
Shigella species.
This innovative approach, employing injection of a monoclonal antibody
directed against a protein on the host cell, makes it possible to
foresee the development of a vaccine strategy and new therapeutic
approaches against HCV, and also against other pathogens that use
similar infection mechanisms.
