Life Sciences Division

Despite the major advances achieved in the control of HIV, the infection still causes millions of deaths each year. The search for new cellular targets for novel antiviral therapies remains an important challenge.

Researchers at the Institute of Structural Biology (1) have been working on a receptor called DC-SIGN which is found on the surface of dendritic cells: immune cells that are present in contact zones with the exterior, such as the skin or mucous membranes, and the first sites to encounter pathogens. DC-SIGN is involved in the initial phases of HIV infection, and constitutes a potential therapeutic target that has not yet been exploited.

What role does DC-SIGN play? DC-SIGN normally captures pathogens by recognizing certain characteristic oligosaccharides present on their surface. The pathogens are then internalized by dendritic cells which break them down and display the fragments at their surface. These cells then move to lymphoid tissues where they trigger the body’s immune response, i.e. the production of T-lymphocytes that can fight the pathogen. HIV, though, uses DC-SIGN to travel – intact – as far as the T-lymphocytes it will then infect. Importantly, it attacks CD4+ T-lymphocytes (carrying a molecule called CD4 that is HIV-sensitive), which are the main target that the virus uses to spread.

The research team has engineered a compound capable of inhibiting the process by which HIV is transmitted to CD4+ T-lymphocytes. This tetravalent compound, endowed with four functional groups that mimic the oligosaccharides carried by pathogens, is recognized by DC-SIGN, thus preventing HIV from using the receptor to travel to the lymphoid tissues. It has some particularly useful properties, including high solubility in physiological media, negligible cytotoxicity (2), and a long-lasting effect (even after washing the cells, the blocker effect can continue for several hours). Furthermore, the compound has a simple-enough structure that makes it an ideal candidate for large-scale industrial production.

One final but important point is that there are other pathogens that also use DC-SIGN to circumvent the immune system. The compound developed by the research team could also be used to inhibit infection by hepatitis C, dengue, Ebola and SARS (3) viruses, by the Mycobacterium tuberculosis bacterium (which causes tuberculosis), and a number of parasites. In fact, it may even prove more effective in these cases than with VIH. This compound could therefore be added to the list of antiviral glycomimetics, compounds designed on the basis of oside structures found in nature, such as Tamiflu which is used to control seasonal influenza.

Its efficacy in preventing cell-cell transmission of HIV has been proven in vitro, and the researchers have moved to protect their compound with a patent filed jointly by the CNRS and Joseph Fourrier University. Next step: tests in animal models. In the meantime, until they find a partner or set up their own structure for managing these activities, the team is continuing to enhance the efficacy of their compound to render it more specific to DC-SIGN and increase its interactivity with this receptor.

(1) In collaboration with Italian and Spanish researchers under the European CARMUSYS network project.
(2) Toxic to cells
(3) Severe acute respiratory syndrome