An innate immune response mechanism could protect against HIV-1 infection… if it was not immediately thwarted by the virus itself. This is what Jean-Luc Perfettini’s research team has recently discovered.
Little is currently known about the mechanisms of innate immunity that move into action when the HIV-1 virus enters the body. Yet it is this response which can enable the virus to enter the target cells or – on the contrary – lead to its rejection. For the past few years, the team of Jean-Luc Perfettini* in Villejuif has devoted itself to describing these early stages of infection. In 2011, this research led them to publish an article showing that when the virus binds to a receptor present on the host cell surface, this activates the protein P2Y2 needed for the membrane fusion that enables the virus to enter. A discovery which had encouraged them to understand how P2Y2 is regulated, and to look for its partners. They have recently discovered one of those partners: protein NLRP3, which actually plays a decisive role in the infection.
NLRP3 was already known to scientists: it is implicated in inflammatory reactions, promoting the production of a pro-inflammatory cytokine. But it was Perfettini’s team that discovered its role of protection against HIV-1 infection. Various in vitro experiments have enabled the researchers to observe that P2Y2 and NLRP3 bind naturally to each other in the immune cells. As long as there is a large quantity of NLRP3, the virus is unable to enter the cell and remains blocked outside. NLRP3 prevents the remodeling of the cytoskeleton (structure that gives the cell its form and physical organization) needed for membranes to fuse and the virus to enter.
A novel protection mechanism, albeit bypassed by HIV-1
Unfortunately, HIV-1 knows a neat trick. When it activates P2Y2, a signaling pathway that leads to the degradation of NLRP3 is triggered. As such, the recognition of the host cell by the virus leads irremediably to a reduction in the quantity of NLRP3 and the disappearance of its protective effect. "NLRP3 controls infection with HIV-1 but the virus is able to thwart this protective mechanism and enter the host cell", resumes Perfettini. The researchers confirmed their findings using primary cultures of infected macrophages and lymphocytes, in addition to human and animal biopsies.
The team now hopes to take things further. "P2Y2 was already known, as was NLRP3. But this research is the first to establish the interaction between these proteins, with major consequences on innate response when faced with an infectious agent. It can be said that thanks to our research on HIV-1, we have described a new innate response mechanism. We will now look for the partners of this P2Y2/NLRP3 complex in order to try to modulate this interaction. At the same time we will also verify how this interaction is regulated in other physiological situations. This mechanism possibly has an influence on innate response when faced with other diseases, such as certain cancers or inflammatory diseases, for example", concludes Perfettini.
*unit 1030 Inserm/Université Paris-Sud/Gustave Roussy Institute, Molecular Radiotherapy, Villejuif