Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection

An Interplay between Hypervariable Region 1 of the Hepatitis C Virus E2 Glycoprotein, the Scavenger Receptor BI, and High-Density Lipoprotein Promotes both Enhancement of Infection and Protection against Neutralizing Antibodies

Hepatitis C virus (HCV) circulates in the bloodstream in different forms, including complexes with immunoglobulins and/or lipoproteins. To address the significance of such associations, we produced or treated HCV pseudoparticles (HCVpp), a valid model of HCV cell entry and its inhibition, with naïve or patient-derived sera. We demonstrate that infection of hepatocarcinoma cells by HCVpp is increased more than 10-fold by human serum factors, of which high-density lipoprotein (HDL) is a major component. Infection enhancement requires scavenger receptor BI, a molecule known to mediate HDL uptake into cells as well as HCVpp entry, and involves conserved amino acid positions in hypervariable region 1 (HVR1) of the E2 glycoprotein. Additionally, we show that the interaction with human serum or HDL, but not with low-density lipoprotein, leads to the protection of HCVpp from neutralizing antibodies, including monoclonal antibodies and antibodies present in patient sera. Finally, the deletion or mutation of HVR1 in HCVpp abolishes infection enhancement and leads to increased sensitivity to neutralizing antibodies/sera compared to that of parental HCVpp. Altogether, these results assign to HVR1 new roles which are complementary in helping HCV to survive within its host. Besides immune escape by mutation, HRV1 can mediate the enhancement of cell entry and the protection of virions from neutralizing antibodies. By preserving a balance between these functions, HVR1 may be essential for the viral persistence of HCV

A transition support system to build decarbonization scenarios in the academic community

International audienceA growing portion of scientists realises the need to not only alert about climate change, but also change their professional practices. A range of tools have emerged to promote more sustainable activities, yet many scientists struggle to go beyond simple awareness-raising to create concrete transition actions. Here we propose a game-based transition support system MaTerre180’ , which has been designed to build scenarios of greenhouse gas (GHG) emission reductions in the academic community. After providing a common scientific background about the context (global warming issue, its causes and consequences) and setting up a challenge (50% reduction of carbon budget by 2030), the participants belonging to the academic community and its governance bodies immerse themselves into fictional characters, to simulate the behaviour of real research groups. The game has been deployed during the year 2021, with six hundred participants from nine countries and 50 cities. Results explore clear pathways for GHG reductions between 25 and 60%, and a median reduction of 46%. The alternatives allowing the greatest reduction are video communication tools (36%), followed by mutualization of professional activities and voluntary cancellation or reduction, that represent 22 and 14% of reduction, respectively. The remaining 28% of reduction consists of transport alternative, relocation of professional activities, extended duration of some travels, etc. In addition, the analyses pointed out the importance of the guided negotiation phase to bring out some alternatives such as relocation, local partners and computing optimization. An added value of this transition support system is that the information it collects (anonymously) will be used to answer pressing research questions in climate change science and environmental psychology regarding the use of serious games for promoting changes in attitudes and behaviours towards sustainability, and including broader questions on how network structures influence “climate behaviour”, knowledge and the governance of the commons. Modestly, MaTerre180’ offers an innovative game-based transition support system to build scenarios of greenhouse gas (GHG) emission reductions in the academic community. It is not simply a question of moving tokens on a virtual gameboard and a playful adjustment of practices, but rather a question of brainstorming about possible and desirable ways of remodelling research and teaching communities and embracing a new paradigm. After tens of workshops, our results show clear pathways for reaching up to 50% GHG reductions and stress the importance of guided negotiations to bring out alternatives to carbonized activities. This first attempt reinforces our belief that scientific engagement is at the heart of the international development agenda and a key approach to tear down the institutional barriers that inhibit the transformation needed to achieve a more sustainable society