Under the supervision of Daniela Tudor and Morgane Bomsel, team Mucosal entry of HIV and mucosal immunity
The mucosae are epithelia that form a surface for interaction with the external environment and protect the organism from infections resulting from this interaction. We have developed antiviral approaches targeting the virus or the host, against HIV-1 and SARS-CoV-2 respectively.
CD8+ T response directed against HIV-1 is associated with the protection and control of HIV-1 infection. However, the mechanisms of induction of this HIV-specific CD8+ T response remain poorly characterized. Recently, the infusion of broadly neutralizing antibodies (bNAbs) has led to the induction of a protective CD8+ T response against HIV, independent of neutralizing activity. This suggests a role for FcR-mediated signaling and phagocytosis (ADCP) in the induction of an IgG antibody-dependent CD8+ T response. However, no study has documented the impact of IgA-formatted bNAb on the induction of CD8+ T-mediated protection, despite the fact that CD8+ T-mediated protection predominates in mucosal tissues.
Using the gp41-specific bNAb 2F5 as a model, in IgG (2F5-IgG) and IgA (2F5-IgA) form, we have shown that 2F5-IgA induces phagocytosis (ADCP) of HIV-infected cells more efficiently than IgG isotype. We hypothesized that increased phagocytosis by anti-gp41 IgA would favor the presentation of viral antigens to HIV-specific CD8+ T cells. In a co-culture model with CD8+ T cells from infected patients, we were able to show that only 2F5-IgA increased the activation of HIV-1-specific CD8+ T cells. Precise characterization of the fate of the effector monocyte using RNA-seq and flow cytometry enabled us to show that the functions induced by the Fc part of IgA promote the differentiation of effector monocytes into macrophages. The latter acquire a mixed profile, which enables them to undergo immune training. Furthermore, chemokines secreted by monocytes after ADCP promote the recruitment of neutrophils, monocytes and CD8+ T cells, which are associated with infection control in humans. Our work proposes a new mechanism of antibody protection by phagocytosis of infected whole cells as an antigenic source and activating the recruitment of protective immune cells. In particular, these results suggest that an IgA response directed against HIV-1 could lead to the implementation of mechanisms resulting from cooperation between effectors of innate and adaptive immunity, reinforcing mucosal protective immunity.
SARS-CoV-2 emerged in 2019 and was rapidly responsible for a global pandemic for which no therapeutic approach could be effectively implemented. The viral cycle proceeds by altering lipid metabolism by promoting the accumulation of lipid droplets, but also by parasitizing the autophagy pathway by inhibiting the fusion of autophagosomes with lysosomes. Activation of AMP-activated protein kinase, or AMPK, is chemically possible and we set out to determine the antiviral potential of a specific agonist, MK-8722.
We showed in vitro that the drug has a strong antiviral potential that is not associated with the death of infected cells, nor with an alteration in viral entry, but rather with a restoration of lipid metabolism and the completion of autophagic flux. This inhibition was verified after post-infection treatment and resulted in a restoration of the interferon response, essential for the control of SARS-CoV-2 pathology. Our results suggest a new class of antiviral molecules for viral infections dependent on altered lipid metabolism and autophagy, such as other emerging coronaviruses, or arboviruses such as Dengue and Yellow Fever viruses.
Key words : IgA – ADCP – CD8 T Lymphocyte – HIV – SARS-CoV-2 – Antiviral – AMPK – lipids – autophagy