Final Report Summary - HUMANTIVIRUSES (Human Antibody Responses to Viruses)
The humoral arm of the immune system relies on the remarkable variety of immunoglobulin molecules (or antibodies) expressed as receptors on B cells or secreted in body fluids, which ensure the recognition of a theoretically infinite number of foreign antigens. Adaptive immune responses naturally occurring upon infection or induced by vaccination generate high affinity antibodies to culprit antigens, and memory B-cell subsets to respond to further antigenic challenges, providing protection against infections and re-infections. Our research has focused on understanding the mechanisms governing human antibody memory B-cell response to viral pathogens, and to make use of these findings to develop therapeutic strategies. Using cutting-edge technologies including single-cell capture, cloning and detailed characterization of human anti-viral monoclonals, we investigated the memory B-cell responses to HIV-1, Chikungunya and Hepatitis viruses in the blood and tissues of pathogens-exposed humans. Overall, our studies show that antibody memory B-cell responses to distinct viruses differ in terms of magnitude, and diversity of the immunoglobulin repertoire, targeted epitopes and antiviral activities. We found that the humoral response to HIV-1 differs between blood and mucosal compartments, and that exacerbated virus-escape driven maturation can lead to devolution of B-cell lineages by loss-of-function mutations. We could delineate the molecular parameters controlling ADCC activity of HIV-1 broadly neutralizing antibodies (bNAbs), and demonstrate that bNAbs could protect mucosal tissues by neutralizing transcytosed virions crossing mucosa epithelium. Moreover, we discovered that the conformational plasticity of bNAbs’ antigen-binding sites could facilitate binding to HIV-1 variants and but also promote polyreactivity to topologically distinct non-HIV-1 molecules. Antibodies we generated from individuals remitted from CHIKV infection were found to be, for most of them, diverse in terms of gene repertoire and targeted epitopes, and potent neutralizers with some able to decrease viraemia in vivo. These data provide solid proofs for a key role of antibodies in clearing infection, and of CHIKV-specific memory B cells expressing those antibodies to confer protection against re-infection.