Community Research and Development Information Service - CORDIS


HumAntiViruses Report Summary

Project ID: 337146
Funded under: FP7-IDEAS-ERC
Country: France

Mid-Term Report Summary - HUMANTIVIRUSES (Human Antibody Responses to Viruses)

“Humoral memory” is composed of high affinity antibodies that mediate long-lived immunity against infectious agents, e.g., by providing protection against re-infection. The molecular dissection of anti-pathogen B-cell responses using modern technologies to generate and characterize antigen-specific human monoclonal antibodies has allowed breakthrough discoveries in antiviral responses to viruses such as Influenza virus and HIV-1. These recombinant antibodies represent unique “fingerprints” for each B-cell clone and when characterized at a molecular and functional level, provide crucial information about the humoral response to a given pathogen. Moreover, in addition to the antibodies’ potential therapeutic interest, it has now become evident that studying the biology of neutralizing antibodies is also pivotal in designing candidate immunogens for vaccine development.
Our research aims to study the molecular basis of antibody B-cell responses to viruses such as HIV-1, and how anti-viral antibodies may participate in controlling the infection in humans. Using cutting-edge technologies including single-cell capture and cloning of human monoclonals, we are currently investigating the memory B-cell responses to HIV-1 at the peripheral and mucosal level in individuals who developed extremely potent and broad neutralizing HIV-1 antibodies (bNAbs), this in trying to understand how these rare antibodies develop. To get insights on how these bNAbs work, we characterized some of their various antiviral properties such as their inhibitory activity against the passage of HIV-1 through epithelial cells of the mucosal tissues (called transcytosis), as well as their antiviral functions known as effector functions. Indeed, we recently showed that bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, and published that some of them can efficiently exert antibody-dependent cellular cytotoxicity (ADCC) in cell culture and kill HIV-1 infected lymphocytes through NK engagement. In addition, we are also trying to dissect the molecular and structural mechanisms responsible for their broad neutralizing activity against divergent HIV-1 strains. A substantial part of our research investigations also use this research strategy and methodology to study B-cell antibody responses to other viral pathogens, particularly those responsible for emerging infections with one project on Chikungunya virus. To this regard, we have isolated and characterize the first CHIKV-specific IgG+ memory B cells. Most of the anti-CHIKV antibodies that we produced have been mapped using our collection of mutant and truncated proteins, and tested for viral neutralization. Importantly, most of the antibodies we generated could neutralize the La Réunion virus, and one third of those were highly potent with neutralization vales (IC50s) below 50 ng/ml. Finally, we recently characterized for the first time the IgA memory B-cell antibodies in healthy humans. Our published findings show that that IgA+ and IgG+ memory B-cell antibodies cloned from the same healthy humans share common immunoglobulin gene features. IgA and IgG memory antibodies have comparable lack of reactivity to vaccines, common mucosa-tropic viruses and commensal bacteria. However, the IgA+ memory B-cell compartment contains fewer polyreactive clones and importantly, only rare self-reactive clones compared to IgG+ memory B cells. Self-reactivity of IgAs is acquired following B-cell affinity maturation but not antibody class switching. Together, these data suggest the existence of different regulatory mechanisms for removing autoreactive clones from the IgG+ and IgA+ memory B-cell repertoires.

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