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    Team: Mucosal entry of HIV and mucosal immunity

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    Team leader


     Transcytosis

     

    The local mucosal immune system may interfere with several stages of HIV sexual transmission. Initial mucosal targets include epithelial cells that HIV-1 cross by transcytosis, mucosal dendritic cells that capture HIV-1  prior to access to submucosal CD4+ lymphocyte or dendritic cells.  Secretions of individuals remaining uninfected despite unprotected sex with HIV+ partners; i.e., Highly Exposed Sero-Negatives (HESN), contain S-IgA to HIV envelope, suggest that these S-IgA may be involved in protection and could be included in a microbicide formulation.

     

    Laboratory results

    To cross the rectal, gastro-intestinal or endocrevix mucosa, HIV-1 infected cells may interact with epithelial surface forming a virological synapse. This synaptic contact induces the polarized budding of viral particles that cross the epithelial layer by transcytosis, without cell infection. The transcytozed virus is then captured by submucosal cell, and infection can spread. In contrast, cell-free  HIV-1 is inneficient at crossing the mucosa. Secretory IgA (S-IgA) and polymeric IgA (P-IgA) directed to HIV envelope gp41 can inhibit one pathway of HIV entry across mucosa, i.e. transcytosis across an epithelial barrier. Neutralizing Igs recognize P1, a conserved peptide of gp41 that mediates HIV entry in epithelial cells as well as in mucosal dendritic cells prior transfer to CD4+T cells. These in vivo and our in vitro results point to the role of conserved epitopes of HIV envelope subunit gp41 in neutralisation of HIV mucosal transmission. Hence, P1 mucosal immunisation in mice induces P1-specific seric IgG and mucosal IgA neutralizing HIV transcytosis. To characterize mucosal monoclonalHIV-1 specific  IgA neutralizing HIV-1 infection and transcytosis, we have constructed an Fab IgA library from mucosal B cells  highly exposed but IgG seronegative individuals. These subject have neutralizing anti HIV-1 envelope IgA in there secretion. Such neutralizing IgA are one correlate to protection. Screening on various HIV envelope antigen has allowed the characterization of several neutralizing  monoclonal IgAs.

     

    Objectives

    1 -  Describe, at the cellular and molecular levels, the interaction of HIV with its initial mucosal targets; i.e. epithelial and dendritic cells, in order to define new viral determinants to be targeted by vaccines. Decipher P1 structure and antigenicity.

    2
    - Analyse mucosal Igs generated by mucosal immunisation with these determinants (Coll. with T. Mor/ CJ. Arntzen, Arizona State University, USA: P1 coupled to CTB, mouse model; Coll. with S. Fleury, Mymetics, USA: P1 coupled to virosomes, rhesus monkey model ).

    3 - Exploit the combinatorial mucosal IgA Fab library from HESN constructed by us to characterise neutralising monoclonal IgA. These could be included in microbicide formulation (EEC program ).

    4 - Establish new mucosal in vitro models (buccal mucosa and froreskin) containing epthelial and immunocompetent cells, closer to the in vivo situation in humans, - to test the antibody neutralisation potential against HIV-1 (Coll. C. Dezutter, Lyon, France).

     

    Perspectives

    Characterize neutralizing epitopes on HIV envelope glycoproteins, with a preference for conserved sites, which could be used to develop a mucosal anti-HIV vaccinal strategy. New directions will appear within the discussion group we have established on HIV mucosal infection and immunity.