Characterization of HIV-1 IgA bNAbs and ADCP function

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PROJECT SUMMARY HIV-1 spreads mainly through mucosal exposures. Dominant in mucosal secretions, IgA has long been the class of antibodies desired at the portal of entrance to block infection. However, due to a paucity of IgA responses to HIV-1, as compared to IgG, previous antibody isolation efforts and antibody repertoire analyses have focused on IgG+ B cells and missed IgA+ B cells. With a novel vesicular stomatitis virus (VSV)-based platform, we were able to display the membrane-embedded HIV-1 envelope (Env) trimer on the surface, use it to probe Env-specific memory B cells, and isolate HIV-1 broadly neutralizing antibodies (bNAbs) from infected individuals. During this process, we included the IgA transcripts in antibody repertoire analyses and identified two HIV-1 bNAb lineages that class-switched to both IgG and IgA, thus for the first time identified IgA bNAbs produced during the course of HIV-1 natural infection. Additionally, we have isolated two HIV-1 Env-directed IgA monoclonal antibodies (mAbs) that exhibited partial virus neutralization capability; these IgAs also mediated potent antibody-dependent cellular phagocytosis (ADCP) function to eliminate HIV-1-infected cells. Supported by these scientific premises, we propose in this application to identify additional HIV-1 IgA bNAbs and ADCP IgA mAbs from clade-B and non-clade-B infected individuals, including those followed longitudinally (Aim 1), and then characterize the IgA target epitopes on HIV-1 Env (Aim 2), and test a representative IgA bNAb and ADCP IgA for protection efficacy in rhesus macaque SHIV mucosal challenge model (Aim 3). We aim to test the hypothesis that 1) significant IgA bNAbs and ADCP responses are elicited during HIV-1 infection; 2) IgA bNAbs and ADCP IgAs may target novel sites of vulnerability on HIV-1 Env; 3) an IgA bNAb is comparable to or better than its IgG bNAb counterpart at protection against SHIV mucosal challenge, and an ADCP IgA may also protect macaques from SHIV mucosal challenge. If successful, the project will unveil and validate the potential antiviral functions of IgA to fight against HIV-1.