Characterization of HIV-1 IgA bNAbs and ADCP function - 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.
