OA25.03
Background: The partially successful RV144 vaccine trial produced non-neutralizing antibodies that mediate ADCC against HIV-1. These antibodies recognize the CD4-induced (CD4i) C1 region of gp120. However, such findings are enigmatic in view of previous arguments that CD4i epitopes are hidden on viral trimers before, and during interaction with host cell. It is therefore critical to understand the antigenicity of these conserved epitopes that become exposed during productive viral replication, to provide important guidance for designing antiviral strategies such as vaccines to raise protective antibody responses.
Methods: We studied the antigenicity of conserved epitopes by visualizing their exposure on single HIVJRFL virus particles as they interact with target TZM-bl cells using confocal microscopy. Epitope exposure was probed by visualizing the binding of neutralizing antibodies b12 and 2G12, and CD4i antibodies A32, 17b and C11.
To reconcile the question of CD4i antigenicity, we examined the location of CD4i antibody attachment with 20nm precision using superresolution microscopy.
Results: CD4i antibodies can access their cognate epitopes on TZM-bl cell-bound HIVJRFL virions. Patterns of exposure varied with antibody; however, in general the level of CD4i exposure was similar to neutralizing epitopes b12 and 2G12. CD4i epitopes appear distal to the virus-cell contact site, where they can be accessed by antibodies involved in ADCC.
Conclusions: The patterns of CD4i epitope exposure are consistent with the ADCC activities of cognate antibodies against bound virions. CD4i antibodies were able to gain access to their targets due to the unexpected epitope exposure on gp120, distal to the site of contact with cell surface CD4. These findings indicate that HIV-1 exhibits a diversity of epitope exposure upon attachment that may provide unique insights for understanding how humoral immunity impacts HIV infection.
