Broadly neutralising antibodies that are capable of blocking HIV-1 infection at the mucosal portal of viral entry are probably the most researched types of antibodies. Both IgG and IgA antibodies are present in genital and rectal mucosal surfaces where HIV-1 infection is mainly acquired. While IgG only exists as a monomer, IgA is predominantly found as dimer in the mucosal compartment and as monomer in serum. Yet, very little is known about: (1) how envelope-specific IgG1-4 and IgA1-2 isotypes and structures influence antibody antiviral function, (2) which of these isotypes and structures provide the most effective mechanism to block HIV-1 infection and (3) how IgG and IgA may interact to prevent HIV-1 infection. This thesis seeks to test the hypothesis that, in addition to antibody epitope specificity, isotype and structure influence antibody ability to bind, capture and neutralise HIV-1 virions. Furthermore, it is proposed that the kinetic parameters of antibody-virus interaction have a critical impact on antiviral function. Finally, it is posited that competition between isotypes may cross-modulate their different antiviral functions.
The findings of this study indicate that IgG antibodies present greater ability to capture and neutralise HIV-1 particles than mIgA and dIgA antibodies targeting the same epitope and that this correlates with their faster association constant rates. Moreover, it was observed that dIgA antibodies displayed enhanced antiviral functions compared to their mIgA counterparts depending on the epitope specificity. Competitive assays also demonstrated that IgG and IgA antibodies of identical specificity competed for interaction with HIV-1 virions, potentially mitigating IgG effector functions.
Thus, this research suggests that antibody epitope specificity, isotype and structure all influence antiviral functions and indicates that the ability of an antibody-based vaccine to prevent HIV-1 infection may be critically dependent on the spectrum and proportions of induced isotypes and their relative expression within systemic and mucosal compartments.