Abstract
Antibody subclasses exhibit extensive polymorphisms (allotypes) that could potentially impact the quality of HIV-vaccine induced B cell responses. Allotypes of immunoglobulin (Ig) G1, the most abundant serum antibody, have been shown to display altered functional properties in regard to serum half-life, Fc-receptor binding and FcRn-mediated mucosal transcytosis. To investigate the potential link between allotypic IgG1-variants and vaccine-generated humoral responses in a cohort of 14 HIV vaccine recipients, we developed a novel protocol for rapid IgG1-allotyping. We combined PCR and ELISA assays in a dual approach to determine the IgG1 allotype identity (G1m3 and/or G1m1) of trial participants, using human plasma and RNA isolated from PBMC. The IgG1-allotype distribution of our participants mirrored previously reported results for caucasoid populations. We observed elevated levels of HIV gp140-specific IgG1 and decreased IgG2 levels associated with the G1m1-allele, in contrast to G1m3 carriers. These data suggest that vaccinees homozygous for G1m1 are predisposed to develop elevated Ag-specific IgG1:IgG2 ratios compared to G1m3-carriers. This elevated IgG1:IgG2 ratio was further associated with higher FcγR-dimer engagement, a surrogate for potential antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) function. Although preliminary, these results suggest that IgG1 allotype may have a significant impact on IgG subclass distribution in response to vaccination and associated Fc-mediated effector functions. These results have important implications for ongoing HIV vaccine efficacy studies predicated on engagement of FcγR-mediated cellular functions including ADCC and ADCP, and warrant further investigation. Our novel allotyping protocol provides new tools to determine the potential impact of IgG1 allotypes on vaccine efficacy.
Highlights
Antibodies are generally accepted to contribute to vaccine induced protection against many infectious diseases including HIV [1]
We wished to assess whether IgG-allotypes might be linked to differences in the IgG-subclass profile of Ag-specific antibody responses generated in the context of HIV-1 vaccination [28, 29]
The IgG1 allotype abundance mirrors previously reported most frequent alleles representative of Caucasian population enrolled in this study (G1m3; G1m 17, 1; and G1m17,1,2), the concurring results demonstrate the interchangeability of the PCR and ELISA protocol for IgG1-allotyping
Summary
Antibodies are generally accepted to contribute to vaccine induced protection against many infectious diseases including HIV [1]. It has been suggested that Ig subclass composition may influence a wide range of Fc-mediated effector functions including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) [2] In this respect Fc-mediated effector functions likely augment the potency of broadly neutralizing antibodies [3] and are critical to the function of non-neutralizing antibodies. Divergent antibody subclass profiles have been associated with variable antibody effector functions among HIV-1 controllers, where levels of HIV-specific IgG1/3 were the major distinguishing factor [7], while IgG2/IgG4 HIV specific antibodies were associated with poorer overall antibody activity [8] In this respect, inter-individual variation in the antibody subclass response profiles to HIV-1 infection and/or vaccination provides significant challenges in the development of a globally effective vaccine
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