title: Contribution of Fc-Effector Mechanisms to the Immunogenicity of Fc-Fusion Proteins and to the Efficacy of Passive Immunization Strategies Against HIV-1
title: Der Beitrag von Fc-Effektor-Mechanismen zur Immunogenität von Fc-Fusionsproteinen und zur Wirksamkeit von Passiven Immunisierungsstrategien Gegen HIV-1
Creators: name: Richel, Elie
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2025

description: Vaccination strategies that aim at eliciting broadly neutralizing antibodies (bnAbs) are considered as the most promising approaches to generate a protective vaccine against HIV-1. Ultimately, an effective vaccine would additionally benefit from the induction of long-lived immune responses eliciting high Env-specific antibody titers. As Fc-fusion proteins, defined by the fusion of an Fc-portion to a given antigen, retain the functional properties of immunoglobulins to interact with antigen-presenting cells, several studies suggested that Fc-fusion protein immunizations elicit stronger antigen-specific humoral immune responses than the unfused antigen by virtue of Fc-effector mechanisms. However, since dimerization of the antigen and prolongation of its half-life may also account for the immunogenicity enhancement, the present study aimed at elucidating whether employing Fc-effector mechanisms may represent a valuable approach to elicit strong and long-lasting anti-Env antibodies. To that extent, the immunogenicity of Fc-fusion proteins consisting of HIV gp120 fused to Fc-portions with impaired or improved affinity for the murine FcγRs were compared in immunization studies in mice to the non-mutated gp120-Fc fusion and unfused dimer of the antigen. Although each gp120 antigen induced detectable gp120-specific antibodies in immunized mice, immunizations with gp120 fused to functional Fc-portions appeared to elicit lower humoral immune responses than the Fc-effector function-deprived antigens. In contrast, similar immunization strategies conducted with SARS-CoV-2 RBD antigen did not point out substantial differences in terms of RBD-specific antibody levels. Therefore, the outcomes highlight that Fc-effector mechanisms accentuate the atypical immunogenicity of HIV Env / gp120 and emphasize the need for alternative strategies to prevent HIV-1 infection. Favorably, several reports demonstrated the efficacy of bnAb adoptive transfer for the prevention of systemic HIV-1 infection. Notably, a previous study from our group demonstrated that bnAbs can mediate the prevention of mucosal infection of the first cells since bnAb-infused macaques were protected against infection by a challenge virus relying on HIV Env-mediated entry into the first target cell, but then switched to SIV Env usage for the subsequent round of replications. Nonetheless, whether Fc-effector mechanisms assisted neutralizing activities for providing sterilizing immunity remained unclarified. For that purpose, the present study aimed at producing additional challenge viruses co-incorporating SIV Env and a graded number of fusion-defective Env trimers, as target of non-neutralizing mechanisms of the PGT121 bnAb. Following the adoptive transfer of PGT121, or its variant impaired for Fc-effector functions, rhesus macaques were rectally exposed to these challenge viruses and to those relying initially on HIV Env- or SIV Env-mediated entry. While the infection events of the challenge viruses that incorporated fusion-defective HIV-1 Env trimers at densities observed in primary virus isolates were not significantly reduced by any of the PGT121 treatments, both antibody variants reduced the infection of the HIV Env challenge virus to a factor close to 200. Hence, the results highlight that the low densities of bnAb binding sites on HIV-1 virions restrain the contribution of Fc-effector functions to provide sterilizing immunity against mucosal viral infection. In summary, the outcomes presented in this report underline the complexity of harnessing Fc-effector functions for the protection against HIV-1 and may require strategies that promote the degree of opsonization.