An HIV-1 Env–Antibody Complex Focuses Antibody Responses to Conserved Neutralizing Epitopes

Abstract

Elicitation of broadly neutralizing antibody (bNAb) responses to the conserved elements of the HIV-1 envelope glycoproteins (Env), including the primary receptor CD4 binding site (CD4bs), is a major focus of vaccine development yet to be accomplished. However, a large number of CD4bs-directed bNAbs have been isolated from HIV-1 infected individuals. Comparison of the the routes of binding used by the CD4bs-directed bNAbs from patients and the vaccine-elicited CD4bs-directed monoclonal antibodies (MAbs) indicates that the latter fail to neutralize primary virus isolates since they approach the Env spike with a vertical angle and contact the specific surface residues occluded in the native spike, including the bridging sheet on gp120. To preferentially expose the CD4bs and direct the immune response away from the bridging sheet, resulting in an altered angle of approach, we engineered an immunogen consisting of gp120 core in complex with the prototypic CD4i antibody, 17b. This mAb directly contacts the bridging sheet but not the CD4bs. The complex was further stabilized by chemical crosslinking to prevent dissociation. Rabbits immunized with the crosslinked complex displayed earlier affinity maturation, achieving tier 1 virus neutralization compared to animals immunized with gp120 core alone. Immunization with the crosslinked complex induced transient antibody responses with binding specificity similar to the CD4bs-directed bNAbs. MAbs derived from complex-immunized rabbits displayed footprints on gp120 more distal from the bridging sheet as compared to previous vaccine-elicited CD4bs antibodies, indicating that Env-antibody complexes effectively dampen immune responses to undesired immunodominant bridging sheet determinants.

Targeting HIV Env immunogens to B cell follicles in non-human primates through immune complex or protein nanoparticle formulations

“…Immune complex vaccines have been studied for many years preclinically 28 and have also entered clinical trials 31,32,48 . In the setting of HIV vaccines, complexation with mAbs has been used to alter the accessibility of neutralizing vs. non-neutralizing epitopes or alter conformations of the immunogen, promoting B cell responses against neutralizing epitopes 28 .…”

“…Immune complex vaccines have been studied for many years preclinically 28 and have also entered clinical trials 31,32,48 . In the setting of HIV vaccines, complexation with mAbs has been used to alter the accessibility of neutralizing vs. non-neutralizing epitopes or alter conformations of the immunogen, promoting B cell responses against neutralizing epitopes 28 . Motivated by the recent findings that the base of Env trimers is a highly immunodominant non-neutralizing target on SOSIP immunogens 46,49,50 , we utilized a mAb isolated from macaques recognizing a base epitope for IC formation, with the goal of masking humoral responses against the base.…”

“…Fusion of antigens with multiple copies of recombinant C3 has been shown to enhance humoral immunity 24 , but this strategy has not been widely applied and may be difficult to implement generally. Another approach is to form synthetic immune complexes with recombinant monoclonal antibodies [25][26][27][28] . Immunization with ICs in animal models has been shown in some cases to enhance IgG titers and duration, and to affect which epitopes are targeted [27][28][29][30] .…”

“…Another approach is to form synthetic immune complexes with recombinant monoclonal antibodies [25][26][27][28] . Immunization with ICs in animal models has been shown in some cases to enhance IgG titers and duration, and to affect which epitopes are targeted [27][28][29][30] . Early-stage clinical trials of IC immunization have shown this approach to also be safe 31,32 .…”

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

“…These studies revealed the specificities of neutralizing antibody responses in Env-vaccinated animals by isolating MAbs that recapitulate the plasma neutralizing capacity. The determined neutralizing specificities are mostly restricted to tier 1 viruses (10,(15)(16)(17)(18) or autologous tier 2 viruses (12,19,20). Thus, characterization of vaccine-elicited tier 2 virus NAb responses at a clonal level would provide an improved understanding of Env-specific Ab repertoires induced by vaccination, which is more relevant for future translational vaccine studies, in contrast to the characterization of infection-induced bNAbs pursued extensively in previous studies.…”