JK: Formal Analysis, Methodology, Visualization, Writing review & editing. (UFO-BG.V3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitopein vitro. == Results == Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.V3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited IL18BP antibody neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater GSK2141795 (Uprosertib, GSK795) potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses. == Conclusion == These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.V3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.V3 complexed with V2i mAb 2158. Keywords:HIV-1 vaccine, HIV-1 Env, antibody, immune complex (IC), virus neutralization, ADCP == Introduction == Developing HIV envelope (Env) immunogens capable of eliciting antibodies (Abs) effective against a broad array of HIV-1 isolates is a major challenge in HIV vaccine development. Phase 2b/3 vaccine trials, including the recent HVTN 706, HVTN 705, and HVTN 702 trials testing different vaccine platforms and regimens to elicit cross-reactive Abs against Env, have yielded no efficacy signals (13). HIV-1 vaccine candidates designed to generate broadly neutralizing Abs (bNAbs) have not attained their ultimate goals, although a germline-targeting strategy utilizing a self-assembling nanoparticle vaccine with 60 copies of gp120 engineered outer domain (eOD-GT8 60mer) was reported to stimulate precursors of VRC01-class bNAbs against the CD4-binding site (CD4bs) in nearly all vaccine recipients in a phase I trial (4). During HIV-1 infection, bNAbs are produced after multiple years of chronic infection only in a small subset of HIV-1seropositive individuals (58). Although exposure to diverse variants over years has been implicated in promoting or guiding bNAb development and maturation (9,10), other factors contributing to the generation of bNAbs are not fully understood. This study sought to examine whether anti-Env Abs that form immune complexes (ICs) could exert any modulatory effects on GSK2141795 (Uprosertib, GSK795) Ab responses against bNAb epitopes on Env. Gach et al. utilized IC vaccines to suppress Ab responses to the immunogenic, strain-specific glycan hole on the GSK2141795 (Uprosertib, GSK795) BG505 SOSIP.664 trimer, but the blockage did not divert the Ab responses toward broadly reactive neutralizing epitopes (11). Other studies tested IC vaccines of the gp120 core cross-linked or fused with CD4i mAbs against the bridging sheet that preferentially expose the CD4bs epitope for the VRC01 bnAb lineage. Immunization with these ICs promoted the generation of Abs with similar binding footprints as the VRC01-class bNAbs (12,13). A similar study examined IC vaccines of gp120 cross-linked with mAb A32 to allosterically stabilize the chemokine receptor-binding site, but IC-induced neutralizing titers were comparable GSK2141795 (Uprosertib, GSK795) to those attained by gp120 alone (14). In earlier studies, we also observed the allosteric effects of CD4bs mAbs that enhanced exposure and stability of the crown region of the V3 loop on gp120, resulting in greater Ab reactivity against V3 (1518). Immunization with ICs made of gp120 and a CD4bs mAb elicited higher levels of cross-reactive Ab responses against the V3 crown, but the neutralizing activity was limited to.
