Wyatt, R. T. | bioRxiv Science

bioRxiv2025

HIV Env trimers elicit NHP apex cross-neutralizing antibodies mimicking human bNAbs

As a chronically replicating virus, HIV has evolved extreme sequence variability and effective shielding of functionally constrained spike protein determinants by host-derived glycans. Broadly neutralizing antibodies (bNAbs), though rare, can be isolated from people living with HIV, revealing conserved Env sites as key targets for vaccine development. One such target is the apex of the envelope glycoprotein (Env) spike. Here, we identified a vaccination strategy using heterologous HIV Env trimers covalently coupled to liposomes for multivalent display that resulted in the elicitation of cross-neutralizing HIV serum antibody responses in all immunized non-human primates (NHPs). Critically, we isolated a set of monoclonal antibodies (mAbs) that cross-neutralized multiple divergent HIV clinical isolates. High-resolution cryoEM structural analysis of mAbs from three different NHPs demonstrated that they targeted the Env trimer apex in a manner remarkably similar to that of the human infection-elicited, apex-directed bNAb PG9, representing a substantial advance in HIV vaccine development.

immunology↗

bioRxiv2021

Structurally related but genetically unrelated antibody lineages converge on an immunodominantHIV-1 Env neutralizing determinant following trimer immunization

Understanding the molecular mechanisms by which antibodies target and neutralize the HIV-1 envelope glycoprotein (Env) is critical in guiding immunogen design and vaccine development aimed at eliciting cross-reactive neutralizing antibodies (NAbs). Here, we analyzed monoclonal antibodies (mAbs) isolated from non-human primates (NHPs) immunized with variants of a native flexibly linked (NFL) HIV-1 Env stabilized trimer derived from the tier 2 clade C 16055 strain. The antibodies displayed neutralizing activity against the autologous virus with potencies ranging from 0.005 to 3.68 ug/ml (IC50). Structural characterization using negative-stain EM and X-ray crystallography identified the variable region 2 (V2) of the 16055 NFL trimer to be the common epitope for these antibodies. The crystal structures revealed that the V2 segment adopts a {beta}-hairpin motif identical to that observed in the 16055 NFL crystal structure. These results depict how vaccine-induced antibodies derived from different clonal lineages penetrate through the glycan shield to recognize a hypervariable region within V2 (residues 184-186) that is unique to the 16055 strain. They also provide an explanation for the potent autologous neutralization of these antibodies, confirming the immunodominance of this site and revealing that multiple angles of approach are permissible for affinity/avidity that results in potent neutralizing capacity. The structural analysis reveals that the most negatively charged paratope correlated with the potency of the mAbs. The atomic level information is of interest to both define the means of autologous neutralization elicited by different tier 2-based immunogens and facilitate trimer redesign to better target more conserved regions of V2 to potentially elicit cross-neutralizing HIV-1 antibodies. Author summaryNHPs immunizations with an HIV-1 immunogen (native-like tier 2 clade C 16055 strain) elicit potent HIV-1 tier 2 autologous polyclonal neutralizing antibodies. To understand the basis of the autologous neutralization, we determined structures of antibodies isolated from the vaccinated NHPs in complex with their epitopes. Our structural analysis reveals that the V2 hypervariable region, unique to 16055, is immunodominant and targeted by antibodies from diverse lineages. Additionally, vaccine-elicited V2 NAbs use different binding angles to avoid Env N-glycan shield and the more negatively charged paratope displays potent autologous neutralizing function. In summary, detailed analysis of how vaccine-elicited monoclonal antibodies interact with the target antigen provide valuable information for the design of immunogens aimed to elicit more broadly HIV-neutralizing antibodies. The use of cocktail/prime-boost sequential regimens that include a range of sequence variation combined with the removal/shielding of unwanted immunodominant epitopes will likely be needed to reach this goal.

biochemistry↗

bioRxiv2018

Vaccine-induced protection from homologous Tier 2 simian-human immunodeficiency virus challenge in nonhuman primates

Passive administration of HIV neutralizing antibodies (nAbs) can protect macaques from hard-to-neutralize (Tier 2) chimeric simian-human immunodeficiency virus (SHIV) challenge. However, conditions for nAb-mediated protection following vaccination have not been established. Here, we selected groups of 6 rhesus macaques with either high or low serum nAb titers from a total of 78 animals immunized with recombinant native-like (SOSIP) Env trimers from the BG505 HIV isolate. Repeat intrarectal challenge with homologous Tier 2 SHIVBG505 led to rapid infection in unimmunized and low-titer animals. In contrast, high-titer animals demonstrated protection that was gradually lost as nAb titers waned over weeks to months. From these results, we determined that an autologous serum ID50 nAb titer of ~1:500 was required to afford over 90% protection from medium-dose SHIV infection. We further identified autologous nAb titers, but not ADCC or T cell activity, as strong correlates of protection. These results provide proof-of-concept that Env protein-based vaccination strategies can protect against hard-to-neutralize SHIV challenge in rhesus macaques by inducing Tier 2 nAbs, provided appropriate neutralizing titers can be reached and maintained.

immunology↗