Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

Author summary Major efforts are currently directed towards developing vaccine strategies to successfully elicit broadly neutralizing antibodies (bNAbs) against HIV-1. However, how to achieve this goal remains a critical problem. Soluble native-like HIV-1 envelope glycoproteins (Env) have shown promise as vaccine candidates in pre-clinical studies. Here, the antibody response against the BG505 SOSIP.664 Env trimer was studied through the isolation of monoclonal antibodies (mAbs) in rhesus macaques (RMs) after immunization. Overall, a diverse landscape of mAbs was elicited that target the Env trimer in highly similar ways in two animals. By mapping the target epitopes of all of the mAbs isolated from the immunized RMs, rather than focusing only on the neutralizing mAbs, we were able to identify several non-neutralizing and potentially immunodominant epitopes that would ideally be eliminated in future immunization studies. In addition, we identified neutralizing mAbs that recognize the highly conserved fusion peptide in a similar way as human broadly neutralizing antibodies. These insights can be further used to develop immunogens and immunization strategies able to induce bNAb-like responses that can protect against infection. The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.