SHIV-infected rhesus macaques as a model for HIV-1 bNAb development

About This Grant

PROJECT SUMMARY A major roadblock to the development of rational HIV-1 prevention strategies is the lack of a suitable primate model in which broadly neutralizing antibodies (bNAbs) can be commonly induced and the molecular, biological and immunological mechanisms responsible for eliciting such responses studied in a reproducible and iterative fashion. Recently, we demonstrated that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses (SHIVs) in rhesus macaques (RMs), elicited patterns of Env-antibody coevolution strikingly similar to humans infected by homologous virus strains, leading to neutralization breadth in approximately 20% of monkeys after 1-3 yrs of infection (Science 371:142, 2021). These similarities in bNAb induction between humans and rhesus included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env amino acid substitutions, insertions and deletions selecting for antibody affinity maturation. However, to be useful for immunogen design, an outbred model is needed where a much higher proportion of animals develop bNAbs in a shorter period of time so that the model can serve as an iterative guide or “blueprint” for immunogen development. We show in the Progress Report that we have reached this milestone for V2 apex, V3 glycan, CD4bs and FP epitope targets using novel SHIV designs that immunofocus naïve germline B cell responses to canonical bNAb epitope supersites on HIV-1 Env. In this application, we propose to develop this model further by showing that bNAb elicitation by such germline-targeted (GT) SHIVs can be recapitulated by GT-immunogens and that these immunogens can elicit clinically protective antibodies against heterologous tier 2 SHIV challenge. Specific aims are: (i) To isolate rhesus bNAb mAbs targeting V2 apex, V3 glycan, CD4bs, FP and SF epitopes, characterize their breadth, potency, immunogenetics, target epitopes and structural solutions to epitope recognition, and decipher Env-Ab coevolution from germline B cell precursors to mature bNAbs. This will define the molecular roadmap for rhesus bNAb elicitation. (ii) To design new immunofocused, GT-Envs that exhibit enhanced binding to diverse rhesus bNAb UCAs from Aim 1. We will introduce these Envs into new SHIV designs, infect RMs, and assess them for increased frequency of bNAb precursor priming and accelerated rates of bNAb induction. Env-Ab coevolution analysis will then identify candidate prime and boost immunogens to recapitulate bNAb induction. (iii) To downselect lead Env candidates from Aim 2 and conduct an immunogenicity trial in RMs testing the hypothesis that immunofocused, GT-Env trimer immunogens can prime, boost and affinity-mature bNAb responses in RMs to an extent that is superior to conventional Env trimers. We will then challenge monkeys by repeated low-dose intrarectal inoculation with a heterologous tier 2 SHIV to determine neutralization titer thresholds required for sterilizing protection from heterologous virus acquisition.