Saturday, May 31, 2025
5/31/2025
SHIV-guided design of novel HIV-1 fusion peptide immunogens - Abstract. SHIV-infected rhesus macaques (RMs) develop HIV-1 broadly neutralizing antibodies (bNAbs) via Env-Ab coevolutionary pathways that recapitulate events in HIV-1 infected humans (Science 371:eabd2638, 2021). We hypothesize that SHIV-infected RMs can thus serve as a novel “molecular guide” for HIV-1 immunogen design, allowing for an iterative and reproducible analysis of the critical steps in bNAb elicitation, including efficient priming of naïve B cell precursors, immunofocused boosting, and affinity-maturation leading to breadth and potency. In this application submitted in response to PAR-23-169 (Innovation for HIV Vaccine Discovery), we propose to design novel germline-targeting SHIVs and to use them to decipher each of these steps in SHIV-infected monkeys where, unlike in humans, we can analyze multiple animals infected by the same SHIVs and identify Env-Ab co-evolutionary pathways that are shared among different animals. Based on these findings, we will design and test novel prime and boost protein immunogens corresponding to key Env “immunotypes” responsible for elicitation of bNAbs in the SHIV-infected monkeys. Our proposal focuses on immunogen design for one of the most advanced HIV-1 vaccine targets (fusion peptide, FP) but one where boosting regimens that lead to high level breadth and potency have been challenging to develop. Our immunogen platforms include BG505, CH1012 and Ce1176 transmitted/founder Envs, each of which we show to be capable of eliciting FP bNAbs in RMs. The novel aspect of this application is that we propose to enhance the efficiency of priming, boosting and affinity maturation steps by designing new SHIVs with selected glycans deleted surrounding the FP site of vulnerability. We show that such SHIVs replicate efficiently and immunofocus early B cell responses to FP epitopes leading to neutralization breadth and potency. By deciphering Env-Ab coevolution leading to consistent bNAb induction in SHIV infection, we will then design and test new FP targeted protein immunogens that are practical for vaccine development. Specific aims are: (i) to construct novel SHIVs with BG505, CH1012 and Ce1176 Envs that are depleted of N-linked glycan sites surrounding the FP and to characterize their antigenicity, neutralization sensitivity, infectivity and replication in primary rhesus CD4+ T cells; (ii) to infect RMs with glycan-depleted SHIVs from Aim #1, epitope-map autologous and heterologous neutralizing antibody responses, identify germline B cell precursors to FP bNAbs and decipher molecular patterns of Env-Ab coevolution leading to neutralization breadth; (iii) to design novel Env trimers corresponding to key Env immunotypes that bind FP bNAb UCAs and intermediate stage Abs and to express them as stabilized prefusion Env trimer immunogens; and (iv) to conduct a proof-of-concept preclinical vaccine trial in RMs testing the hypothesis that SHIV-guided, B lineage-designed Env trimers can prime, boost and affinity-mature bNAb responses in RMs to an extent that is superior to conventional immunogens and that these bNAbs protect RMs against low-dose intrarectal challenge by heterologous tier-2 SHIVs.
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