Pratap Payal P, Cottrell Christopher A, Quinn James, Carnathan Diane G, Bader Daniel L V, Tran Andy S, Enemuo Chiamaka A, Ngo Julia T, Richey Sara T, Gao Hongmei, Shen Xiaoying, Greene Kelli M, Hurtado Jonathan, Michaels Katarzyna Kaczmarek, Ben-Akiva Elana, Lemnios Ashley, Melo Mariane B, Allen Joel D, Ozorowski Gabriel, Crispin Max, Briney Bryan, Montefiori David, Silvestri Guido, Irvine Darrell J, Crotty Shane, Ward Andrew B
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Center for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA, 92037, USA.
bioRxiv. 2025 Jun 5:2024.11.27.625755. doi: 10.1101/2024.11.27.625755.
During infection, the fusion peptide (FP) of HIV envelope glycoprotein (Env) serves a central role in viral fusion with the host cell. As such, the FP is highly conserved and therefore an attractive epitope for vaccine design. Here, we describe a vaccination study in non-human primates (NHPs) where glycan deletions were made on soluble HIV Env to increase FP epitope exposure. When delivered via implantable osmotic pumps, this immunogen primed immune responses against the FP, which were then boosted with heterologous trimers resulting in a focused immune response targeting the conserved FP epitope. Although autologous immunizations did not elicit high affinity FP-targeting antibodies, the conserved FP epitope on a heterologous trimer further matured the lower affinity, FP-targeting B cells. This study suggests using epitope conservation strategies on distinct Env trimer immunogens can focus humoral responses on desired neutralizing epitopes and suppress immune-distracting antibody responses against non-neutralizing epitopes.
在感染过程中，HIV包膜糖蛋白（Env）的融合肽（FP）在病毒与宿主细胞的融合中起核心作用。因此，FP高度保守，是疫苗设计中一个有吸引力的表位。在此，我们描述了一项在非人类灵长类动物（NHP）中的疫苗接种研究，其中对可溶性HIV Env进行了聚糖缺失，以增加FP表位的暴露。当通过植入式渗透泵递送时，这种免疫原引发了针对FP的免疫反应，然后用异源三聚体进行加强免疫，从而产生针对保守FP表位的集中免疫反应。尽管自体免疫未引发高亲和力的靶向FP抗体，但异源三聚体上保守的FP表位进一步使低亲和力的靶向FP B细胞成熟。这项研究表明，在不同的Env三聚体免疫原上使用表位保守策略可以将体液反应集中在所需的中和表位上，并抑制针对非中和表位的分散免疫的抗体反应。
