Matsuda Kenta, Harrison Mitra, Wettstein Eleanor, Pederson Jessica, Pullano Alyssa A, Bolkhovitinov Lyuba, Kim Breanna, Steinberg Isabel, Griesman Trevor, Stuccio Sarah, Rogan Daniel, Patamawenu Andy, Shofner Tulley, Wright Nathaniel E, Webber Jonathan D, Van't Veer Freya, Roenicke Rachel, Koory Emma, Roeder Peyton M, Ober Ellison, Leach Benjamin, Tsybovsky Yaroslav, Stephens Tyler, Del Moral-Sanchez Ivan, Bontjer Ilja, McGinnes-Cullen Lori W, Chu Eric, Liang Jason, Torres Jonathan L, Lin Ryan N, Tran Andy S, Dziubla Gabrielle, Serebryannyy Leonid, Narpala Sandeep, Lin Bob, Castro Mike, Ozorowski Gabriel, Ward Andrew B, Sanders Rogier W, Kwong Peter D, Guenaga Javier, Wyatt Richard, Morrison Trudy, Connors Mark
HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Nat Commun. 2025 Jun 3;16(1):5162. doi: 10.1038/s41467-025-60481-2.
HIV-1 Env glycoprotein (Env) immunogenicity is limited in part by structural instability and extensive glycan shielding and is likely the greatest obstacle to an HIV-1 vaccine. Stabilized Env trimers can elicit serum neutralizing antibodies, but the response is short-lived. Here we use Newcastle Disease Virus-like particle (NDV-VLP) platform to present stabilized versions of HIV-1 Env at high valency and in the context of varied conformational stability, adjuvants, dose, and antigen persistence. Influenza virus hemagglutinin, or SARS-CoV2 Spike-bearing VLPs rapidly induce neutralizing antibodies, in contrast, they were not induced by those bearing Env. A replicating adenovirus type 4 expressing Env rapidly induces autologous neutralizing antibodies. However, durable neutralizing antibodies are induced only when multiple features of a replicating virus infection are combined, with the largest impact from dose and escalating dose. In summary, we show here immunogenicity of HIV-1 Env could be improved by reproducing features of virus infection.
HIV-1包膜糖蛋白（Env）的免疫原性部分受到结构不稳定性和广泛聚糖屏蔽的限制，这可能是HIV-1疫苗面临的最大障碍。稳定化的Env三聚体可引发血清中和抗体，但这种反应是短暂的。在此，我们利用新城疫病毒样颗粒（NDV-VLP）平台以高单价形式呈现不同构象稳定性、佐剂、剂量和抗原持久性背景下的HIV-1 Env稳定化版本。相比之下，流感病毒血凝素或携带SARS-CoV2刺突蛋白的VLPs能快速诱导中和抗体，而携带Env的VLPs则不能。表达Env的复制型腺病毒4型能快速诱导自体中和抗体。然而，只有当复制型病毒感染的多个特征相结合时，才能诱导产生持久的中和抗体，其中剂量和递增剂量的影响最大。总之，我们在此表明，通过重现病毒感染的特征可提高HIV-1 Env的免疫原性。
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