用 DNA 编码的具有 HIV 包膜天然三聚体的小鼠诱导 2 级中和抗体。

Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer.

机构信息

Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

出版信息

Nat Commun. 2022 Feb 4;13(1):695. doi: 10.1038/s41467-022-28363-z.

DOI:10.1038/s41467-022-28363-z

PMID:35121758

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8816947/

Abstract

HIV Envelope (Env) is the main vaccine target for induction of neutralizing antibodies. Stabilizing Env into native-like trimer (NLT) conformations is required for recombinant protein immunogens to induce autologous neutralizing antibodies(nAbs) against difficult to neutralize HIV strains (tier-2) in rabbits and non-human primates. Immunizations of mice with NLTs have generally failed to induce tier-2 nAbs. Here, we show that DNA-encoded NLTs fold properly in vivo and induce autologous tier-2 nAbs in mice. DNA-encoded NLTs also uniquely induce both CD4 + and CD8 + T-cell responses as compared to corresponding protein immunizations. Murine neutralizing antibodies are identified with an advanced sequencing technology. The structure of an Env-Ab (C05) complex, as determined by cryo-EM, identifies a previously undescribed neutralizing Env C3/V5 epitope. Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines.

摘要

HIV 包膜（Env）是诱导中和抗体的主要疫苗靶标。为了使重组蛋白免疫原诱导针对难以中和的 HIV 株（Tier-2）的同源中和抗体（nAbs），需要将 Env 稳定为天然样三聚体（NLT）构象。用 NLT 对兔子和非人类灵长类动物进行免疫接种通常不能诱导 Tier-2 nAbs。在这里，我们表明，体内编码的 NLT 正确折叠，并在小鼠中诱导同源 Tier-2 nAbs。与相应的蛋白免疫接种相比，DNA 编码的 NLT 还独特地诱导了 CD4+和 CD8+T 细胞反应。使用先进的测序技术鉴定了鼠类中和抗体。通过冷冻电镜确定的 Env-Ab（C05）复合物结构，确定了一个以前未描述的中和 Env C3/V5 表位。除了潜在的功能性免疫获益外，DNA 疫苗还允许体内折叠结构抗原，并为快速评估新的 HIV 疫苗提供了显著的成本和速度优势。