接种免疫复合物可调节针对 HIV-1 的功能性抗体的产生。

INTRODUCTION: Neutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge. OBJECTIVE: This study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env). METHODS: Four groups of rabbits received a DNA vaccine expressing the V1V2 domain of the CRF01_AE A244 strain on a trimeric 2J9C scaffold (V1V2-2J9C) along with a protein vaccine consisting of an uncleaved prefusion-optimized A244 Env trimer with V3 truncation (UFO-BG.ΔV3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitope . RESULTS: Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses. CONCLUSION: These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158.

简介：中和抗体（Abs）是预防病毒感染所需的免疫成分之一。然而，开发能够诱导针对广泛的 HIV-1 分离株的中和 Abs 的疫苗一直是一项艰巨的挑战。

目的：本研究旨在测试针对 HIV-1 包膜（Env）V1V2 顶点的中和表位诱导 Abs 的疫苗。

方法：四组兔子接受了一种在三聚体 2J9C 支架上表达 CRF01_AE A244 株 V1V2 结构域的 DNA 疫苗（V1V2-2J9C），以及一种由未切割的前融合优化的 A244 Env 三聚体组成的蛋白疫苗，带有 V3 截短（UFO-BG.ΔV3）或 V1V2-2J9C 蛋白及其各自的免疫复合物（IC）。这些 IC 疫苗是使用 2158 制成的，2158 是一种针对 V1V2 的单克隆 Ab（mAb），它结合 V1V2 腹部下方的 V2i 表位，同时变构促进广泛中和 mAb PG9 与其 V2 顶端表位的结合。

结果：接受 DNA 疫苗和未复合或复合 UFO-BG.ΔV3 蛋白（DNA/UFO-UC 或 IC）的兔子组显示出相似的 Env 和 V1V2 结合 Abs 谱，但与接受 DNA 疫苗和未复合或复合 V1V2-2J9C 蛋白（DNA/V1V2-UC 或 IC）的兔子组不同，后者产生了更多的交叉反应性 V1V2 Abs，而没有检测到与 gp120 或 gp140 Env 的结合。值得注意的是，DNA/UFO-UC 疫苗诱导体外中和 Abs 针对来自不同谱系的一些异源 tier 1 和 tier 2 病毒，尽管滴度较低，且仅在部分动物中，但 DNA/V1V2-UC 或 IC 疫苗则没有。与 DNA/UFO-UC 组相比，DNA/UFO-IC 组对 TH023.6 的中和作用呈上升趋势，并且 V1V2 特异性 Ab 依赖性细胞吞噬作用（ADCP）的效力更高，但未能中和异源病毒。

结论：这些数据表明，V1V2-2J9C 编码的 DNA 疫苗与 UFO-BG.ΔV3 结合，而不是与 V1V2-2J9C 蛋白疫苗结合，能够在兔子中诱导同源和异源中和活性。UFO-BG.ΔV3 与 V2i mAb 2158 复合的递送调节了中和和 ADCP 活性的产生。