Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, UK.
Glycotechnology Laboratory, Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo Miramón 182, 20014 San Sebastian, Spain.
Cell Rep. 2022 Mar 29;38(13):110611. doi: 10.1016/j.celrep.2022.110611.
The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development.
HIV-1 包膜糖蛋白（Env）是广泛中和抗体（bnAbs）的唯一靶标。Env 高度糖基化，带有宿主来源的 N-聚糖，许多 bnAbs 通过与 Env 糖基结合或依赖于 Env 糖基来中和病毒。尽管在 HIV 感染个体中经常检测到糖结合 bnAbs，但由于 Env N-聚糖的免疫原性差，尝试诱导它们产生一直未能成功。在这里，我们报告了糖结合 bnAbs 与自身和非自身 N-聚糖以及曼氏血吸虫不同生命阶段的糖蛋白抗原的交叉反应性。我们使用 IAVI Protocol C HIV 感染队列，研究了曼氏血吸虫血清阳性与靶向糖依赖性表位的 bnAbs 发展之间的关系。我们表明，从 S. mansoni 血清阳性的 HIV 感染供体中分离出来的 N332/V3 特异性 bnAb 谱系 PCDN76 的未突变共同祖先与曼氏血吸虫尾蚴结合，而缺乏对 gp120 的反应性。总的来说，这些结果提出了一种诱导糖反应性 bnAbs 的策略，该策略可用于 HIV-1 疫苗的开发。
