Broadly neutralizing antibody epitopes on HIV-1 particles are exposed after virus interaction with host cells.
Broadly neutralizing antibody epitopes on HIV-1 particles are exposed after virus interaction with host cells.
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DOI：
10.1128/jvi.00710-23
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发表时间：
2023-09-28
影响因子：
5.4
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中科院分区：
文献类型：
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HIV-1病毒粒子上的包膜糖蛋白（Env）是广泛中和抗体（bNAb）的唯一靶标和疫苗的焦点。然而，许多交叉反应的保守表位往往被封闭在病毒颗粒上，有助于逃避体液免疫。本研究旨在鉴定HIV-1颗粒上暴露/封闭的Env表位，并研究导致其掩蔽的机制。使用流式细胞术为基础的分析，三个HIV-1分离株，和一组抗体，我们表明，只有选择表位，包括V2 i，gp 120-g41接口，和gp 41-MPER，是可访问的HIV-1颗粒，而V3，V2 q，并选择CD 4 bs表位被掩盖。这些表位在通过选择Ab的预结合诱导变构构象变化后变得可接近，这促使我们测试这些Ab是否需要类似的构象变化来表现出其中和能力。我们测试了HIV-1中和，其中在加入靶细胞之前将病毒-mAb混合物预孵育/未预孵育1小时。在两种测定条件下观察到相似的中和水平，表明病毒和靶细胞之间的相互作用使病毒体敏感，从而通过bNAb进行中和。我们进一步表明，凝集素-聚糖相互作用也可以暴露这些表位。然而，这种作用依赖于凝集素的特异性。鉴于此，bNAb是提供杀菌免疫的理想选择，也是目前HIV-1疫苗工作的目标，这些数据提供了关于HIV-1如何从宿主免疫反应中封闭这些脆弱表位的见解。此外，这些发现可以指导用于治疗用途的有效抗体组合的配制。人类免疫缺陷病毒（HIV-1）包膜（Env）糖蛋白介导病毒进入，是中和抗体的唯一靶标。我们的数据表明，包括V2 q（例如，PG 9，PGT 145），CD 4 b（例如，VRC 01，3BNC 117）和V3（2219，2557）在HIV-1颗粒上被掩蔽。PG 9和2219表位在通过选择的mAb的预结合诱导构象解蔽后变得可用于结合。试图了解掩蔽机制导致的启示，病毒和宿主细胞之间的相互作用是需要敏化病毒粒子的中和广泛中和抗体（bNAb）。这些数据提供了关于bNAb如何获得这些封闭表位以发挥其中和作用并阻断HIV-1感染的见解。这些发现对我们评估抗体中和效力的方式具有重要意义，并可能指导疫苗设计。
The envelope (Env) glycoproteins on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAbs) and the focus of vaccines. However, many cross-reactive conserved epitopes are often occluded on virus particles, contributing to the evasion of humoral immunity. This study aimed to identify the Env epitopes that are exposed/occluded on HIV-1 particles and to investigate the mechanisms contributing to their masking. Using a flow cytometry-based assay, three HIV-1 isolates, and a panel of antibodies, we show that only select epitopes, including V2i, the gp120-g41 interface, and gp41-MPER, are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are masked. These epitopes become accessible after allosteric conformational changes are induced by the pre-binding of select Abs, prompting us to test if similar conformational changes are required for these Abs to exhibit their neutralization capability. We tested HIV-1 neutralization where the virus-mAb mix was pre-incubated/not pre-incubated for 1 hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. We further show that lectin-glycan interactions can also expose these epitopes. However, this effect is dependent on the lectin specificity. Given that, bNAbs are ideal for providing sterilizing immunity and are the goal of current HIV-1 vaccine efforts, these data offer insight on how HIV-1 may occlude these vulnerable epitopes from the host immune response. In addition, the findings can guide the formulation of effective antibody combinations for therapeutic use. The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein mediates viral entry and is the sole target of neutralizing antibodies. Our data suggest that antibody epitopes including V2q (e.g., PG9, PGT145), CD4bs (e.g., VRC01, 3BNC117), and V3 (2219, 2557) are masked on HIV-1 particles. The PG9 and 2219 epitopes became accessible for binding after conformational unmasking was induced by the pre-binding of select mAbs. Attempts to understand the masking mechanism led to the revelation that interaction between virus and host cells is needed to sensitize the virions for neutralization by broadly neutralizing antibodies (bNAbs). These data provide insight on how bNAbs may gain access to these occluded epitopes to exert their neutralization effects and block HIV-1 infection. These findings have important implications for the way we evaluate the neutralizing efficacy of antibodies and can potentially guide vaccine design.
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影响因子：
2
作者：
Altman, J. B.;Liu, X.;Powell, R. L. R.
通讯作者：
Powell, R. L. R.
影响因子：
32.4
作者：
Bobardt, MD;Saphire, ACS;Gallay, PA
通讯作者：
Gallay, PA
影响因子：
7.8
作者：
Cheng, Cho-Chin;Platen, Louise;Christa, Catharina;Tellenbach, Myriam;Kappler, Verena;Bester, Romina;Liao, Bo-Hung;Holzmann-Littig, Christopher;Werz, Maia;Schonhals, Emely;Platen, Eva;Eggerer, Peter;Treguer, Laetitia;Kuchle, Claudius;Schmaderer, Christoph;Heemann, Uwe;Renders, Lutz;Protzer, Ulrike;Braunisch, Matthias Christoph
通讯作者：
Braunisch, Matthias Christoph
DOI：
10.1126/science.1213782
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diskin R;Scheid JF;Marcovecchio PM;West AP Jr;Klein F;Gao H;Gnanapragasam PN;Abadir A;Seaman MS;Nussenzweig MC;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
3.7
作者：
Davis, Katie L.;Gray, Elin S.;Shaw, George M.
通讯作者：
Shaw, George M.