We have recently shown that MUC16, a component of the glycocalyx of some mucosal barriers, has elevated binding to the G0 glycoform of the Fc portion of IgG. Therefore, IgG from patients chronically infected with human immunodeficiency virus (HIV), who typically exhibit increased amounts of G0 glycoforms, showed increased MUC16 binding compared to uninfected controls. Using the rhesus macaque simian immunodeficiency virus SIVmac251 model, we can compare plasma antibodies before and after chronic infection. We find increased binding of IgG to MUC16 after chronic SIV infection. Antibodies isolated for tight association with MUC16 (MUC16-eluted antibodies) show reduced FcγR engagement and antibody-dependent cellular cytotoxicity (ADCC) activity. The glycosylation profile of these IgGs was consistent with a decrease in FcγR engagement and subsequent ADCC effector function, as they contain a decrease in afucosylated bisecting glycoforms that preferentially bind FcγRs. Testing of the SIV antigen specificity of IgG from SIV-infected macaques revealed that the MUC16-eluted antibodies were enriched for certain specific epitopes, including regions of gp41 and gp120. This enrichment of specific antigen responses for fucosylated bisecting glycoforms and the subsequent association with MUC16 suggests that the immune response has the potential to direct specific epitope responses to localize to the glycocalyx through interaction with this specific mucin.IMPORTANCE Understanding how antibodies are distributed in the mucosal environment is valuable for developing a vaccine to block HIV infection. Here, we study an IgG binding activity in MUC16, potentially representing a new IgG effector function that would concentrate certain antibodies within the glycocalyx to trap pathogens before they can reach the underlying columnar epithelial barriers. These studies reveal that rhesus macaque IgG responses during chronic SIV infection generate increased antibodies that bind MUC16, and interestingly, these MUC16-tethered antibodies are enriched for binding to certain antigens. Therefore, it may be possible to direct HIV vaccine-generated responses to associate with MUC16 and enhance the antibody's ability to mediate immune exclusion by trapping virions within the glycocalyx and preventing the virus from reaching immune target cells within the mucosa. This concept will ultimately have to be tested in the rhesus macaque model, which is shown here to have MUC16-targeted antigen responses.

中文翻译：

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MUC16 IgG 结合活性选择 IgG 的限制子集，该子集富含某些猿猴免疫缺陷病毒表位特异性。

我们最近表明，MUC16 是某些粘膜屏障的糖萼成分，它与 IgG Fc 部分的 G0 糖型的结合增加。因此，与未感染的对照相比，来自慢性感染人类免疫缺陷病毒 (HIV) 的患者的 IgG，通常表现出更多的 G0 糖型，显示出增加的 MUC16 结合。使用恒河猴猿猴免疫缺陷病毒SIVmac251模型，我们可以比较慢性感染前后的血浆抗体。我们发现慢性 SIV 感染后 IgG 与 MUC16 的结合增加。为与 MUC16 紧密结合而分离的抗体（MUC16 洗脱抗体）显示出降低的 FcγR 参与和抗体依赖性细胞毒性 (ADCC) 活性。这些 IgG 的糖基化特征与 FcγR 结合和随后的 ADCC 效应子功能的降低一致，因为它们含有优先结合 FcγR 的非岩藻糖基化二等分糖型的减少。对来自 SIV 感染的猕猴的 IgG 的 SIV 抗原特异性测试表明，MUC16 洗脱抗体富含某些特定表位，包括 gp41 和 gp120 区域。这种对岩藻糖基化二等分糖型的特异性抗原反应的富集以及随后与 MUC16 的关联表明免疫反应有可能通过与这种特定粘蛋白的相互作用来指导特定表位反应定位到糖萼。重要了解抗体如何分布在粘膜中环境对于开发阻止 HIV 感染的疫苗很有价值。在这里，我们研究了 MUC16 中的 IgG 结合活性，它可能代表一种新的 IgG 效应子功能，可以将某些抗体集中在糖萼内，以在病原体到达底层柱状上皮屏障之前将其捕获。这些研究表明，恒河猴在慢性 SIV 感染期间的 IgG 反应会产生更多的结合 MUC16 的抗体，有趣的是，这些 MUC16 栓系抗体因与某些抗原的结合而得到丰富。因此，有可能指导 HIV 疫苗产生的反应与 MUC16 相关联，并通过将病毒粒子捕获在糖萼内并防止病毒到达粘膜内的免疫靶细胞来增强抗体介导免疫排斥的能力。这个概念最终将不得不在恒河猴模型中进行测试，