Stieh Daniel J, King Deborah F, Klein Katja, Aldon Yoann, McKay Paul F, Shattock Robin J
Department of Cellular and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
Mucosal Infection and Immunity Group, Section of Infectious Diseases, Imperial College London, St Mary's Campus, London, W2 1PG, UK.
Retrovirology. 2015 Sep 24;12:81. doi: 10.1186/s12977-015-0207-z.
The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. Although functional Env complexes are thought to require trimerization of cleaved gp41/gp120 heterodimers, variable processing can result in the potential incorporation of non-functional uncleaved proteins (gp160), non-trimeric arrangements of gp41/gp120 heterodimers, and gp120 depleted gp41 stumps. The potential distribution of functional and non-functional Env forms across replication-competent viral populations may have important implications for neutralizing and non-neutralizing antibody functions. This study applied an immuno-bead viral capture assay (VCA) to interrogate the potential distribution (heterologous vs homologous) of functional and non-functional forms of virion associated Env.
The VCA revealed a significant association between depletion of infectious virions and virion Env incorporation, but not between infectivity and p24-gag. Three distinct subpopulations of virions were identified within pools of genetically homogenous viral particles. Critically, a significant subpopulation of infectious virions were exclusively captured by neutralizing antibodies (nAbs) indicative of a homologous distribution of functional trimeric Env forms. A second infectious subpopulation bound both neutralizing and non-neutralizing antibodies (nnAbs) representative of a heterologous distribution of Env forms, while a third non-infectious subpopulation was predominantly bound by nnAbs recognizing gp41 stumps.
The observation that a distinct and significant subpopulation of infectious virions is exclusively captured by neutralizing antibodies has important implications for understanding antibody binding and neutralization, as well as other antibody effector functions.
HIV-1包膜糖蛋白（Env）的结构在整个病毒体上具有灵活性和异质性。虽然功能性Env复合物被认为需要裂解的gp41/gp120异二聚体三聚化，但可变加工可能导致非功能性未裂解蛋白（gp160）的潜在掺入、gp41/gp120异二聚体的非三聚体排列以及gp120缺失的gp41残端。功能性和非功能性Env形式在具有复制能力的病毒群体中的潜在分布可能对中和抗体和非中和抗体功能具有重要意义。本研究应用免疫珠病毒捕获试验（VCA）来探究病毒体相关Env的功能性和非功能性形式的潜在分布（异源与同源）。
VCA显示感染性病毒体的耗竭与病毒体Env掺入之间存在显著关联，但感染性与p24 - gag之间不存在关联。在基因同质的病毒颗粒池中鉴定出三个不同的病毒体亚群。至关重要的是，一个显著的感染性病毒体亚群仅被中和抗体（nAbs）捕获，这表明功能性三聚体Env形式存在同源分布。第二个感染性亚群与中和抗体和非中和抗体（nnAbs）都结合，代表Env形式的异源分布，而第三个非感染性亚群主要被识别gp41残端nnAbs结合。
感染性病毒体的一个独特且显著的亚群仅被中和抗体捕获这一观察结果，对于理解抗体结合、中和以及其他抗体效应功能具有重要意义。
