Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers
Divergent Antibody Subclass and Specificity Profiles but Not Protective HLA-B Alleles Are Associated with Variable Antibody Effector Function among HIV-1 Controllers
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DOI：
10.1128/jvi.03130-13
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发表时间：
2014-03-01
影响因子：
5.4
通讯作者：
Ackerman, Margaret E.
中科院分区：
文献类型：
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作者：
Lai, Jennifer I.;Licht, Anna F.;Ackerman, Margaret E.
了解体液免疫和细胞免疫反应之间的协调可能是开发保护性疫苗的关键，并且由于长期HIV-1非进展者的遗传研究将特定的HLA-B等位基因与病毒复制的自发控制相关联，因此该主题组提供了一个研究适应性免疫系统臂之间关系的机会。鉴于有证据表明细胞免疫可能在病毒抑制中发挥作用，我们试图确定体液免疫反应是否以及如何在控制者之间变化。值得注意的是，Fc介导的抗体效应子功能同样与持久的病毒控制相关。在这项研究中，我们比较了效应器的功能和生物物理特征的HIV特异性抗体在一个队列的控制器和没有保护性HLA-B等位基因，以调查是否有证据表明多个路径的HIV-1控制，或是否细胞和体液免疫武器可能表现出协调的配置文件。然而，除了IgG 2抗体的gp 41，HLA状态与不同的体液反应。这一发现并不是因为受试者之间的抗体反应一致，因为控制者可以根据其HIV特异性抗体亚类特异性特征的强烈差异进行重新分组。这些不同的抗体谱进一步与非中和抗体效应子功能的显著差异相关，HIV特异性IgG 1水平是主要的区分因素。因此，虽然HLA背景之间的控制器与体液功能的差异最小，抗体亚类和特异性配置文件与不同的效应器功能，这表明这些功能可以用来进行功能预测。由于这些非中和抗体活性与感染受试者的自发病毒控制、病毒载量降低和非进展以及接种受试者的保护有关，因此了解具有增强效应子功能的IgG的具体特征可能对疫苗和治疗性抗体开发至关重要。我们通过研究不同遗传背景的HIV-1控制者之间的抗体反应，调查了获得性免疫的体液和细胞分支是否表现出协调或补偿性活性。
Understanding the coordination between humoral and cellular immune responses may be the key to developing protective vaccines, and because genetic studies of long-term HIV-1 nonprogressors have associated specific HLA-B alleles with spontaneous control of viral replication, this subject group presents an opportunity to investigate relationships between arms of the adaptive immune system. Given evidence suggesting that cellular immunity may play a role in viral suppression, we sought to determine whether and how the humoral immune response might vary among controllers. Significantly, Fc-mediated antibody effector functions have likewise been associated with durable viral control. In this study, we compared the effector function and biophysical features of HIV-specific antibodies in a cohort of controllers with and without protective HLA-B alleles in order to investigate whether there was evidence for multiple paths to HIV-1 control, or whether cellular and humoral arms of immunity might exhibit coordinated profiles. However, with the exception of IgG2 antibodies to gp41, HLA status was not associated with divergent humoral responses. This finding did not result from uniform antibody responses across subjects, as controllers could be regrouped according to strong differences in their HIV-specific antibody subclass specificity profiles. These divergent antibody profiles were further associated with significant differences in nonneutralizing antibody effector function, with levels of HIV-specific IgG1 acting as the major distinguishing factor. Thus, while HLA background among controllers was associated with minimal differences in humoral function, antibody subclass and specificity profiles were associated with divergent effector function, suggesting that these features could be used to make functional predictions. Because these nonneutralizing antibody activities have been associated with spontaneous viral control, reduced viral load, and nonprogression in infected subjects and protection in vaccinated subjects, understanding the specific features of IgGs with potentiated effector function may be critical to vaccine and therapeutic antibody development.IMPORTANCEIn this study, we investigated whether the humoral and cellular arms of adaptive immunity exhibit coordinated or compensatory activity by studying the antibody response among HIV-1 controllers with different genetic backgrounds.