Lai Jennifer I, Licht Anna F, Dugast Anne-Sophie, Suscovich Todd, Choi Ickwon, Bailey-Kellogg Chris, Alter Galit, Ackerman Margaret E
Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, USA.
J Virol. 2014 Mar;88(5):2799-809. doi: 10.1128/JVI.03130-13. Epub 2013 Dec 18.
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.
In 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.
了解体液免疫和细胞免疫反应之间的协调作用可能是开发保护性疫苗的关键，并且由于对长期HIV-1非进展者的基因研究已将特定的HLA - B等位基因与病毒复制的自发控制相关联，这一研究对象群体为研究适应性免疫系统各分支之间的关系提供了契机。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在病毒控制者中是否存在差异以及如何存在差异。值得注意的是，Fc介导的抗体效应功能同样与持久的病毒控制相关。在本研究中，我们比较了一组具有和不具有保护性HLA - B等位基因的病毒控制者中HIV特异性抗体的效应功能和生物物理特征，以研究是否有证据表明存在多种控制HIV-1的途径，或者免疫的细胞和体液分支是否可能表现出协调的特征。然而，除了针对gp41的IgG2抗体外，HLA状态与不同的体液反应无关。这一发现并非源于受试者之间一致的抗体反应，因为病毒控制者可根据其HIV特异性抗体亚类特异性谱的强烈差异重新分组。这些不同的抗体谱还与非中和抗体效应功能的显著差异相关，HIV特异性IgG1的水平是主要的区分因素。因此，虽然病毒控制者中的HLA背景与体液功能的微小差异相关，但抗体亚类和特异性谱与不同的效应功能相关，这表明这些特征可用于进行功能预测。由于这些非中和抗体活性与自发病毒控制、病毒载量降低、感染受试者的病情非进展以及疫苗接种受试者的保护相关，了解具有增强效应功能的IgG的特定特征可能对疫苗和治疗性抗体的开发至关重要。
在本研究中，我们通过研究不同遗传背景的HIV-1病毒控制者之间的抗体反应，调查了适应性免疫的体液和细胞分支是否表现出协调或补偿性活动。
