Zhou Mingkui, Ruprecht Ruth M
Department of Virology & Immunology, Texas Biomedical Research Institute, 7620 NW Loop 410, San Antonio, TX, 78227, USA.
Southwest National Primate Research Center, 7620 NW Loop 410, San Antonio, TX, 78227, USA.
Retrovirology. 2014 Dec 14;11:109. doi: 10.1186/s12977-014-0109-5.
An estimated 90% of all HIV transmissions occur mucosally. Immunoglobulin A (IgA) molecules are important components of mucosal fluids. In a vaccine efficacy study, in which virosomes displaying HIV gp41 antigens protected most rhesus monkeys (RMs) against simian-human immunodeficiency virus (SHIV), protection correlated with vaginal IgA capable of blocking HIV transcytosis in vitro. Furthermore, vaginal IgG exhibiting virus neutralization and/or antibody-dependent cellular cytotoxicity (ADCC) correlated with prevention of systemic infection. In contrast, plasma IgG had neither neutralizing nor ADCC activity. More recently, a passive mucosal immunization study provided the first direct proof that dimeric IgAs (dIgAs) can prevent SHIV acquisition in RMs challenged mucosally. This study compared dimeric IgA1 (dIgA1), dIgA2, or IgG1 versions of a human neutralizing monoclonal antibody (nmAb) targeting a conserved HIV Env epitope. While the nmAb neutralization profiles were identical in vitro, dIgA1 was significantly more protective in vivo than dIgA2. Protection was linked to a new mechanism: virion capture. Protection also correlated with inhibition of transcytosis of cell-free virus in vitro. While both of these primate model studies demonstrated protective effects of mucosal IgAs, the RV144 clinical trial identified plasma IgA responses to HIV Env as risk factors for increased HIV acquisition. In a secondary analysis of RV144, plasma IgA decreased the in vitro ADCC activity of vaccine-induced, Env-specific IgG with the same epitope specificity. Here we review the current literature regarding the potential of IgA - systemic as well as mucosal - in modulating virus acquisition and address the question whether anti-HIV IgA responses could help or harm the host.
据估计，所有HIV传播中有90%是通过黏膜发生的。免疫球蛋白A（IgA）分子是黏膜分泌物的重要组成部分。在一项疫苗效力研究中，展示HIV gp41抗原的病毒体保护了大多数恒河猴（RM）免受猿猴-人类免疫缺陷病毒（SHIV）感染，这种保护作用与能够在体外阻断HIV转胞吞作用的阴道IgA相关。此外，具有病毒中和及/或抗体依赖性细胞毒性（ADCC）作用的阴道IgG与预防全身感染相关。相比之下，血浆IgG既无中和活性也无ADCC活性。最近，一项被动黏膜免疫研究首次直接证明，二聚体IgA（dIgA）可预防经黏膜攻击的恒河猴感染SHIV。该研究比较了针对保守HIV Env表位的人源中和单克隆抗体（nmAb）的二聚体IgA1（dIgA1）、dIgA2或IgG1变体。虽然nmAb在体外的中和谱相同，但dIgA1在体内的保护作用显著强于dIgA2。保护作用与一种新机制有关：病毒体捕获。保护作用还与体外抑制无细胞病毒的转胞吞作用相关。虽然这两项灵长类动物模型研究都证明了黏膜IgA的保护作用，但RV144临床试验却将血浆中针对HIV Env的IgA反应确定为HIV感染增加的危险因素。在对RV144的二次分析中，血浆IgA降低了具有相同表位特异性的疫苗诱导的Env特异性IgG的体外ADCC活性。在此，我们综述了当前有关IgA（包括全身和黏膜IgA）在调节病毒感染方面潜力的文献，并探讨抗HIV IgA反应对宿主是有益还是有害的问题。
