Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
Department of Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2022 Jul 27;14(655):eabn9662. doi: 10.1126/scitranslmed.abn9662.
HIV broadly neutralizing antibodies (bNAbs) are capable of both blocking viral entry and driving innate immune responses against HIV-infected cells through their Fc region. Vaccination or productive infection results in a polyclonal mixture of class-switched immunoglobulin G (IgG) antibodies composed of four subclasses, each encoding distinct Fc regions that differentially engage innate immune functions. Despite evidence that innate immunity contributes to protection, the relative contribution of individual IgG subclasses is unknown. Here, we used vectored immunoprophylaxis in humanized mice to interrogate the efficacy of individual IgG subclasses during prevention of vaginal HIV transmission by VRC07, a potent CD4-binding site-directed bNAb. We find that VRC07 IgG2, which lacks Fc-mediated functionality, exhibited substantially reduced protection in vivo relative to other subclasses. Low concentrations of highly functional VRC07 IgG1 yielded substantial protection against vaginal challenge, suggesting that interventions capable of eliciting modest titers of functional IgG subclasses may provide meaningful benefit against infection.
HIV 广谱中和抗体（bNAb）能够通过其 Fc 区域阻断病毒进入并引发针对 HIV 感染细胞的固有免疫反应。接种疫苗或发生感染会导致由四个亚类组成的同种型转换免疫球蛋白 G（IgG）抗体的多克隆混合物，每个亚类编码不同的 Fc 区域，这些区域以不同的方式参与固有免疫功能。尽管有证据表明固有免疫有助于保护，但个体 IgG 亚类的相对贡献尚不清楚。在这里，我们使用载体免疫预防在人源化小鼠中研究了 VRC07 预防阴道 HIV 传播期间个体 IgG 亚类的功效，VRC07 是一种有效的 CD4 结合位点定向 bNAb。我们发现，缺乏 Fc 介导功能的 VRC07 IgG2 在体内的保护作用明显低于其他亚类。高浓度的高度功能性 VRC07 IgG1 对阴道攻击产生了实质性的保护作用，这表明能够引发适度功能 IgG 亚类滴度的干预措施可能对感染提供有意义的益处。
