Data Sheet 1_Vaginal microbiome dysbiosis and sexually transmitted infections correlate with concentrations of immunoglobulin isotypes in human cervicovaginal mucus: insights into HIV-1 transmission.docx

IntroductionLittle is known about the relationship between antibody isotype in cervicovaginal mucus (CVM) and the local microenvironment and how this impacts HIV-1 transmission at the female genital mucosa.
MethodsIn a cohort of 139 adult women in Kenya, we measured antibody isotypes in CVM and describe their associations with local pH, serum concentrations of estrogen and progesterone, and sexually transmitted infections (STIs), including HIV-1.
ResultsWe found that immunoglobulin G2 (IgG2) was the most abundant and IgG4 was the least abundant in the CVM. Overall, IgG1 concentrations were significantly lower in CVM samples from women with bacterial vaginosis (BV) compared to those without BV. Among women with BV, IgG1 concentrations declined further as vaginal pH increased, suggesting possible pH-mediated degradation. We also report negative associations of BV status with IgG3 and IgG4. In addition, infection with Mycoplasma genitalium and Neisseria gonorrhoeae was positively associated with concentrations of IgA and IgM, respectively. We also found the relationship between antibody isotype and subclasses with HIV-1 viral mobility in vitro. IgG3 concentrations negatively correlated with CAP045 HIV-1 mobility and IgG1 concentrations negatively correlated with the mobility of the 92TH023 recombinant HIV-1 strain upon VRC01 depletion. These observations point towards a potentially protective role for IgG1 and IgG3 in trapping certain HIV-1 strains in the CVM.
DiscussionImportantly, our study builds on previous work, providing a potential mechanism by which BV and STIs may modulate immunoglobulin isotype and subclass content in the CVM. These results highlight the need for proper treatment of BV and other STIs, as this could impact the effectiveness of HIV-1 vaccines targeted at enhancing specific immunoglobulin responses in the cervicovaginal mucosa.

引言
目前学界对宫颈阴道黏液（cervicovaginal mucus, CVM）中的抗体同种型与局部微环境的关联，以及该关联如何影响女性生殖道黏膜处的HIV-1传播，尚缺乏充分认知。

方法
本研究纳入肯尼亚139名成年女性队列，对其宫颈阴道黏液内的抗体同种型进行检测，并分析其与局部pH值、血清雌激素及孕酮浓度，以及包括HIV-1在内的性传播感染（sexually transmitted infections, STIs）的关联。

结果
我们发现，宫颈阴道黏液中免疫球蛋白G2（immunoglobulin G2, IgG2）丰度最高，免疫球蛋白G4（immunoglobulin G4, IgG4）丰度最低。整体而言，相较于无细菌性阴道病（bacterial vaginosis, BV）的女性，细菌性阴道病患者的宫颈阴道黏液样本中免疫球蛋白G1（IgG1）浓度显著更低。在细菌性阴道病患者中，随着阴道pH值升高，IgG1浓度进一步下降，提示可能存在pH介导的降解过程。我们还观察到，细菌性阴道病患病状态与IgG3、IgG4呈负相关。此外，生殖支原体（Mycoplasma genitalium）感染与IgA浓度呈正相关，淋病奈瑟菌（Neisseria gonorrhoeae）感染则与IgM浓度呈正相关。我们还发现抗体同种型及亚类与体外HIV-1病毒迁移能力存在关联：IgG3浓度与CAP045 HIV-1毒株的迁移能力呈负相关；在VRC01耗竭条件下，IgG1浓度与92TH023重组HIV-1毒株的迁移能力呈负相关。上述结果提示，IgG1与IgG3可能在宫颈阴道黏液捕获特定HIV-1毒株的过程中发挥保护性作用。

讨论
值得注意的是，本研究在既往研究基础上，进一步阐明了细菌性阴道病与性传播感染可能调控宫颈阴道黏液内抗体同种型及亚类组成的潜在机制。上述结果凸显了规范治疗细菌性阴道病及其他性传播感染的必要性，因为这或可影响以增强女性生殖道黏膜特异性抗体应答为目标的HIV-1疫苗的保护效力。