Department of Pathology, Duke University, Durham, North Carolina, United States of America.
Department of Pediatrics, Weill Cornell Medical College, New York, New York, United States of America.
PLoS Pathog. 2023 Oct 23;19(10):e1011378. doi: 10.1371/journal.ppat.1011378. eCollection 2023 Oct.
Cytomegalovirus (CMV) is the most common congenital infection and cause of birth defects worldwide. Primary CMV infection during pregnancy leads to a higher frequency of congenital CMV (cCMV) than maternal re-infection, suggesting that maternal immunity confers partial protection. However, poorly understood immune correlates of protection against placental transmission contributes to the current lack of an approved vaccine to prevent cCMV. In this study, we characterized the kinetics of maternal plasma rhesus CMV (RhCMV) viral load (VL) and RhCMV-specific antibody binding and functional responses in a group of 12 immunocompetent dams with acute, primary RhCMV infection. We defined cCMV transmission as RhCMV detection in amniotic fluid (AF) by qPCR. We then leveraged a large group of past and current primary RhCMV infection studies in late-first/early-second trimester RhCMV-seronegative rhesus macaque dams, including immunocompetent (n = 15), CD4+ T cell-depleted with (n = 6) and without (n = 6) RhCMV-specific polyclonal IgG infusion before infection to evaluate differences between RhCMV AF-positive and AF-negative dams. During the first 3 weeks after infection, the magnitude of RhCMV VL in maternal plasma was higher in AF-positive dams in the combined cohort, while RhCMV glycoprotein B (gB)- and pentamer-specific binding IgG responses were lower magnitude compared to AF-negative dams. However, these observed differences were driven by the CD4+ T cell-depleted dams, as there were no differences in plasma VL or antibody responses between immunocompetent AF-positive vs AF-negative dams. Overall, these results suggest that levels of neither maternal plasma viremia nor humoral responses are associated with cCMV following primary maternal infection in healthy individuals. We speculate that other factors related to innate immunity are more important in this context as antibody responses to acute infection likely develop too late to influence vertical transmission. Yet, pre-existing CMV glycoprotein-specific and neutralizing IgG may provide protection against cCMV following primary maternal CMV infection even in high-risk, immunocompromised settings.
巨细胞病毒（CMV）是全球最常见的先天性感染和出生缺陷原因。妊娠期间原发性 CMV 感染比母体再感染导致先天性 CMV（cCMV）的频率更高，这表明母体免疫提供了部分保护。然而，对抗胎盘传播的保护性免疫相关因素仍知之甚少，这导致目前缺乏预防 cCMV 的批准疫苗。在这项研究中，我们描述了一组 12 名免疫功能正常的急性原发性 RhCMV 感染母体的母血浆恒河猴 CMV（RhCMV）病毒载量（VL）和 RhCMV 特异性抗体结合和功能反应的动力学。我们将 cCMV 传播定义为通过 qPCR 在羊水中检测到 RhCMV。然后，我们利用过去和目前在 RhCMV 血清阴性的恒河猴初孕期/早中孕期原发性 RhCMV 感染的大量研究，包括免疫功能正常（n=15）、CD4+ T 细胞耗竭（n=6）和未耗竭（n=6），在感染前输注 RhCMV 特异性多克隆 IgG，以评估 RhCMV 阳性和 RhCMV 阴性母猴之间的差异。在感染后的前 3 周，合并队列中 RhCMV 阳性母猴的母血浆 RhCMV VL 幅度更高，而 RhCMV 糖蛋白 B（gB）和五聚体特异性结合 IgG 反应的幅度较低。然而，这些观察到的差异是由 CD4+ T 细胞耗竭的母猴引起的，因为免疫功能正常的 RhCMV 阳性与 RhCMV 阴性母猴之间的血浆 VL 或抗体反应没有差异。总体而言，这些结果表明，在健康个体中，原发性母体感染后，母血浆病毒血症或体液反应水平均与 cCMV 无关。我们推测，在这种情况下，与先天免疫相关的其他因素更为重要，因为急性感染后的抗体反应可能发展得太晚，无法影响垂直传播。然而，针对 CMV 糖蛋白的预先存在的特异性和中和 IgG 可能为原发性母体 CMV 感染后的 cCMV 提供保护，即使在高危免疫功能低下的情况下也是如此。
