Hepatitis C virus (HCV) can be transmitted from mother to child during pregnancy and childbirth. However, the timing and precise biological mechanisms that are involved in this process are incompletely understood, as are the determinants that influence transmission of particular HCV variants. Here we report results of a longitudinal assessment of HCV quasispecies diversity and composition in 5 cases of vertical HCV transmission, including 3 women coinfected with human immunodeficiency virus type 1 (HIV-1). The population structure of HCV variant spectra based on E2 envelope gene sequences (nucleotide positions 1491 to 1787), including hypervariable regions 1 and 2, was characterized using next-generation sequencing and median-joining network analysis. Compatible with a loose transmission bottleneck, larger numbers of shared HCV variants were observed in the presence of maternal coinfection. Coalescent Bayesian Markov chain Monte Carlo simulations revealed median times of transmission between 24.9 weeks and 36.1 weeks of gestation, with some confidence intervals ranging into the 1st trimester, considerably earlier than previously thought. Using recombinant autologous HCV pseudoparticles, differences were uncovered in HCV-specific antibody responses between coinfected mothers and mothers infected with HCV alone, in whom generalized absence of neutralization was observed. Finally, shifts in HCV quasispecies composition were seen in children around 1 year of age, compatible with the disappearance of passively transferred maternal immunoglobulins and/or the development of HCV-specific humoral immunity. Taken together, these results provide insights into the timing, dynamics, and biologic mechanisms involved in vertical HCV transmission and inform preventative strategies.

IMPORTANCE Although it is well established that hepatitis C virus (HCV) can be transmitted from mother to child, the manner and the moment at which transmission operates have been the subject of conjecture. By carrying out a detailed examination of viral sequences, we showed that transmission could take place comparatively early in pregnancy. In addition, we showed that when the mother also carried human immunodeficiency virus type 1 (HIV-1), many more HCV variants were shared between her and her child, suggesting that the mechanism and/or the route of transmission of HCV differed in the presence of coinfection with HIV-1. These results could explain why cesarean section is ineffective in preventing vertical HCV transmission and guide the development of interventions to avert pediatric HCV infection.

丙型肝炎病毒（HCV）可以在怀孕和分娩期间从母亲传播给孩子。但是，该过程涉及的时间安排和精确的生物学机制以及影响特定HCV变异传播的决定因素尚未完全理解。在这里，我们报告了5例HCV垂直传播病例中HCV准种多样性和组成的纵向评估结果，其中包括3例共同感染1型人类免疫缺陷病毒（HIV-1）的妇女。使用下一代测序和中值连接网络分析对基于E2包膜基因序列（核苷酸位置1491至1787）（包括高变区1和2）的HCV变异谱的种群结构进行了表征。兼容宽松的传输瓶颈，在孕产妇合并感染的情况下，观察到大量共享的HCV变异体。合并的贝叶斯马尔可夫链蒙特卡罗模拟显示，妊娠的中位传播时间为24.9周至36.1周，某些置信区间为妊娠中期，大大早于先前的设想。使用重组自体HCV假颗粒，未发现共感染母亲与仅感染HCV的母亲之间在HCV特异性抗体反应方面存在差异，但普遍未发现中和现象。最后，在1岁左右的儿童中发现了HCV准种组成的变化，与被动转移的母体免疫球蛋白的消失和/或HCV特异性体液免疫的发展相适应。在一起

重要信息尽管已经公认丙型肝炎病毒（HCV）可以从母体传播到儿童，但传播方式和时机一直是推测的对象。通过对病毒序列进行详细检查，我们表明传播可以在妊娠早期进行。此外，我们发现，当母亲还携带人类免疫缺陷病毒1型（HIV-1）时，她和她的孩子之间共享了更多的HCV变异体，这表明HCV的传播机理和/或传播途径有所不同。 HIV-1合并感染的存在。这些结果可以解释为什么剖宫产不能有效地预防垂直HCV传播，并指导避免小儿HCV感染的干预措施的发展。