Duke Human Vaccine Institute, Duke University Medical Centre, Durham, North Carolina, United States of America.
Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
PLoS Pathog. 2021 Apr 2;17(4):e1009478. doi: 10.1371/journal.ppat.1009478. eCollection 2021 Apr.
Despite considerable reduction of mother-to-child transmission (MTCT) of HIV through use of maternal and infant antiretroviral therapy (ART), over 150,000 infants continue to become infected with HIV annually, falling far short of the World Health Organization goal of reaching <20,000 annual pediatric HIV cases worldwide by 2020. Prior to the widespread use of ART in the setting of pregnancy, over half of infants born to HIV-infected mothers were protected against HIV acquisition. Yet, the role of maternal immune factors in this protection against vertical transmission is still unclear, hampering the development of synergistic strategies to further reduce MTCT. It has been established that infant transmitted/founder (T/F) viruses are often resistant to maternal plasma, yet it is unknown if the neutralization resistance profile of circulating viruses predicts the maternal risk of transmission to her infant. In this study, we amplified HIV-1 envelope genes (env) by single genome amplification and produced representative Env variants from plasma of 19 non-transmitting mothers from the U.S. Women Infant Transmission Study (WITS), enrolled in the pre-ART era. Maternal HIV Env variants from non-transmitting mothers had similar sensitivity to autologous plasma as observed for non-transmitting variants from transmitting mothers. In contrast, infant variants were on average 30% less sensitive to paired plasma neutralization compared to non-transmitted maternal variants from both transmitting and non-transmitting mothers (p = 0.015). Importantly, a signature sequence analysis revealed that motifs enriched in env sequences from transmitting mothers were associated with broadly neutralizing antibody (bnAb) resistance. Altogether, our findings suggest that circulating maternal virus resistance to bnAb-mediated neutralization, but not autologous plasma neutralization, near the time of delivery, predicts increased MTCT risk. These results caution that enhancement of maternal plasma neutralization through passive or active vaccination during pregnancy may potentially drive the evolution of variants fit for vertical transmission.
尽管通过使用母婴抗逆转录病毒疗法（ART），已经大大降低了 HIV 母婴传播（MTCT）的发生率，但每年仍有超过 15 万名婴儿感染 HIV，远远低于世界卫生组织到 2020 年实现全球每年儿科 HIV 病例数<2 万例的目标。在妊娠期间广泛使用 ART 之前，超过一半感染 HIV 的母亲所生婴儿可免受 HIV 感染。然而，母体免疫因素在预防垂直传播方面的作用仍不清楚，这阻碍了制定协同策略以进一步降低 MTCT 的进展。已经证实，婴儿传播/创始（T/F）病毒通常对母体血浆具有耐药性，但尚不清楚循环病毒的中和耐药谱是否可预测母体将病毒传播给婴儿的风险。在这项研究中，我们通过单基因组扩增扩增了 HIV-1 包膜基因（env），并从美国妇女婴儿传播研究（WITS）中 19 名未传播母亲的血浆中产生了具有代表性的 Env 变体，这些母亲均在 ART 前时代入组。未传播母亲的 HIV Env 变体与从传播母亲中获得的非传播变体一样，对自身血浆具有相似的敏感性。相比之下，与从传播和未传播母亲中获得的非传播母体 Env 变体相比，婴儿变体对配对血浆中和的敏感性平均降低了 30％（p = 0.015）。重要的是，特征序列分析表明，在传播母亲的 env 序列中富集的基序与广谱中和抗体（bnAb）耐药性相关。总而言之，我们的发现表明，在分娩时，循环母体病毒对 bnAb 介导的中和的耐药性，而不是对自身血浆的中和，可预测 MTCT 风险增加。这些结果表明，在怀孕期间通过被动或主动免疫接种增强母体血浆中和作用，可能会导致适合垂直传播的变体进化。
