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母体广谱且强效抗体应答背景下的垂直 HIV-1 传播。

Vertical HIV-1 Transmission in the Setting of Maternal Broad and Potent Antibody Responses.

机构信息

Duke Human Vaccine Institute, Duke Universitygrid.26009.3d Medical Center, Durham, North Carolina, USA.

BioAgilytix Labs, Durham, North Carolina, USA.

出版信息

J Virol. 2022 Jun 8;96(11):e0023122. doi: 10.1128/jvi.00231-22. Epub 2022 May 10.

Abstract

Despite the worldwide availability of antiretroviral therapy (ART), approximately 150,000 pediatric HIV infections continue to occur annually. ART can dramatically reduce HIV mother-to-child transmission (MTCT), but inconsistent drug access and adherence, as well as primary maternal HIV infection during pregnancy and lactation are major barriers to eliminating vertical HIV transmission. Thus, immunologic strategies to prevent MTCT, such as an HIV vaccine, will be required to attain an HIV-free generation. A primary goal of HIV vaccine research has been to elicit broadly neutralizing antibodies (bnAbs) given the ability of passive bnAb immunization to protect against sensitive strains, yet we previously observed that HIV-transmitting mothers have more plasma neutralization breadth than nontransmitting mothers. Additionally, we have identified infant transmitted/founder (T/F) viruses that escape maternal bnAb responses. In this study, we examine a cohort of postpartum HIV-transmitting women with neutralization breadth to determine if certain maternal bnAb specificities drive the selection of infant T/F viruses. Using HIV pseudoviruses that are resistant to neutralizing antibodies targeting common bnAb epitopes, we mapped the plasma bnAb specificities of this cohort. Significantly more transmitting women with plasma bnAb activity had a mappable plasma bnAb specificity (six of seven, or 85.7%) compared to that of nontransmitting women with plasma bnAb activity (7 of 21, or 33.3%,  = 0.029 by 2-sided Fisher exact test). Our study suggests that having multispecific broad activity and/or uncommon epitope-specific bnAbs in plasma may be associated with protection against the vertical HIV transmission in the setting of maternal bnAb responses. As mother to child transmission (MTCT) of HIV plays a major part in the persistence of the HIV/AIDS epidemic and bnAb-based passive and active vaccines are a primary strategy for HIV prevention, research in this field is of great importance. While previous MTCT research has investigated the neutralizing antibody activity of HIV-infected women, this is, to our knowledge, the largest study identifying differences in bnAb specificity of maternal plasma between transmitting and nontransmitting women. Here, we show that among HIV-infected women with broad and potent neutralization activity, more postpartum-transmitting women had a mappable plasma broadly neutralizing antibody (bnAb) specificity, compared to that of nontransmitting women, suggesting that the nontransmitting women more often have multispecific bnAb responses or bnAb responses that target uncommon epitopes. Such responses may be required for protection against vertical HIV transmission in the setting of maternal bnAb responses.

摘要

尽管全世界都可以获得抗逆转录病毒疗法(ART),但每年仍有约 15 万例儿科 HIV 感染。ART 可以显著降低母婴 HIV 传播(MTCT),但药物获取和依从性不一致,以及孕妇和哺乳期原发性 HIV 感染,是消除垂直 HIV 传播的主要障碍。因此,需要免疫策略来预防 MTCT,例如 HIV 疫苗,以实现无 HIV 世代。HIV 疫苗研究的一个主要目标是诱导广泛中和抗体(bnAb),因为被动 bnAb 免疫能够保护敏感株,但我们之前观察到,HIV 传播的母亲比非传播的母亲具有更多的血浆中和广度。此外,我们已经确定了逃避母体 bnAb 反应的婴儿传播/起源(T/F)病毒。在这项研究中,我们检查了一组产后 HIV 传播的妇女的中和广度,以确定是否存在某些母体 bnAb 特异性会驱动婴儿 T/F 病毒的选择。使用对针对常见 bnAb 表位的中和抗体具有抗性的 HIV 假病毒,我们绘制了该队列的血浆 bnAb 特异性。与具有血浆 bnAb 活性的非传播妇女相比,具有可映射血浆 bnAb 特异性的传播妇女(七分之六,或 85.7%)明显更多(双侧 Fisher 精确检验,  = 0.029)。我们的研究表明,血浆中具有多特异性广泛活性和/或罕见表位特异性 bnAb 的存在可能与母体 bnAb 反应情况下对垂直 HIV 传播的保护有关。由于母婴传播(MTCT)HIV 在 HIV/AIDS 流行的持续存在中起着重要作用,并且 bnAb 为基础的被动和主动疫苗是 HIV 预防的主要策略,因此该领域的研究非常重要。虽然以前的 MTCT 研究已经调查了感染 HIV 的妇女的中和抗体活性,但据我们所知,这是最大的研究,确定了在传播和非传播妇女之间母体血浆中 bnAb 特异性的差异。在这里,我们表明,在具有广泛而有效的中和活性的 HIV 感染妇女中,与非传播妇女相比,更多的产后传播妇女具有可映射的血浆广泛中和抗体(bnAb)特异性,这表明非传播妇女更常见具有多特异性 bnAb 反应或针对罕见表位的 bnAb 反应。这种反应可能是在母体 bnAb 反应的情况下防止垂直 HIV 传播所必需的。

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