Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Medical Scientist Training Program, University of Washington, Seattle, Washington, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.01594-19.
Infants of HIV-positive mothers can acquire HIV infection by various routes, but even in the absence of antiviral treatment, the majority of these infants do not become infected. There is evidence that maternal antibodies provide some protection from infection, but gestational maternal antibodies have not yet been characterized in detail. One of the most studied vertically infected infants is BG505, as the virus from this infant yielded an Envelope protein that was successfully developed as a stable trimer. Here, we isolated and characterized 39 HIV-specific neutralizing monoclonal antibodies (nAbs) from MG505, the mother of BG505, at a time point just prior to vertical transmission. These nAbs belonged to 21 clonal families and employed a variety of VH genes. Many were specific for the HIV-1 Env V3 loop, and this V3 specificity correlated with measurable antibody-dependent cellular cytotoxicity (ADCC) activity. The isolated nAbs did not recapitulate the full breadth of heterologous or autologous virus neutralization by contemporaneous plasma. Notably, we found that the V3-targeting nAb families neutralized one particular maternal Env variant, even though all tested variants had low V3 sequence diversity and were measurably bound by these nAbs. None of the nAbs neutralized BG505 transmitted virus. Furthermore, the MG505 nAb families were found at relatively low frequencies within the maternal B cell repertoire; all were less than 0.25% of total IgG sequences. Our findings illustrate an example of the diversity of HIV-1 nAbs within one mother, cumulatively resulting in a collection of antibody specificities that can contribute to the transmission bottleneck. Mother-to-child-transmission of HIV-1 offers a unique setting in which maternal antibodies both within the mother and passively transferred to the infant are present at the time of viral exposure. Untreated HIV-exposed human infants are infected at a rate of 30 to 40%, meaning that some infants do not get infected despite continued exposure to virus. Since the potential of HIV-specific immune responses to provide protection against HIV is a central goal of HIV vaccine design, understanding the nature of maternal antibodies may provide insights into immune mechanisms of protection. In this study, we isolated and characterized HIV-specific antibodies from the mother of an infant whose transmitted virus has been well studied.
HIV 阳性母亲的婴儿可通过多种途径感染 HIV，但即使没有抗病毒治疗，大多数婴儿也不会感染。有证据表明，母体抗体提供了一定程度的抗感染保护，但妊娠期母体抗体尚未得到详细描述。研究最多的垂直感染婴儿之一是 BG505，因为来自该婴儿的病毒产生了一种成功开发为稳定三聚体的包膜蛋白。在这里，我们在垂直传播之前的时间点从 BG505 的母亲 MG505 中分离和鉴定了 39 种 HIV 特异性中和单克隆抗体（nAb）。这些 nAb 属于 21 个克隆家族，并使用了多种 VH 基因。许多针对 HIV-1 包膜蛋白的 V3 环，这种 V3 特异性与可测量的抗体依赖性细胞毒性（ADCC）活性相关。分离的 nAb 并没有再现同时期血浆对异源或同源病毒的完全中和广度。值得注意的是，我们发现针对 V3 的 nAb 家族中和了一种特定的母体包膜蛋白变异体，尽管所有测试的变异体的 V3 序列多样性都很低，并且这些 nAb 都可测量地结合了它们。没有一种 nAb 能中和 BG505 传播的病毒。此外，MG505 nAb 家族在母体 B 细胞库中的频率相对较低；所有都低于总 IgG 序列的 0.25%。我们的研究结果说明了一个母亲体内 HIV-1 nAb 多样性的例子，这些多样性累积起来形成了一组抗体特异性，可以有助于传播瓶颈。HIV-1 的母婴传播为母体抗体提供了一个独特的环境，在病毒暴露时，母体抗体既存在于母体中，也被动转移到婴儿体内。未经治疗的 HIV 暴露婴儿的感染率为 30%至 40%，这意味着尽管持续接触病毒，仍有一些婴儿未被感染。由于 HIV 特异性免疫反应提供对 HIV 保护的潜力是 HIV 疫苗设计的核心目标，因此了解母体抗体的性质可能为免疫保护机制提供一些见解。在这项研究中，我们从一个婴儿的母亲身上分离和鉴定了 HIV 特异性抗体，该婴儿的传播病毒已得到很好的研究。
