Role of neutralizing antibodies in HIV-1-infected and vaccinated mothers in MTCT

 描述(申请人提供)：尽管婴儿占世界人口的2%，但每年仍有超过20万婴儿感染艾滋病毒-1，占全球艾滋病毒-1传播的八分之一。虽然孕产妇抗逆转录病毒(ARV)治疗可以显著减少母婴传播，但即使是最有效的方案也无法消除传播，其影响因产妇的依从性、可及性和监测不力而减弱。最近，在怀孕期间增加了第三个抗逆转录病毒病毒，减少了围产期艾滋病毒-1的传播率为0.5%，但以更高的早产儿和婴儿死亡率为代价，强调了消除儿童艾滋病毒-1的额外和更安全策略的必要性。开发免疫干预措施以消除艾滋病毒-1垂直传播将需要确定母亲艾滋病毒-1环境特异性抗体的保护特性，这些抗体在出生前和通过母乳喂养被动传播给婴儿。我们最近使用妇婴传播研究(WITS，n=248)的样本确定了共同激发的母体抗体反应，这些抗体反应预测MTCT的风险降低。WITS是一组在ARV前时代登记的美国HIV-1感染母婴对队列：1)针对Env Variable loop 3(V3)的IgG反应，2)CD4结合位点特异性抗体反应，以及3)支系匹配的Ti1 HIV-1变种的中和。我们可能解释了这些已识别的母体免疫相关因素背后的机制，我们证明了母体环境V3特异性单抗可以中和同时循环的自体病毒变体，尽管对难以中和的异源第2层病毒没有活性。因此，我们假设，共同诱导的非广谱中和抗体(如针对V3环和CD4结合位点的抗体)的自体中和作用是保护MTCT的机械性免疫相关因素，并可由母体Env免疫诱导。在这项资助中，我们将根据我们确定的母婴传播风险的相关因素，探索共同诱导的抗体作为预防母婴传播的一种保护机制。我们将确定自体中和敏感性是否区分婴儿传播的变种和母亲非传播的变种(目标1)，绘制定义婴儿传播的病毒中和敏感性的Env区域和氨基酸残基(目标2)，并在历史临床试验中确定是否可以通过异源Env免疫在感染艾滋病毒的孕妇中增强自体中和反应(目标3)。我们的结果将确定自体中和是否是预防MTCT的一种机制，以及疫苗策略是否可以引发一种反应。这项工作将确定设计和评估艾滋病毒-1免疫战略的指导原则，这是消除儿童艾滋病毒-1流行病所必需的。

 DESCRIPTION (provided by applicant): More than 200,000 infants continue to become infected with HIV-1 annually, accounting for 1/8th of the worldwide HIV-1 transmission, despite infants representing <2% of the world's population. Although maternal antiretroviral (ARV) treatment can dramatically reduce MTCT, even the most potent regimens have been unable to eliminate transmission, and their impact is weakened by poor maternal adherence, access, and monitoring. Recently, the addition of a 3rd ARV during pregnancy reduced peripartum HIV-1 transmission to <0.5%, yet came at the expense of a higher prematurity and death rate in infants, underscoring the need for additional and safer strategies to eliminate pediatric HIV-1. Developing immunologic interventions to eliminate vertical HIV-1 transmission will require defining the protective properties of maternal HIV-1 Env-specific antibodies that are passively transferred to the infant prior to birth and via breastfeeding. We recently identified commonly-elicited maternal antibody responses that predict reduced risk of MTCT using samples from the Women and Infants Transmission Study (WITS, n = 248), a cohort of U.S. HIV-1-infected mother-infant pairs enrolled in the pre-ARV era: 1) IgG responses directed against the Env variable loop 3 (V3), 2) CD4 binding site-specific antibody responses, and 3) neutralization of clade-matched tier 1 HIV-1 variants. Potentially explaining the mechanism behind these identified maternal immune correlates, we demonstrated that maternal Env V3-specific monoclonal antibodies can neutralize concurrently circulating autologous virus variants, despite having no activity against heterologous tier 2, difficult-to-neutralize viruses. Thus, we hypothesize that autologous neutralization by commonly-elicited, non-broadly neutralizing antibodies, such as those directed against the V3 loop and CD4 binding site, are mechanistic immune correlates of protection against MTCT and can be elicited by maternal Env immunization. In this grant, we will probe autologous neutralization by commonly-elicited Abs as a mechanism of protection against MTCT, based on our identified correlates of MTCT risk. We will determine whether autologous neutralization sensitivity distinguishes infant transmitted variants from maternal non- transmitted variants (Aim 1), map the Env regions and amino acid residues that define the neutralization sensitivity of infant transmitted viruses (Aim 2), and determine whether autologous neutralization responses can be enhanced by heterologous Env immunization among HIV-infected pregnant women in a historical clinical trial (Aim 3). Our results will establish whether autologous neutralization is a mechanism of protection against MTCT and a response that can be elicited by vaccine strategies. This work will establish guiding principles for design and evaluation of HIV-1 immunization strategies that will be necessary to eliminate the pediatric HIV-1 epidemic.