Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection

项目摘要/摘要，免疫控制(项目4) 对于越来越多的感染艾滋病毒的婴儿来说，找到艾滋病毒感染的治疗方法尤为重要， 如果治疗方案无效，儿童和青少年将不得不接受终身抗逆转录病毒治疗 有空。最近的进展表明，实现HIV-1感染的功能性治愈可能不需要 彻底消灭所有完整的艾滋病毒-1前病毒；相反，针对完整的前病毒可能就足够了 整合在允许的染色质位置，支持HIV-1转录，更容易感染病毒 重新激活信号。这种治愈HIV-1感染的模式似乎是精英管制员的例子，在他们身上 我们记录了一个非常独特的染色体整合部位景观，其特征是完整的 异染色质区域的前病毒。值得注意的是，这种前病毒整合站点的“屏蔽和锁定”模式 可能代表了细胞免疫选择力量的结果，这些力量成功地消除了 在可接近的染色质位置的前病毒，而在异染色质位置的前病毒可以长期存在。 这一概念增加了免疫介导的选择机制可以强化或加速的可能性 通过治疗性疫苗接种，在开始抗逆转录病毒治疗的HIV-1感染婴儿中可能优先诱导 感染早期阶段。在这里，我们建议对婴儿的病毒库动力学进行详细的分析。 接受含有多洛替格列韦的抗逆转录病毒治疗(ART)，最终目的是告知未来的临床 通过个人化治疗性信使核糖核酸诱导“封闭和锁定”病毒库结构的试验 含有自体前病毒序列的疫苗。在特定目标1中，我们将研究病毒序列 并确定开始使用含多洛替格列韦的抗逆转录病毒疗法的婴儿中完整前病毒的频率， 与接受洛匹那韦/利托那韦抗逆转录病毒治疗的婴儿现有的相应数据相关；这些研究 将使我们能够追踪完整和有缺陷的前病毒的自然进化，并生成完整的地图集 可考虑纳入个性化治疗性mRNA疫苗的前病毒将在 未来的原则证明研究。在特定目标2中，我们将对染色体定位进行纵向评估 这些婴儿在持续ART期间的完整前病毒；我们假设免疫介导的选择 至少在一些婴儿中，机制可以促进和促进前病毒整合部位的环境， 近似精英控制器中观察到的“被阻止和锁定”的前病毒体系结构；这样的选择 在未来的研究中，可能会通过有计划的个性化信使核糖核酸疫苗进一步强化这种机制。 在具体目标3中，我们将进行开创性研究，以表征细胞和 SARS-CoV2基因疫苗诱导HIV-1感染儿童的体液免疫应答 来自博茨瓦纳的患者；这样的研究将为未来所有针对HIV-1的特异性治疗提供高度信息 在信使核糖核酸平台上的疫苗接种方法。

Project Summary/Abstract, Immune Control (Project 4) Finding a cure for HIV-1 infection is of particular importance for the growing number of HIV-1-infected infants, children and teenagers who will have to take lifelong antiretroviral therapy if curative treatment options will not be available. Recent advances suggest that achieving a functional cure of HIV-1 infection may not require complete elimination of all intact HIV-1 proviruses; instead, it may be sufficient to target intact proviruses integrated in permissive chromatin positions that support HIV-1 transcription and are more susceptible to viral reactivation signals. This model for a cure of HIV-1 infection seems to be exemplified by elite controllers, in whom we documented a highly distinct chromosomal integration site landscape characterized by location of intact proviruses in heterochromatin regions. Notably, such a “blocked and locked” pattern of proviral integration sites likely represents the consequence of cellular immune selection forces that have successfully eliminated proviruses in accessible chromatin locations, while proviruses in heterochromatin positions can persist long term. This concept raises the possibility that immune-mediated selection mechanisms can be intensified or accelerated through therapeutic vaccination, and may be preferentially inducible in HIV-1-infected infants starting ART at early stages of infection. Here, we propose to conduct a detailed analysis of viral reservoir dynamics in infants undergoing dolutegravir-containing antiretroviral therapy (ART), with the ultimate aim of informing future clinical trials designed to induce a “blocked and locked” viral reservoir structure through personalized therapeutic mRNA vaccines incorporating autologous proviral sequences. In specific aim 1, we will investigate viral sequences near birth and determine the frequency of intact proviruses in infants started on dolutegravir-containing ART, relative to existing corresponding data from infants undergoing lopinavir/ritonavir-containing ART; these studies will allow us to track the natural evolution of intact and defective proviruses, and generate an atlas of intact proviruses that can be considered for inclusion into personalized therapeutic mRNA vaccines to be tested in future proof-of-principle studies. In specific aim 2, we will longitudinally evaluate the chromosomal positioning of intact proviruses during continuous ART in these infants; we hypothesize that immune-mediated selection mechanisms can at least in some infants promote and facilitate a proviral integration site landscape that approximates the “blocked and locked” proviral architecture observed in elite controllers; such selection mechanisms may then be further intensified through planned personalized mRNA vaccination in future studies. In specific aim 3, we will conduct pioneering studies to characterize the quantity and functionality of cellular and humoral immune responses induced by the licensed SARS-CoV2 mRNA vaccine in HIV-1-infected pediatric patients from Botswana; such studies will be highly informative for all future HIV-1-specific therapeutic vaccination approaches on the mRNA platform.