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

儿科 HIV-1 感染免疫控制的开创性精准医学方法

基本信息

批准号：
10696263
负责人：
Mathias Lichterfeld
金额：
$ 8.25万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696263
关键词：
2019-nCoV Acceleration Adolescent Architecture Atlases Autologous Binding Biotechnology Birth Botswana COVID-19 vaccination Cells Child Chromatin Chromosome 19 Clinical Trials Design Country Data Development Disease Early treatment Evolution Frequencies Future Genes Genetic Transcription HIV HIV vaccine HIV-1 Heterochromatin Human Genome Immune Immune response Immunologics Infant Infection Length Licensing Location Lopinavir/Ritonavir Mass Vaccinations Mediating Memory Memory B-Lymphocyte Messenger RNA Methodology Modeling Patients Pattern Persons Pharmaceutical Preparations Positioning Attribute Predisposition Pregnant Women Probability Provirus Integration Proviruses RNA RNA vaccination RNA vaccine Research Resources Satellite DNA Signal Transduction Structure T cell response Techniques Teenagers Testing Therapeutic Vaccination Vaccine Design Vaccine Research Vaccine Therapy Vaccines Viral Viral reservoir Viremia Work antiretroviral therapy chromosomal location clinically significant curative treatments design immune activation immunogenicity improved infant infection integration site neonatal infection next generation sequencing novel novel strategies patient population pediatric human immunodeficiency virus pediatric patients permissiveness personalized therapeutic precision medicine response sequencing platform technology platform theories therapeutic vaccine zinc finger nuclease

项目摘要

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.

项目总结/摘要，免疫控制（项目 4）寻找 HIV-1 感染的治疗方法对于越来越多的 HIV-1 感染婴儿尤为重要，如果治疗方案不能有效治疗，儿童和青少年将不得不终生接受抗逆转录病毒治疗最近的进展表明，实现 HIV-1 感染的功能性治愈可能不需要。完全消除所有完整的 HIV-1 原病毒；相反，它可能足以针对完整的原病毒整合到支持 HIV-1 转录并且更容易受到病毒感染的允许染色质位置这种治疗 HIV-1 感染的模型似乎以精英控制者为例证，其中我们记录了一个高度独特的染色体整合位点景观，其特征是完整的染色体整合位点位置值得注意的是，原病毒整合位点的这种“封锁和锁定”模式。可能代表细胞免疫选择力已成功消除的结果原病毒位于可接近的染色质位置，而原病毒位于异染色质位置可以长期存在。这一概念提出了增强或加速免疫介导的选择机制的可能性通过治疗性疫苗接种，并且可能优先在开始 ART 的 HIV-1 感染婴儿中诱导在这里，我们建议对婴儿的病毒库动态进行详细分析。接受含多替拉韦的抗逆转录病毒治疗 (ART)，最终目的是为未来的临床提供信息旨在通过个性化治疗性 mRNA 诱导“阻断和锁定”病毒库结构的试验含有自体原病毒序列的疫苗在具体目标 1 中，我们将研究病毒序列。临近出生并确定开始接受含多替拉韦的 ART 的婴儿中完整原病毒的频率，相对于接受含洛匹那韦/利托那韦的 ART 的婴儿的现有相应数据；将使我们能够追踪完整和有缺陷的原病毒的自然进化，并生成完整的图谱可以考虑将原病毒纳入个性化治疗性 mRNA 疫苗中进行测试在未来的原理验证研究中，我们将纵向评估染色体定位。在这些婴儿的连续 ART 过程中，我们追求免疫介导的选择；机制至少可以在某些婴儿中促进和促进前病毒整合位点景观近似于精英控制器中观察到的“阻塞和锁定”原病毒架构；在未来的研究中，可以通过计划的个性化 mRNA 疫苗接种来进一步强化机制。在具体目标 3 中，我们将进行开创性研究，以表征细胞和细胞的数量和功能。获得许可的 SARS-CoV2 mRNA 疫苗在 HIV-1 感染儿童中诱导体液免疫反应来自博茨瓦纳的患者；此类研究将为所有未来的 HIV-1 特异性治疗提供大量信息 mRNA 平台上的疫苗接种方法。