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

• 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
• 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

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.

项目摘要/摘要，免疫控制（项目4） 对于日益增长的HIV-1感染婴儿，找到HIV-1感染的治愈方法尤其重要， 如果治疗治疗方法不得 可用。最近的进步表明，实现HIV-1感染的功能治疗可能不需要 完全消除所有完整的HIV-1病毒；相反，靶向完整的病毒可能足够 集成在支持HIV-1转录的宽敞染色质位置，并且更容易受到病毒的影响 重新激活信号。这种用于治愈HIV-1感染的模型似乎是由精英控制者举例说明的，其中 我们记录了一个高度不同的染色体整合地点景观，其特征是完整的位置 异染色质区域中的病毒。值得注意的是，这种病毒集成站点的“阻塞和锁定”模式 可能代表成功消除的细胞免疫选择力的结果 可访问的染色质位置中的预科病毒，而异染色质位置处的原病毒可以长期持续。 这个概念增加了可以启发或加速免疫介导的选择机制的可能性 通过热疫苗接种，可以优先在HIV-1感染的婴儿开始 感染的早期阶段。在这里，我们建议对婴儿的病毒疗效动态进行详细的分析 接受含Dolutegravir的抗逆转录病毒疗法（ART），其最终目的是告知未来的临床 旨在通过个性化治疗mRNA诱导“阻塞和锁定”病毒储层结构的试验 编码自体临时序列的疫苗。在特定的目标1中，我们将研究病毒序列 近出生并确定婴儿含Dolutegravir Art的婴儿完整病毒的频率， 相对于接受lopinavir/ritonavir的婴儿的现有相应数据；这些研究 将使我们能够跟踪完整和有缺陷的病毒的自然演变，并产生完整的地图集 可以考虑将其纳入个性化治疗的mRNA疫苗的病毒病毒。 未来的原则研究。在特定目标2中，我们将纵向评估染色体定位 这些婴儿连续艺术期间完整的原病毒；我们假设免疫介导的选择 机制至少可以在某些婴儿中促进和促进病毒的整合现场景观 近似于精英控制器中观察到的“被阻塞和锁定”的规定；这样的选择 然后，可以通过计划的个性化mRNA疫苗在以后的研究中进一步启发机制。 在特定的目标3中，我们将进行开创性研究，以表征细胞和功能的数量和功能和功能 HIV-1感染的儿科诱导的持牌SARS-COV2 mRNA疫苗引起的体液免疫反应 来自博茨瓦纳的患者；对于所有未来的HIV-1特异性疗法，此类研究将非常有用 疫苗接种接近mRNA平台。