Early prevention interventions towards ART-free pediatric HIV remission

首席调查员(最后、第一、中间)：徐焕斌 项目摘要/摘要： 然而，尽管在预防HIV-1垂直传播方面取得了显著进展，但几乎没有数据可以指导 高危新生儿MTCT的最佳早期治疗方案。当前推荐 儿童的抗逆转录病毒疗法是从成人的临床试验中推断出来的。最近，我们的研究表明 一项包含整合酶链转移抑制物(INSTI)的短期联合抗逆转录病毒疗法(CART)在 感染后3天(Dpi)，但不超过一天，可以迅速将病毒血症抑制到无法检测到的水平。 新生儿，这种方案的长期9个月早期干预导致持续的病毒学缓解 停药后满2.5年者占4/5。令人惊讶的是，我们进一步的初步数据显示 延迟治疗(例如，新生猕猴接种SIV/SIV AD8和5dpi开始的CART)或 彻底治疗较大的婴儿(例如，在3dpi开始使用CART治疗暴露于SIV的1.5个月大的婴儿猕猴) 在同样的9个月早期干预中断后，改变了结果，如病毒在 4/5和3/3动物。这些发现表明，儿童持续病毒学缓解的结果 似乎对婴儿的年龄(例如，新生儿与婴儿)和时机(例如，前驱)非常敏感 水库播种？)然而，病毒缓解的确切机制仍然不清楚。新的 抗病毒药物也在涌现，每月一次的DTG类似物卡替格列韦(CAB)显示出更好的疗效 在最近的成人临床试验中预防艾滋病毒感染和复制的潜力，但其有效性和安全性 儿科艾滋病毒治疗还没有被检查过。鉴于新生儿缺乏组织良好的淋巴组织 (抗逆转录病毒药物渗透和病毒库的避难所)，同时拥有更具活力和 与成人相比，预防性干预对婴儿的再生能力可能是独一无二的，因为它可能会有更多 有效的抗病毒活性，用于不含ART的艾滋病毒缓解，导致关键免疫细胞和 免疫系统的正常发育。在这项提案中，我们假设早期预防干预， 基于适当的初始时间、持续时间和INSTI组合，可以有效地阻断病毒基因组 整合并完全消除早期病毒库，从而实现持续的无病毒技术 接触或感染艾滋病毒的婴儿的缓解，以及随后整个过程中正常的免疫发育 婴儿期。利用艾滋病毒的儿科NHP模型，我们的总体目标是：SA1，影响 前病毒贮存库对婴儿预防性干预结果的影响，同时评估 临床前试验中的卡波替格韦；SA2，实现儿童艾滋病毒的最佳预防干预策略 缓解，和；SA3，ART在独特的婴儿灵长类动物中的药代动力学和免疫学变化 主持人。总体而言，这些研究将为实现可持续发展的最佳预防干预提供洞察 对出生时接触或感染艾滋病毒的婴儿进行无病毒缓解，这将有显著的意义 对一般婴儿HIV感染治疗的翻译意义。

Principal Investigators (Last, first, middle): Xu, Huanbin PROJECT SUMMARY/ABSTRACT: Despite remarkable advances in prevention of vertical HIV-1 transmission, however, there is little data to guide the optimal early treatment regimens in vulnerable neonates with high risk of MTCT. Current recommended antiretroviral regimens for children are extrapolated from clinical trial in adults. Most recently, our studies show that a short-term combined ART (cART) incorporating an integrase strand transfer inhibitor (INSTI), initiated at 3 days post infection (dpi) but not one day beyond, can rapidly suppress viremia to undetectable levels in neonates, and a prolonged 9-month-early intervention of this regimen results in sustained virologic remission in 4 of 5 infants for more than 2.5 years after treatment cessation. Surprisingly, our further preliminary data showed that delaying treatment (e.g., newborn macaques inoculated with SIV/SHIV AD8 and cART initiated at 5dpi) or treating older infants (e.g., 1.5-month old infant macaques exposed to SIV with cART initiated at 3dpi) drastically altered the outcomes after interruption of the same 9-month-early intervention, as indicated by viral rebound in 4/5 and 3/3 animals, respectively. These findings suggest that outcome of pediatric sustained virologic remission appears to be very sensitive to the age of infants (e.g., newborn versus infants) and the timing (e.g., proviral reservoir seeding?) of intervention initiation, yet the exact mechanisms of viral remission remain elusive. New antivirals are also emerging and a once-monthly analog of DTG called cabotegravir (CAB) shows even greater potential for preventing HIV acquisition and replication in recent adult clinical trials, yet its efficacy and safety in pediatric HIV therapy have not been examined. Given newborn neonates lack well-organized lymphoid tissues (sanctuary sites for antiretrovirals penetration and viral reservoirs) while possessing more dynamic and regenerative capacity than an adult, prophylactic intervention in infants may be unique in that it may have more effective antiviral activity for ART-free HIV remission, resulting in more replenishment of key immune cells and normal development of the immune system. In this proposal, we hypothesize that early prevention interventions, based on appropriate initial timing, duration and INSTI combination, could effectively block viral genome integration and completely eliminate early viral reservoirs, resulting in a sustained state of ART-free virologic remission in infants exposed to or infected with HIV, and subsequently, normal immune development throughout infancy. Utilizing the pediatric NHP model of HIV, our overarching objective is address: SA1, the impact of proviral reservoirs on prophylactic intervention outcomes in infants while assessing the efficacy and safety of cabotegravir in a preclinical trial; SA2, the optimum prevention intervention strategy for achieving pediatric HIV remission, and; SA3, the pharmacokinetics and immunological alterations of ART in the unique infant primate host. Overall, these studies will provide insight into the optimal prevention intervention that achieves a sustained state of ART-free virologic remission for infants exposed to or infected with HIV at birth, which will have significant translational significance towards the treatment of HIV infection of infants in general.