Early prevention interventions towards ART-free pediatric HIV remission

主要研究者（末、首、中）：徐焕斌 项目总结/摘要： 尽管在预防HIV-1垂直传播方面取得了显著进展，但是， 探讨高危新生儿母婴传播的早期治疗方案。当前推荐 儿童抗逆转录病毒疗法是从成人临床试验中推断出来的。最近，我们的研究表明 一个短期的联合ART（cART）纳入整合酶链转移抑制剂（CITI），开始于 感染后3天（dpi），但不能超过1天，可以迅速将病毒血症抑制到无法检测的水平， 新生儿，并延长9个月的早期干预，这种方案的结果持续病毒学缓解， 4/5例婴儿在治疗停止后超过2.5年。令人惊讶的是，我们进一步的初步数据显示， 延迟治疗（例如，接种SIV/SHIV AD 8的新生猕猴和在5dpi开始的cART）或 治疗较大的婴儿（例如，1.5-暴露于SIV并在3dpi开始cART的1个月大的婴儿猕猴） 在中断相同的9个月早期干预后， 分别为4/5和3/3只动物。这些发现表明，儿童持续病毒学缓解的结果 似乎对婴儿的年龄非常敏感（例如，新生儿对婴儿）和定时（例如，前病毒 水库播种？）然而，病毒缓解的确切机制仍然难以捉摸。新 抗病毒药物也在出现，一种每月一次的DTG类似物称为cabotegravir（CAB）， 在最近的成人临床试验中， 儿童艾滋病治疗尚未得到检验。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），同时拥有更多的动态和 再生能力比成人，婴儿的预防性干预可能是独特的，因为它可能有更多的再生能力。 - 有效的抗病毒活性，用于无ART的HIV缓解，导致更多的关键免疫细胞的补充， 免疫系统的正常发育。在这项建议中，我们假设早期预防干预， 基于适当的起始时机、持续时间和RNAi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储库，导致无ART病毒学的持续状态 暴露于或感染艾滋病毒的婴儿缓解，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，我们的首要目标是解决：SA 1， 前病毒储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cabotegravir; SA 2，实现儿科HIV的最佳预防干预策略 缓解; SA 3，ART在独特的灵长类动物中的药代动力学和免疫学改变 主持人总的来说，这些研究将为实现持续的预防干预提供见解。 出生时暴露于或感染艾滋病毒的婴儿的无抗逆转录病毒治疗病毒学缓解状态，这将对 对一般婴儿HIV感染的治疗具有转化意义。

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.