The impact of early antiretroviral therapy on HIV persistence and inflammation

描述(申请人提供)：虽然有效的抗逆转录病毒治疗可以预防艾滋病和其他并发症，但它不能完全恢复健康。治疗期间出现的高发病率是由几个因素造成的，包括直接药物毒性、持续的病毒复制/产生以及艾滋病毒相关炎症的高水平。因此，可能需要旨在实现彻底根除病毒的战略，以便充分恢复艾滋病毒感染者的健康。开展根除研究的主要障碍之一是对疾病阶段、炎症和病毒持久性之间的相互作用缺乏完整的了解。此外，尚未开发和验证可用于更大规模临床研究的病毒持久性检测方法。这一应用的中心前提是，长期治疗期间炎症加剧既是病毒持续存在的原因，也是病毒持续存在的结果，旨在根除艾滋病毒的战略将需要集中努力，以减少这种炎症。这也是这一应用的一个主要前提，在进行任何临床试验之前，将需要一种经过良好验证的、高通量的分析，可以直接或间接地测量潜在储存库的大小。为了达到这些目标，我们建议对HIV感染者队列中的HIV病毒库和炎症进行深入调查。在急性、早期和晚期感染期间接受治疗的60名患者将被包括在内，因为这三种患者的宿主/病毒动态可能不同。在目标1中，我们将在有效的抗逆转录病毒治疗的五年中测量量化前病毒DNA、超敏感的血浆HIV RNA、基于细胞的RNA和外体DNA。在目标2中，我们将在五年内测量与艾滋病毒相关的宿主反应。对于每个目标，主要的结果衡量标准将是在治疗第五年或之后血液和肠道粘膜中具有复制能力的艾滋病毒水平。最后，在目标3中，我们将确定HIV在各种T细胞亚群中的分布，并确定炎症与HIV分布之间的关系。在每个目标中都将提出几个新的假设。所获得的关于经治疗的艾滋病毒感染的自然历史的知识将为设计和实施大规模根除研究提供有价值的信息。从这项研究中获得的知识也可能解决许多关于慢性炎症在驱动病毒持久性方面的作用的不确定性，因此可能导致新干预措施的开发。 公共卫生相关性：虽然有效的抗逆转录病毒治疗可以预防艾滋病和其他并发症，但它不能完全恢复健康。治疗期间出现的高发病率是由几个因素造成的，包括直接药物毒性、持续的病毒复制/产生以及艾滋病毒相关炎症的高水平。我们将定义衡量病毒持久性的多种方法中的哪一种可以预测病毒(在血液和粘膜组织中)的复制能力程度，并确定艾滋病毒如何在T细胞亚群中分布，以及疾病阶段和炎症对这种分布的影响。我们的工作也可能为慢性炎症在驱动病毒持久性中的作用提供重要的见解，从而可能导致新干预措施的开发。

DESCRIPTION (provided by applicant): Although effective antiretroviral therapy prevents AIDS and other complications, it does not completely restore health. The excess morbidity that occurs during treatment is due to several factors, including direct drug- toxicity, persistent viral replication/production and high levels of HIV-associated inflammation. Hence, strategies aimed at achieving complete viral eradication may be needed in order to fully restore health among HIV infected individuals. One of the major barriers to pursuing studies of eradication is the lack of a complete understanding regarding the interaction between disease stage, inflammation and viral persistence. Also, no assay of viral persistence amendable to larger clinical studies has been developed and validated. It is the central premise of this application that heightened inflammation during long-term therapy is both a cause and consequence of viral persistence, and that strategies aimed at eradicating HIV will require focused efforts aimed at reducing this inflammation. It is also a major premise of this application that a well validated, high throughput assay that can either directly or indirectly measure the size of the latent reservoir will be needed before any clinical trials can be performed. To address these objectives we propose an intensive investigation of HIV viral reservoirs and inflammation in a well characterized cohort of HIV infected patients. Sixty patients who received therapy during acute, early and late infection will be included, as the host/virus dynamics likely differ in these three patient populations. In Aim 1 we will measure quantify proviral HIV DNA, ultrasensitive plasma HIV RNA, cell-based RNA, and episomal DNA during five years of effective antiretroviral therapy. In Aim 2 we will measure the HIV associated host responses over five years. For each aim, the primary outcome measure will be the level of replication competent HIV in blood and gut mucosa at or after year five of therapy. Finally, in Aim 3 we will determine the distribution of HIV in various T cell subsets, and define the relationship between inflammation and HIV distribution. Several novel hypotheses will be addressed in each aim. Knowledge gained regarding the natural history of treated HIV infection will provide valuable information for the design and implementation of large scale eradication studies. Knowledge gained from this study may also resolve many of the uncertainties regarding the role of chronic inflammation in driving viral persistence, and hence could lead to the development of novel interventions. PUBLIC HEALTH RELEVANCE: Although effective antiretroviral therapy prevents AIDS and other complications, it does not completely restore health. The excess morbidity that occurs during treatment is due to several factors, including direct drug- toxicity, persistent viral replication/production and high levels of HIV-associated inflammation. We will define which of the many ways to measure viral persistence predicts the degree of replication competent virus (in blood and mucosa tissues), and determine how HIV is distributed among T cell subsets, as well as the effect that disease stage and inflammation has on this distribution. Our work may also provide important insights in the role of chronic inflammation in driving viral persistence, and hence may lead to the development of novel interventions.