The impact of early antiretroviral therapy on HIV persistence and inflammation

描述（由申请人提供）：虽然有效的抗逆转录病毒疗法可以预防艾滋病和其他并发症，但不能完全恢复健康。治疗期间发生的过度发病率是由于几个因素，包括直接药物毒性、持续的病毒复制/产生和高水平的HIV相关炎症。因此，可能需要采取旨在实现完全根除病毒的战略，以便完全恢复艾滋病毒感染者的健康。进行根除研究的主要障碍之一是缺乏对疾病阶段，炎症和病毒持续性之间相互作用的完整理解。此外，尚未开发和验证适用于更大规模临床研究的病毒持久性检测方法。本申请的中心前提是，长期治疗期间炎症加剧既是病毒持续存在的原因，也是其结果，旨在根除HIV的策略将需要集中精力减少这种炎症。这也是本申请的一个主要前提，即在进行任何临床试验之前，需要一种经过充分验证的高通量测定法，该测定法可以直接或间接测量潜在储库的大小。为了解决这些问题，我们提出了一个深入的调查艾滋病毒的水库和炎症在一个很好的特点队列的艾滋病毒感染患者。将纳入60例在急性、早期和晚期感染期间接受治疗的患者，因为这三个患者人群的宿主/病毒动力学可能不同。在目标1中，我们将在五年有效的抗逆转录病毒治疗期间定量测量前病毒HIV DNA、超敏感血浆HIV RNA、细胞RNA和附加体DNA。在目标2中，我们将衡量五年内与艾滋病毒相关的宿主反应。对于每一个目标，主要的结局指标将是治疗5年或之后血液和肠粘膜中有复制能力的HIV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，并定义炎症与HIV分布之间的关系。在每个目标中将讨论几个新的假设。所获得的关于经治疗的HIV感染的自然史的知识将为大规模根除研究的设计和实施提供有价值的信息。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续性中的作用的不确定性，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疗法可以预防艾滋病和其他并发症，但它不能完全恢复健康。治疗期间发生的过度发病率是由于几个因素，包括直接药物毒性、持续的病毒复制/产生和高水平的HIV相关炎症。我们将定义测量病毒持久性的多种方法中的哪一种可以预测病毒的复制能力（在血液和粘膜组织中），并确定HIV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。我们的工作还可能为慢性炎症在驱动病毒持续性中的作用提供重要见解，因此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.