The impact of early antiretroviral therapy on HIV persistence and inflammation

早期抗逆转录病毒治疗对艾滋病毒持续性和炎症的影响

• 批准号: 7838717
• 负责人: STEVEN Grant DEEKS
• 金额: $ 72.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7838717
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Acute; Address; Adherence; Anti-Retroviral Agents; Architecture; Automobile Driving; Biological Assay; Biological Markers; Blood; CD4 Positive T Lymphocytes; Cell Count; Cell Separation; Cells; Chronic; Chronic Disease; Classification; Clinical Research; Clinical Trials; Coculture Techniques; Collecting Cell; Consensus; Cytomegalovirus; DNA; Data; Development; Disease; Drug toxicity; Environment; Fibrosis; Frequencies; Future; HIV; HIV Infections; Health; Highly Active Antiretroviral Therapy; Immune; Immune response; Immunologic Deficiency Syndromes; In Situ Hybridization; Individual; Infection; Inflammation; Inflammatory; Intervention; Investigation; Knowledge; Lead; Leukapheresis; Life; Lymphoid; Lymphoid Tissue; Measurement; Measures; Memory; Morbidity - disease rate; Mucous Membrane; Natural History; Outcome; Outcome Measure; Pathogenesis; Patients; Plasma; Population; Production; Protocols documentation; RNA; Relative (related person); Residual Tumors; Residual state; Role; Specimen; Staging; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Tissues; Toxic effect; Uncertainty; Viral; Viral Load result; Viral Markers; Virus; Work; advanced disease; antiretroviral therapy; base; cohort; cost; cytokine; design; falls; high risk; high throughput screening; inflammatory marker; insight; microbial; novel; novel therapeutic intervention; patient population; peripheral blood; prevent; primary outcome; public health relevance; rectal; symposium; viral DNA

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.

描述（由申请人提供）：尽管有效的抗逆转录病毒疗法可以阻止艾滋病和其他并发症，但并不能完全恢复健康。治疗期间发生的过量发病率是由于多种因素，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，为了完全恢复受艾滋病毒感染者的健康状况，可能需要实现旨在实现完全消除病毒的策略。追求根除研究的主要障碍之一是缺乏对疾病阶段，炎症和病毒持久性之间相互作用的完全了解。同样，尚未开发和验证对大型临床研究的病毒持久性测定。这种应用的主要前提是，长期治疗期间的炎症增加既是病毒持久性的原因和结果，旨在消除HIV的策略将需要旨在减少这种炎症的集中精力。这也是该应用程序的主要前提，即经过良好验证的高通量测定法可以直接或间接测量潜在储层的大小，然后才能进行任何临床试验。为了解决这些目标，我们提出了对艾滋病毒病毒库和炎症的深入研究，其中包括艾滋病毒感染患者的良好表征。在急性，早期和晚期感染期间接受治疗的60例患者将包括宿主/病毒动态，这三名患者种群可能有所不同。在AIM 1中，我们将在有效的抗逆转录病毒疗法的五年内测量量化病毒HIV DNA，超敏感性血浆HIV RNA，基于细胞的RNA和偶发性DNA。在AIM 2中，我们将在五年内衡量HIV相关的宿主反应。对于每个目标，主要结局措施将是治疗五年前或第五年后血液和肠粘膜中复制均能胜任的艾滋病毒水平。最后，在AIM 3中，我们将确定艾滋病毒在各种T细胞子集中的分布，并定义炎症与HIV分布之间的关系。每个目标都将解决一些新的假设。关于治疗的艾滋病毒感染的自然史获得的知识将为大规模根除研究的设计和实施提供宝贵的信息。从这项研究中获得的知识也可以解决有关慢性炎症在驱动病毒持久性中的作用的许多不确定性，因此可能导致新干预的发展。 公共卫生相关性：尽管有效的抗逆转录病毒疗法可以阻止艾滋病和其他并发症，但并不能完全恢复健康。治疗期间发生的过量发病率是由于多种因素，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。我们将定义哪种测量病毒持久性的方法中的哪种方法可以预测复制能力的病毒（在血液和粘膜组织中），并确定HIV如何在T细胞亚群中分布，以及疾病和炎症对疾病和炎症对这个分布。我们的工作还可以提供有关慢性炎症在驱动病毒持久性中的作用的重要见解，因此可能导致新的干预措施的发展。