SIV Pathogenesis in African Green Monkeys and Pigtailed Macaques

非洲绿猴和尾猴的 SIV 发病机制

• 批准号: 9043488
• 负责人: Ivona Vasile Pandrea
• 金额: $ 14.56万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043488
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Alcohols; Animal Model; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antibiotics; Arterial Disorder; Atherosclerosis; Biological Assay; Biological Markers; Blood; Cardiovascular Abnormalities; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cercopithecus pygerythrus; Chelating Agents; Cholesterol; Chronic; Clinical; Clinical Management; Coagulation Process; Combined Antibiotics; Comorbidity; Data; Detection; Development; Diagnosis; Diagnostic; Diet; Disease Progression; Drug Combinations; Elements; Extravasation; Fibrosis; Funding; Grant; HIV; HIV Infections; Highly Active Antiretroviral Therapy; Human; Hypertrophy; Immune; Immunoglobulins; Immunologics; Individual; Infection; Inflammation; Intervention; Intestines; Knowledge; Left ventricular structure; Lesion; Link; Lipopolysaccharides; Macaca; Macaca nemestrina; Measures; Mesalamine; Metabolic Marker; Modeling; Monitor; Myocardial; Natural History; Observational Study; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Plasma; Platelet Activation; Publications; Recombinant DNA; Recovery; Regimen; Relative (related person); Reporting; Research Design; Residual state; Risk; Role; SIV; Sampling; Smoking; Staging; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Translational Research; Triglycerides; Urine; Viral; Viremia; Virus; Virus Replication; antimicrobial; antiretroviral therapy; base; cardiovascular risk factor; cell type; clinically relevant; endothelial dysfunction; immune activation; improved; in vivo; insight; intimal medial thickening; lipid metabolism; lipopolysaccharide-binding protein; microbial; nonhuman primate; novel therapeutics; outcome forecast; prevent; research study; response; restoration; rifaximin; sugar

DESCRIPTION (provided by applicant): HIV-infected patients and SIV-infected macaques on highly active antiretroviral therapy (HAART) present with residual immune activation (IA) and inflammation (INFL), which are indicators of poor prognosis even in the setting of controlled viral replication. The causes of IA/INFL under antiretroviral therapy (ART) are not yet fully elucidated. It is currently not known whether IA/INFL is determined by residual virus replication below the detection limits of conventional assays or by irreversible damage of the gut that allows leakage, independent of virus replication. Also, it is not known which tissues/s and what immune cell type/s are predominantly responsible for the residual IA/INFL in the treated patients. It is not clear whether or not the immunologic status of the patient at the time of ART initiation impacts the residual IA/INFL. The consequences of increased IA/INFL in the presence and absence of ART are not completely understood. For example, although observational studies in humans and nonhuman primates (NHPs) suggest a link between IA/INFL and increased cardiovascular (CV) risk, direct proof of causal link is lacking. We will address these aspects of HIV pathogenesis and management of HIV-infected patient in this competitive renewal of RO1 AI064066, which is our grant to study SIV pathogenesis in NHPs. During the previous funding period, which generated 43 scientific publications, we developed the SIVagm- infected pigtailed macaque (PTM) as an ideal model to study the microbial translocation (MT)-induced IA/INFL and SIV-related CV comorbidities. We also identified a combination of drugs that significantly reduces MT and IA/INFL in the highly pathogenic SIVagm infection in PTMs. As a result of this intervention, the coagulation markers are reduced in this model. Based on these preliminary data, our hypothesis is that MT induces generalized IA/INFL that increases the CV risk in HIV-infected patients, including those that control virus replication under HAART. To test this hypothesis in our clinically relevant system, we will use interventions to reduce MT in the absence or in the presence of ART and determine the consequences of these interventions on IA/INFL and CV risk. Treatments will be initiated at key time points during acute, chronic and terminal SIV infection, to model relevant clinical settings and assess efficacy in patients with different immune status. Invasive sampling will be performed to measure virus replication, IA/INFL and to diagnose CV lesions. Such experiments cannot be performed in humans. This study design will allow us to determine: (i) the relative role of virus replication and MT in inducing IA/INFL and CV disease during each stage of infection, in the presence or in the absence of ART; (ii) the origin of IA/INFL under ART; (iii) the timing and the pathways of CV disease development during SIV infection; (iv) if reduction of MT will normalize IA/INFL and CV risk under ART; (v) the role of immune status in the response to these two therapeutic approaches; (vi) the optimal timing for initiating individual and combined therapies. These highly translational experiments address major gaps in our current knowledge of HIV pathogenesis and treatment and have the potential to improve clinical management and survival of HIV-infected patients by targeting residual IA/INFL under ART, immune recovery and HIV/SIV-related CV disease.

描述（由申请人提供）：受HIV感染的患者和SIV感染的猕猴在高度活跃的抗逆转录病毒疗法（HAART）上，存在残留免疫激活（IA）和炎症（IFF），即使在受控病毒的情况下，这些指标也是预后不良的指标 复制。抗逆转录病毒治疗（ART）下IA/INFR的原因尚未完全阐明。 目前尚不清楚IA/INFR是通过在常规测定的检测限制或肠道的不可逆损害下通过残留病毒复制确定的，该肠道允许泄漏，与病毒复制无关。同样，尚不清楚哪种组织以及哪些免疫细胞类型主要负责治疗患者的残留IA/INFR。目前尚不清楚患者在启动时患者的免疫学状态是否会影响剩余的IA/Infl。在存在和不存在艺术的情况下，IA/Infl的后果尚未完全理解。例如，尽管人类和非人类灵长类动物（NHP）的观察性研究表明，IA/Infl和增加心血管（CV）风险之间存在联系，但缺乏因果关系的直接证明。我们将在RO1 AI064066的这种竞争性更新中解决HIV感染患者的HIV发病机理和管理的这些方面，这是我们研究NHP中SIV发病机理的授权。在上一期生成43个科学出版物的资金期间，我们开发了被Sivagm感染的扎基猕猴（PTM），作为研究微生物易位（MT）诱导的IA/Effer和SIV相关的CV合并症的理想模型。我们还确定了在PTMS高度致病的Sivagm感染中显着降低MT和IA/INFR的药物的组合。由于这种干预，在该模型中降低了凝结标记。基于这些初步数据，我们的假设是MT诱导了普遍的IA/INFR，从而增加了感染HIV感染患者的CV风险，包括控制HAART下的病毒复制的患者。为了在我们的临床相关系统中检验这一假设，我们将使用干预措施在不存在或存在ART的情况下减少MT，并确定这些干预措施对IA/INFR和CV风险的后果。治疗将在急性，慢性和终末SIV感染期间的关键时间点开始，以建模相关的临床环境并评估免疫状态不同的患者的功效。将进行侵入性采样以测量病毒复制，IA/INFR并诊断CV病变。这样的实验不能在人类中进行。这项研究设计将使我们能够确定：（i）在感染的每个阶段，在存在或没有艺术的情况下，病毒复制和MT在诱导IA/INFR和CV疾病中的相对作用； （ii）ART下的IA/Infl的起源； （iii）SIV感染期间CV疾病发展的时间和途径； （iv）如果减少MT将使IA/Infl和CV风险在ART下正常化； （v）免疫地位在对这两种治疗方法反应中的作用； （vi）启动个人和合并疗法的最佳时机。这些高度转化的实验解决了我们目前对HIV发病机理和治疗知识的主要差距，并有可能通过针对ART，免疫恢复和与HIV/SIV相关的CV疾病来瞄准艾滋病毒感染患者的临床管理和存活。