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: 8410328
• 负责人: Ivona Vasile Pandrea
• 金额: $ 75.6万
• 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/8410328
• 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; Functional disorder; 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; Thick; Time; Tissues; Translational Research; Triglycerides; Urine; Viral; Viremia; Virus; Virus Replication; antimicrobial; antiretroviral therapy; base; cardiovascular risk factor; cell type; clinically relevant; immune activation; improved; in vivo; insight; intima media; 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. PUBLIC HEALTH RELEVANCE: We propose a strategy to improve response to antiretroviral therapy in patients with residual immune activation/inflammation (IA/INFL) and cardiovascular comorbidities. Our hypothesis is that translocation of microbial elements from the intestinal lumen crippled by HIV/SIV infection induces generalized IA/INFL that increases the risk of comorbidities in HIV-infected patients, including those that control virus replication. We will combine therapeutic interventions aimed at controlling viral replication (antiretroviral therapy) and microbial translocation (a combination of antibiotics, anti-inflammatory drugs and microbial chelators) in SIVagm-infected pigtailed macaques that have high levels of MT-induced IA/INFL and cardiovascular abnormalities similar to those described in HIV-patients. We identified a drug combination that successfully reduces MT in this animal model. We will determine the impact of these manipulations on residual IA/INFL and on cardiovascular disease associated with SIV infection. If successful, this highly translational research has the potential to: (i) identify a nw therapeutic approach to improve the clinical management of HIV-infected patient and prevent complications of AIDS; (ii) validate biomarkers for the diagnostic of HIV- associated cardiovascular risk and/or disease progression; (iii) implement these biomarkers in clinical settings for treatment monitoring of cardiovascular disease in HIV-infected patients.

描述（由申请人提供）：接受高效抗逆转录病毒治疗（HAART）的 HIV 感染患者和 SIV 感染猕猴存在残余免疫激活（IA）和炎症（INFL），即使在控制条件下，这些也是预后不良的指标病毒性的 复制。抗逆转录病毒治疗 (ART) 下 IA/INFL 的病因尚未完全阐明。 目前尚不清楚 IA/INFL 是由低于常规检测检测限的残留病毒复制决定的，还是由肠道不可逆损伤导致泄漏而决定的，与病毒复制无关。此外，尚不清楚哪些组织和哪些免疫细胞类型主要负责治疗患者中残留的 IA/INFL。目前尚不清楚患者在开始 ART 时的免疫状态是否会影响残留的 IA/INFL。在存在或不存在 ART 的情况下 IA/INFL 增加的后果尚不完全清楚。例如，尽管对人类和非人类灵长类动物 (NHP) 的观察性研究表明 IA/INFL 与心血管 (CV) 风险增加之间存在联系，但缺乏因果关系的直接证据。我们将在 RO1 AI064066 的竞争性更新中解决 HIV 发病机制和 HIV 感染患者管理的这些方面，这是我们用于研究 NHP 中 SIV 发病机制的资助。在上一个资助期间，我们发表了 43 篇科学出版物，我们开发了感染 SIVagm 的猪尾猕猴 (PTM)，作为研究微生物易位 (MT) 诱导的 IA/INFL 和 SIV 相关心血管合并症的理想模型。我们还确定了一种药物组合，可显着降低 PTM 中高致病性 SIVagm 感染中的 MT 和 IA/INFL。由于这种干预，该模型中的凝血标志物减少了。基于这些初步数据，我们的假设是，MT 会诱导全身性 IA/INFL，从而增加 HIV 感染患者的 CV 风险，包括那些在 HAART 下控制病毒复制的患者。为了在我们的临床相关系统中检验这一假设，我们将在不存在或存在 ART 的情况下使用干预措施来减少 MT，并确定这些干预措施对 IA/INFL 和 CV 风险的影响。治疗将在急性、慢性和终末期 SIV 感染期间的关键时间点启动，以模拟相关的临床环境并评估不同免疫状态患者的疗效。将进行侵入性采样以测量病毒复制、IA/INFL 并诊断 CV 病变。此类实验无法在人类身上进行。这项研究设计将使我们能够确定：(i) 在存在或不存在 ART 的情况下，在感染的每个阶段，病毒复制和 MT 在诱导 IA/INFL 和 CV 疾病中的相对作用； (ii) ART 下 IA/INFL 的起源； (iii) SIV 感染期间 CV 疾病发展的时间和途径； (iv) MT 的减少是否会使 ART 下的 IA/INFL 和 CV 风险正常化； (v) 免疫状态在这两种治疗方法的反应中的作用； (vi) 开始单独治疗和联合治疗的最佳时机。这些高度转化的实验解决了我们目前对 HIV 发病机制和治疗知识的主要空白，并有可能通过针对 ART 下残留的 IA/INFL、免疫恢复和 HIV/SIV 相关的 CV 疾病来改善 HIV 感染患者的临床管理和生存。 。 公共卫生相关性：我们提出了一项策略，以改善患有残余免疫激活/炎症（IA/INFL）和心血管合并症的患者对抗逆转录病毒治疗的反应。我们的假设是，HIV/SIV 感染致残的肠腔中微生物成分的易位会诱发全身性 IA/INFL，从而增加 HIV 感染患者合并症的风险，包括那些控制病毒复制的患者。我们将结合旨在控制病毒复制（抗逆转录病毒治疗）和微生物易位（抗生素、抗炎药物和微生物螯合剂的组合）的治疗干预措施，对 SIVagm 感染的猪尾猕猴进行治疗，这些猕猴具有高水平的 MT 诱导的 IA/INFL 和心血管疾病与艾滋病毒患者中描述的异常相似。我们确定了一种药物组合，可以成功减少该动物模型中的 MT。我们将确定这些操作对残留 IA/INFL 以及与 SIV 感染相关的心血管疾病的影响。如果成功，这项高度转化的研究有可能：（i）确定一种新的治疗方法，以改善艾滋病毒感染者的临床管理并预防艾滋病并发症； (ii) 验证用于诊断 HIV 相关心血管风险和/或疾病进展的生物标志物； (iii) 在临床环境中应用这些生物标志物来监测艾滋病毒感染者心血管疾病的治疗情况。