SIV Pathogenesis in African Green Monkeys and Pigtailed Macaques

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），即使在控制病毒感染的情况下，这也是预后不良的指标。 复制的抗逆转录病毒治疗（ART）下IA/INFL的原因尚未完全阐明。 目前尚不清楚IA/INFL是由低于常规检测方法检测限的残留病毒复制还是由肠道的不可逆损伤（允许泄漏，与病毒复制无关）确定的。此外，尚不清楚哪种组织和哪种免疫细胞类型是治疗患者中残留IA/INFL的主要原因。目前尚不清楚患者在ART开始时的免疫状态是否会影响残留的IA/INFL。在ART存在和不存在的情况下，IA/INFL增加的后果尚不完全清楚。例如，尽管人类和非人灵长类动物（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。我们将解决这些方面的艾滋病毒的发病机制和管理的艾滋病毒感染的病人在这个竞争性的更新RO1 AI064066，这是我们的赠款，研究SIV的发病机制在NHP。在产生43篇科学出版物的上一个资助期内，我们开发了SIVagm感染的猪尾猕猴（PTM）作为研究微生物易位（MT）诱导的IA/INFL和SIV相关CV合并症的理想模型。我们还确定了一种药物组合，可显著降低PTM中高致病性SIVagm感染的MT和IA/INFL。作为这种干预的结果，该模型中的凝血标志物减少。基于这些初步数据，我们的假设是MT诱导全身性IA/INFL，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SIV感染期间的关键时间点开始，以模拟相关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。这些实验不能在人类身上进行。本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，病毒复制和MT在感染的每个阶段诱导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IA/INFL和CV风险正常化;（v）免疫状态在对这两种治疗方法的反应中的作用;（vi）开始单独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，并有可能通过靶向ART下的残留IA/INFL、免疫恢复和HIV/SIV相关CV疾病来改善HIV感染患者的临床管理和生存。

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.