Quantifying Immune VS. Viral Killing of SIV Infected and Latently Infected Cells

量化免疫VS。

• 批准号: 9107332
• 负责人: Ruy M Ribeiro
• 金额: $ 69.71万
• 依托单位: LOS ALAMOS NAT SECTY-LOS ALAMOS NAT LAB
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107332
• 关键词: AIDS/HIV problem; Accounting; Animals; Behavior; Biology; CD8B1 gene; Cell model; Cells; Combined Modality Therapy; Communicable Diseases; Control Animal; Coupled; DNA; DNA Integration; Data; Ethics; Follicular Dendritic Cells; HIV; Human; Immune; Immune response; Immune system; Infection; Infection Control; Integrase; Integrase Inhibitors; Interruption; Kinetics; Lead; Macaca; Macaca mulatta; Maintenance; Measures; Modeling; Morbidity - disease rate; Pathogenesis; Population; Process; Production; Protease Inhibitor; Protocols documentation; RNA-Directed DNA Polymerase; SIV; Satellite Viruses; Structure; Suspension substance; Suspensions; T-Lymphocyte; Therapeutic Agents; Time; Vaccine Therapy; Viral; Viral Load result; Viral Proteins; Viral reservoir; Virus; Virus Integration; cell killing; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; killings; mathematical model; mortality; pinacolyl methylphosphonic acid; prevent; public health relevance; research study; viral DNA

DESCRIPTION: The objective of our proposal is to characterize the window of opportunity for CD8-induced killing of cells infected but not yet producing SIV in rhesus macaques (RM). To this end we will compare treatment of SIV infection in control animals and CD8-depleted animals. Although similar experiments were done before (in part) by us and others, those used RTI therapy (PMPA and FTC). Here, we propose that using an integrase strand transfer inhibitor (raltegravir - RAL), we will obtain qualitatively and quantitatively different results that will alow probing of the strength of the immune response during cell infection but before viral production (i.e., before integration). We will extend the standard and successful models of viral therapy to analyze the case of RAL monotherapy, because we expect that the behavior of the decay of virus is different. Analyzing viral load under RAL therapy (and its suspension) in CD8 depleted macaques will provide the best conditions to probe the effect of CD8s on controlling the virus. In addition, we will analyze the number of infected cells, with different forms of HIV DNA (integrated, unintegrated, 2LTR circles) to gain precious insights into the long-term dynamics of viral reservoirs, especially latently infected cells. Our specific aims are: Aim 1. Quantify the dynamics of SIV during RAL monotherapy in rhesus macaques (RM). Hypothesis: The profile of viral load under RAL monotherapy is due to decay of cells infected by virus that have not completed integration but which leak through and become productively infected. We will develop new models of viral dynamics, which take into account the specific mode of action of RAL. Thus, we will quantify the kinetics of cellular reservoirs with unintegrated HIV DNA. Aim 2. Quantify the effect of CD8+ T-cells in killing cells infected with SIVmac before they become productively infected (i.e., before proviral integration). Hypothesis: Most of the CD8+ T cell effect on killing infected cells occurs before the start of viral production by the infected cell. We will quantify te effect of CD8 on killing of cells with unintegrated DNA. Aim 3. Quantify and model the fate of different cellular/viral reservoirs during long-term SIV treatment. Hypothesis: Modeling of long-term combination therapy including structured RAL treatment interruptions will permit a characterization of the decay and maintenance of different cellular/viral reservoirs. We will measure cells with integrated and unintegrated viral DNA (eg., 2-LTR circles), latently infected cells and follicular dendritic cell-associated viruses. We will develop models of these cellular compartments to quantify their decay and understand whether they are replenished throughout treatment or if they continuously decrease. These studies will better characterize the strength of CD8+ T-cells in controlling infection and the long-term decay of different viral reservoirs. Thus, our results will have implications to HIV control (by vaccines and therapy) and probe the limits of the immune response in eradicating the virus.

产品说明：我们的建议的目的是描述CD 8诱导的杀死恒河猴（RM）中感染但尚未产生SIV的细胞的机会窗口。为此，我们将比较对照动物和CD 8耗竭动物中SIV感染的治疗。虽然我们和其他人以前做过类似的实验（部分），但这些实验使用RTI治疗（PMPA和FTC）。在这里，我们提出使用整合酶链转移抑制剂（雷特格韦- RAL），我们将获得定性和定量不同的结果，这将允许在细胞感染期间但在病毒产生之前探测免疫应答的强度（即，整合前）。我们将扩展病毒治疗的标准和成功模型来分析RAL单药治疗的情况，因为我们预计病毒的衰变行为是不同的。在RAL治疗（及其悬浮液）下分析CD 8耗尽的猕猴中的病毒载量将提供最佳条件来探测CD 8 s对控制病毒的作用。此外，我们将分析感染细胞的数量，以及不同形式的HIV DNA（整合的，未整合的，2LTR圈），以获得对病毒储存库，特别是潜伏感染细胞的长期动态的宝贵见解。我们的具体目标是：目标1。定量恒河猴（RM）RAL单药治疗期间SIV的动力学。假设：RAL单药治疗下的病毒载量特征是由于病毒感染的细胞的衰变，这些病毒尚未完成整合，但泄漏并被有效感染。我们将开发新的病毒动力学模型，其中考虑到RAL的特定作用模式。因此，我们将量化未整合的HIV DNA的细胞库的动力学。目标二。量化 CD 8 + T细胞在SIVmac感染的细胞被有效感染之前杀死它们的作用（即，前病毒整合之前）。假设：大部分CD 8 + T细胞对杀伤作用 感染的细胞发生在被感染的细胞开始产生病毒之前。我们将量化CD 8对具有未整合DNA的细胞的杀伤作用。目标3。量化和模拟长期SIV治疗期间不同细胞/病毒储库的命运。假设：包括结构化RAL治疗中断的长期联合治疗的建模将允许表征不同细胞/病毒储库的衰减和维持。我们将测量具有整合和未整合病毒DNA的细胞（例如，2-LTR圆圈）、潜伏感染细胞和滤泡树突细胞相关病毒。我们将开发这些细胞区室的模型，以量化它们的衰减，并了解它们是否在整个治疗过程中得到补充，或者它们是否持续减少。这些研究将更好地表征CD 8 + T细胞在控制感染和不同病毒库的长期衰变中的强度。因此，我们的研究结果将对艾滋病毒控制（通过疫苗和治疗）产生影响，并探索 免疫反应来消灭病毒

项目成果

Mathematics in modern immunology.

• DOI: 10.1098/rsfs.2015.0093
• 发表时间: 2016-04-06
• 期刊: Interface focus
• 影响因子: 4.4
• 作者: Castro M;Lythe G;Molina-París C;Ribeiro RM
• 通讯作者: Ribeiro RM