Monitoring SIV Reservoirs with Whole Body immunoPET

使用全身免疫 PET 监测 SIV 储库

• 批准号: 9301446
• 负责人: PHILIP J SANTANGELO
• 金额: $ 159.08万
• 依托单位: UNIVERSITY OF LOUISIANA AT LAFAYETTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301446
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Affinity; Anatomy; Animal Model; Anti-Retroviral Agents; Antiviral Agents; Biomedical Engineering; Biopsy; Blood; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Clinic; Clinical; Coupled; Development; Disease Progression; Drug Kinetics; Exposure to; Foundations; Goals; HIV; HIV Infections; Human; Image; Imaging Techniques; Immune; In Situ; In Vitro; Individual; Infection; Infection prevention; Interruption; Kinetics; Label; Lymphoid Tissue; Macaca; Macaca mulatta; Maps; Measures; Metabolism; Methods; Modeling; Monitor; Monkeys; Monoclonal Antibodies; Nature; Organ; Outcome; Pathology; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Positron-Emission Tomography; Preventive measure; Primates; Process; Protocols documentation; Radionuclide Imaging; Regimen; Residual state; Route; SIV; Sampling; Signal Transduction; Site; Technetium Tc 99m ciprofloxacin; Techniques; Testing; Therapeutic; Time; Tissue Banks; Universities; Vaccines; Vagina; Variant; Viral; Viral Load result; Viral Proteins; Viral reservoir; Virus; Virus Diseases; Virus Replication; X-Ray Computed Tomography; antiretroviral therapy; base; body map; clinical application; design; imaging modality; immune activation; improved; in vivo; innovation; minimally invasive; nonhuman primate; novel; novel strategies; public health relevance; rectal; simian human immunodeficiency virus; tool; transmission process; viral RNA; viral detection; virus pathogenesis

DESCRIPTION (provided by applicant): With the advent of novel anti-retroviral therapies, the prospect of potentially eliminating HIV from infected patients may become an achievable goal. However, such goal will require new tools with greater sensitivity than currently available to monitor the progress of such therapy, no only in blood but also in organs that do harbor such reservoirs and sites of residual viral replication in vivo. In addition, identifying early seeding of viral reservoirs during acute infecton relative to the route of transmission and disease progression may open novel directions for chemotherapeutic or immune barriers to contain the new virus infection foyers and generalized dissemination of the infection with seeding of viral reservoirs. To harness such early viral dynamics and account for the natural individual variation that exists for such dynamics, there is a need to understand the dissemination patterns of HIV infection following mucosal transmission, the primary transmission mode of infection worldwide. However, the tools currently available to monitor such viral processes are either indirect or relatively invasive and clearly impractical for the human clinic. Even when one uses the nonhuman primate model of AIDS, understanding the viral dynamics in real time is challenging and prohibitively expensive if one chooses to perform serial sacrifices, not to mention fraught by a high degree of variability between individuals. In this project, we propose to optimize our established immuno-positron emission tomography (PET) with simultaneous X-ray computed tomography (CT), to determine real-time whole body maps of simian immunodeficiency virus replication sites in vivo to chart out the total body replication sites of SIV in vivo and determine viral dynamics and sites of residual viral replication during antiretroviral therapy. Thus we propose to determine the anatomic SIV viral dynamics following infection via the IV, rectal and vaginal route to determine the consecutive major sites of viral replication in vivo, which will be confirmed via targeted tissue collections. Next we will compare 2 combination ART therapies for reducing viral reservoirs and document residual foyers of replication in vivo as well as determine which such reservoirs might be fueling the viral resurgence after interruption of ART in vivo. We submit that these studies wil provide critical information for the design of HIV eradication strategies in human HIV infection.

描述(由申请人提供)： 随着新的抗逆转录病毒疗法的出现，潜在地从感染患者身上消除艾滋病毒的前景可能成为一个可实现的目标。然而，这一目标将需要比目前可用的更灵敏的新工具来监测这种治疗的进展，不仅是在血液中，而且在体内确实有这样的宿主和残留病毒复制部位的器官中也是如此。此外，根据病毒传播和疾病进展的途径，在急性感染期间识别病毒宿主的早期播种，可能会为化疗或免疫屏障遏制新的病毒感染门槛和通过病毒宿主播种而广泛传播感染开辟新的方向。为了利用这种早期的病毒动态，并解释这种动态存在的自然个体差异，有必要了解艾滋病毒感染在粘膜传播后的传播模式，黏膜传播是全世界感染的主要传播方式。然而，目前可用于监测这种病毒过程的工具要么是间接的，要么是相对侵入性的，显然对人类临床不切实际。即使在使用艾滋病的非人类灵长类动物模型时，如果选择进行一系列牺牲，实时了解病毒动态也是具有挑战性的，代价也高得令人望而却步，更不用说个人之间的高度变异性了。在这个项目中，我们建议优化我们建立的免疫正电子发射断层扫描(PET)和同步X射线计算机断层扫描(CT)，以确定猴免疫缺陷病毒体内复制部位的实时全身图，以绘制出SIV在体内的全身复制部位，并确定抗逆转录病毒治疗期间的病毒动力学和残留病毒复制部位。因此，我们建议通过静脉、直肠和阴道途径确定SIV病毒感染后的解剖动力学，以确定病毒在体内连续的主要复制部位，这将通过靶向组织收集得到证实。接下来，我们将比较两种减少病毒库的联合ART疗法，记录体内复制的剩余门厅，并确定在体内中断ART后，哪些这样的库可能会助长病毒的复苏。我们认为，这些研究将为人类艾滋病毒感染的根除策略的设计提供关键信息。