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）： 随着新型抗逆转录病毒疗法的出现，从感染患者体内消除艾滋病毒的前景可能成为一个可以实现的目标。然而，这样的目标将需要具有比目前可用的更高灵敏度的新工具来监测这样的治疗的进展，不仅在血液中，而且在体内确实存在这样的储库和残留病毒复制位点的器官中。此外，在急性感染期间，相对于传播途径和疾病进展，识别病毒储库的早期播种可能为化学治疗或免疫屏障开辟新的方向，以遏制新的病毒感染福耶斯和病毒储库播种的感染的广泛传播。为了利用这种早期的病毒动力学，并考虑到这种动力学存在的自然个体变异，有必要了解粘膜传播后HIV感染的传播模式，这是全球感染的主要传播模式。然而，目前可用于监测这种病毒过程的工具是间接的或相对侵入性的，并且对于人类临床显然是不切实际的。即使使用非人灵长类动物的艾滋病模型，如果选择进行连续的牺牲，要了解真实的时间内的病毒动力学也是具有挑战性的，而且成本高得令人望而却步，更不用说个体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）与同步X射线计算机断层扫描（CT），以确定猴免疫缺陷病毒在体内复制位点的实时全身图，绘制出体内SIV的全身复制位点，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位点。因此，我们建议通过IV、直肠和阴道途径感染后确定SIV病毒的解剖学动力学，以确定体内病毒复制的连续主要位点，这将通过靶向组织收集来证实。接下来，我们将比较2种联合ART疗法减少病毒储库，并记录体内复制的残留福耶斯，以及确定哪些储库可能在体内ART中断后助长病毒复苏。我们认为，这些研究将为设计人类HIV感染的HIV根除策略提供重要信息。