EXPERIMENTALLY-INDUCED IMMUNE ACTIVATION IN NATURAL HOSTS OF SIVS

SIVS 自然宿主的实验诱导免疫激活

• 批准号: 7716304
• 负责人: Ivona Vasile Pandrea
• 金额: $ 6.46万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-21 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7716304
• 关键词: Acquired Immunodeficiency Syndrome; Animals; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cercopithecus pygerythrus; Chronic; Computer Retrieval of Information on Scientific Projects Database; Denileukin Diftitox; Disease Progression; Flow Cytometry; Funding; Grant; HLA-DR Antigens; Immune; Infection; Inflammatory; Institution; Measures; Methods; Numbers; Patients; Peripheral; Plasma; Polymerase Chain Reaction; Population; Reporting; Research; Research Personnel; Resistance; Resources; SIV; Source; T-Cell Proliferation; T-Lymphocyte; Time; United States National Institutes of Health; Viral; Week; concept; cytokine; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Background. Immune activation levels were reported to be the best predictor of disease progression in HIV-infected patients. However, there is no direct proof that induction of immune activation during chronic HIV/SIV infection increases viral replication. We therefore experimentally induced immune activation in SIVagm-infected African green monkeys (AGMs) a species resistant to AIDS. Methods. Four SIVagm-infected AGMs were treated with ONTAK (Denileukin Diftitox) during chronic infection to deplete CD4+CD25+ T regulatory cells (Tregs). The dynamics of VL were measured by real-time PCR. Major T-cell populations and subsets were measured by flow-cytometry and the dynamics of pro-inflammatory cytokines in plasma was quantified by Luminex. Results. Ontak did not induce a reduction in the number or function of Tregs in chronically SIV-infected AGMs. However, ONTAK administration induced a significant increase in immune activation in all animals as illustrated by the increases in HLA-DR and CD69 expression on both CD4+ and CD8+ T-cells. Increased CD4+ T-cell proliferation (Ki-67) was also observed, resulting in significant increases in the pool of peripheral CD4+ T-cells. Furthermore, significant increases in the levels of proinflammatory cytokines were observed after ONTAK administration. These changes persisted for three weeks after the initiation of each treatment and resulted in significant increases (2-4 log) in VLs in all animals. Conclusion. We report the first successful experiment aimed at inducing immune activation in a natural host of SIV. Also, our results provide for the first time compelling proof-of concept that induction of immune activation during chronic SIV infection results in significant increases in viral replication, thus supporting the concept that immune activation is a key factor in disease progression during HIV/SIV infection.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 背景。据报道，免疫激活水平是HIV感染患者疾病进展的最佳预测指标。但是，没有直接证据表明，慢性艾滋病毒/SIV感染期间免疫激活的诱导会增加病毒复制。因此，我们在Sivagm感染的非洲绿猴（AGMS）中通过实验引起的免疫激活是一种对艾滋病的抗性物种。 方法。在慢性感染期间，用ONTAK（Denileukin Diftitox）处理了四个Sivagm感染的AGM，以耗尽CD4+ CD25+ T调节细胞（Tregs）。通过实时PCR测量VL的动力学。通过流量仪测量了主要的T细胞种群和亚集，并通过Luminex对血浆中促炎性细胞因子的动力学进行测量。 结果。 ONTAK并未引起长期感染SIV感染的AGM中Treg的数量或功能的减少。然而，ONTAK给药诱导了所有动物的免疫激活显着增加，如CD4+和CD8+ T细胞上HLA-DR和CD69表达的增加所示。还观察到CD4+ T细胞增殖的增加（KI-67），导致外围CD4+ T细胞库显着增加。此外，在安塔克施用后观察到促炎细胞因子的水平显着增加。每种治疗开始后，这些变化持续了三周，并在所有动物的VLS中导致显着增加（2-4 log）。 结论。我们报告了旨在在SIV天然宿主中诱导免疫激活的第一个成功实验。同样，我们的结果首次提供了令人信服的概念，即慢性SIV感染期间免疫激活的诱导会导致病毒复制的显着增加，从而支持这样的概念，即免疫激活是HIV/SIV感染期间疾病进展的关键因素。