EXPERIMENTALLY-INDUCED IMMUNE ACTIVATION IN NATURAL HOSTS OF SIVS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 背景资料。据报道，免疫激活水平是艾滋病毒感染患者疾病进展的最佳预测指标。然而，没有直接证据表明在慢性艾滋病毒/SIV感染期间诱导免疫激活会增加病毒复制。因此，我们在实验中诱导了感染SIVagm的非洲绿猴(AGM)的免疫激活，AGM是一种对艾滋病具有抵抗力的物种。 方法：研究方法。4个感染SIVagm的GM在慢性感染期间用Ontak(Denileukin Diftitox)治疗，以耗尽CD4+CD25+T调节细胞(Tregs)。实时荧光定量聚合酶链式反应(Real-Time-PCR)检测VL的动态变化。用流式细胞仪检测主要T细胞亚群和亚群，用Luminex定量测定血浆中促炎症细胞因子的动态变化。 结果。在慢性SIV感染的AGM中，Ontak没有诱导Tregs的数量或功能的减少。然而，安达克在所有动物中都诱导了显著的免疫激活，这从CD4+和CD8+T细胞上HLA-DR和CD69表达的增加可见一斑。此外，还观察到CD4+T细胞增殖(Ki-67)增加，导致外周血中的CD4+T细胞显著增加。此外，安达克给药后，促炎细胞因子水平显著升高。这些变化在每次治疗开始后持续三周，并导致所有动物的VLS显著增加(2-4log)。 结论。我们报告了第一个成功的实验，旨在诱导SIV自然宿主的免疫激活。此外，我们的结果首次提供了令人信服的概念证据，即在慢性SIV感染期间诱导免疫激活会显著增加病毒复制，从而支持免疫激活是HIV/SIV感染期间疾病进展的关键因素这一概念。

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.