EXPERIMENTALLY-INDUCED IMMUNE ACTIVATION IN NATURAL HOSTS OF SIVS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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因子。然而，没有直接证据表明，在慢性HIV/SIV感染期间诱导免疫激活会增加病毒复制。因此，我们在实验中诱导免疫激活SIVagm感染的非洲绿色猴（AGM），一种抗艾滋病的物种。 方法.在慢性感染期间用ONTAK（Denileukin Diftitox）处理四种SIVagm感染的AGM，以消耗CD 4 + CD 25 + T调节细胞（TCFs）。通过实时荧光定量PCR测定VL的动态。通过流式细胞术测量主要T细胞群和亚群，并通过Luminex定量血浆中促炎细胞因子的动力学。 结果Ontak没有诱导慢性SIV感染的AGM中的TcR的数量或功能减少。然而，ONTAK给药诱导所有动物的免疫活化显著增加，如 CD 4+和CD 8 + T细胞上的HLA-DR和CD 69表达。还观察到CD 4 + T细胞增殖（Ki-67）增加，导致外周CD 4 + T细胞池显著增加。此外，ONTAK给药后观察到促炎细胞因子水平显著升高。这些变化在每次给药开始后持续3周，并导致所有动物的VL显著增加（2-4 log）。 结论我们报告了第一个成功的实验，旨在诱导免疫激活的自然宿主SIV。此外，我们的研究结果首次提供了令人信服的概念证明，即在慢性SIV感染期间诱导免疫激活导致病毒复制显著增加，从而支持免疫激活是HIV/SIV感染期间疾病进展的关键因素的概念。

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.