THE MUCOSAL DENDRITIC CELL-T CELL MILIEU AND SIV SPREAD

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们的研究旨在剖析直肠HIV/SIV感染的早期事件，以了解HIV感染是如何建立和传播的，并探索预防粘膜感染的新的免疫调节策略。Toll样受体(Toll-like Receptor，TLR)激动剂可以通过激活DC来增强天然免疫，其中TLR3是最具特征的病毒dsRNA受体。Poly(IC)是一种人工合成的dsRNA类似物，通过TLR3依赖和独立的机制激活人类和猕猴DC，临床级Poly(IC)(Poly(ICLC)或Hiltonol)已商业化并在人类身上使用，这突显了这种激活模式被开发为抗HIV策略的潜力。我们在体外已经证明，在DC和DC-T细胞共培养中，Poly(IC)信号可以阻止HIV感染。因此，我们假设，体内直肠应用希尔托诺可能类似地激活粘膜DC，触发它们的免疫刺激能力，限制SIV复制，同时增强保护性免疫反应。我们正在比较希尔托诺对印度恒河猴直肠攻击、wt和减毒病毒(nef缺失突变体)的影响，因为我们假设，在没有nef免疫抑制效应的环境中，Hiltonol的影响会更明显，并且在那里，？nef的减弱复制及其对后续wt攻击的保护能力将得到增强。在希尔托诺的应用和挑战之后，我们继续跟踪动物一段时间内对希尔托诺/SIV的反应所引发的病毒和免疫参数：血浆病毒载量、血液DC和T细胞亚群数量和激活的变化、CK/CC水平、抗体产生和T细胞反应(ELISPOT用于干扰素伽马，ICS用于干扰素伽玛、IL-2和IL-17分泌)。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our studies aim to dissect the earliest events in rectal HIV/SIV infection in order to understand how HIV infection is established and spreads, and explore novel immunomodulatory strategies to prevent mucosal infection. Toll-like receptor (TLR) agonists can boost innate immunity through DC activation, with TLR3 the best characterized receptor of viral dsRNA. Poly(IC) is a synthetic dsRNA analog known to activate human and macaque DCs through both TLR3-dependent and independent mechanisms, and clinical grade poly(IC) (poly(ICLC) or Hiltonol) is commercially available and being used in humans, underscoring the potential for this mode of activation to be developed as an anti-HIV strategy. We have shown in vitro that poly(IC) signaling blocks HIV infection in DCs and DC-T cell co-cultures. Thus, we hypothesized that rectal application of Hiltonol in vivo might similarly activate mucosal DCs, triggering their immunostimulatory capability and limiting SIV replication while boosting protective immune responses. We are comparing the effects of Hiltonol on rectal challenge of Indian rhesus macaques with wt and the attenuated virus ¿nef (nef deletion mutant) because we postulated that the effects of Hiltonol would be more pronounced in a setting devoid of the immune suppressive effects of nef, and where the attenuated replication of ¿nef and its protective capacity against subsequent wt challenge would be enhanced. Following Hiltonol application and challenge, we are continuing to follow the animals over time for viral and immune parameters elicited in response to Hiltonol/SIV: plasma viral load, changes to blood DC and T cell subset numbers and activation, CK/CC levels, Ab production, and T cell responses (ELISPOT for IFN gamma and ICS for IFN gamma, TNF gamma, IL-2, and IL-17 secretion).