THE MUCOSAL DENDRITIC CELL-T CELL MILIEU AND SIV SPREAD

粘膜树突状细胞 T 细胞环境和 SIV 传播

• 批准号: 8358075
• 负责人: Melissa J Robbiani
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358075
• 关键词: Agonist; Animals; Attenuated; Blood; Clinical; Coculture Techniques; Dendritic Cells; Double-Stranded RNA; Event; Funding; Grant; HIV; HIV Infections; Human; Immune; Immune response; In Vitro; Infection; Interferon Type II; Interleukin-17; Interleukin-2; Macaca; Macaca mulatta; National Center for Research Resources; Natural Immunity; Plasma; Poly I-C; Poly ICLC; Primates; Principal Investigator; Production; Research; Research Infrastructure; Resources; SIV; Signal Transduction; Source; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; TLR3 gene; TNF gene; Time; Toll-like receptors; United States National Institutes of Health; Viral; Viral Load result; Virus; Virus Receptors; analog; cost; enzyme linked immunospot assay; in vivo; mutant; novel; prevent; rectal; response

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).

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们的研究旨在剖析直肠HIV/SIV感染的最早期事件，以了解HIV感染是如何建立和传播的，并探索新的免疫调节策略来预防粘膜感染。Toll样受体（TLR）激动剂可以通过DC激活来增强先天免疫，其中TLR 3是病毒dsRNA的最佳表征受体。Poly（IC）是一种合成的dsRNA类似物，已知可通过TLR 3依赖性和非依赖性机制激活人和猕猴DC，临床级Poly（IC）（poly（ICLC）或Hiltonol）可商购获得并用于人体，强调了这种激活模式作为抗HIV策略开发的潜力。我们已经在体外证明，poly（IC）信号传导阻断DC和DC-T细胞共培养物中的HIV感染。因此，我们假设体内直肠应用Hiltonol可能类似地激活粘膜DC，触发其免疫刺激能力并限制SIV复制，同时增强保护性免疫应答。我们比较了Hiltonol对印度恒河猴直肠攻击与野生型和减毒病毒<$nef（nef缺失突变体）的影响，因为我们假设Hiltonol的影响在缺乏nef免疫抑制作用的环境中更明显，并且其中<$nef的减毒复制及其对后续野生型攻击的保护能力将得到增强。在Hiltonol应用和攻毒后，我们继续随时间推移随访动物对Hiltonol/SIV的应答所引起的病毒和免疫参数：血浆病毒载量、血液DC和T细胞亚群数量和活化的变化、CK/CC水平、Ab产生和T细胞应答（IFN γ的ELISPOT和IFN γ、TNF γ、IL-2和IL-17分泌的ICS）。