Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles

淋巴滤泡自然杀伤细胞清除 SIV 的机制

基本信息

批准号：
10408913
负责人：
Roger Keith Reeves
金额：
$ 69.76万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408913
关键词：
Acute Adherence African African Green Monkey Anatomy Antiviral Agents Autopsy B-Lymphocytes BLR1 gene Blood CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Cercocebus atys Chronic DNA Methylation Data Disease Disease Progression Early Mobilizations Early treatment Epidemic Evolution Exhibits Face Failure Flow Cytometry Frequencies Future Gut Mucosa HIV HIV-1 HIV/SIV vaccine Human Immunotherapeutic agent Impairment Infection Inflammation Inflammatory Interleukin-15 Left Lentivirus Infections Ligands Lymphoid Follicle Lymphoid Tissue Macaca Macaca mulatta Mediating Medicine Modeling Monkeys Morbidity - disease rate Natural Killer Cells Nature Pathogenesis Pathogenicity Patients Peptides Plasma Population RNA Regimen Research Rest Role SIV Signal Transduction Stains T-Lymphocyte Subsets Techniques Testing Tissues Vaccines Viral Viral Load result Viral reservoir Viremia Virus Virus Replication Work antiretroviral therapy cell killing cost cytotoxic cytotoxic CD8 T cells exhaustion genome analysis immune activation in vivo innovation longitudinal analysis lymph nodes memory CD4 T lymphocyte nonhuman primate novel novel therapeutics purge response secondary lymphoid organ trafficking transcriptomics viral RNA

项目摘要

Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites. A major reservoir of HIV and pathogenic SIV infection in rhesus macaques (RM) are lymph node follicles (via replication in TFH cells and viral trapping by FDC) that generally prohibit access to cytotoxic CD8+ T cells. Interestingly, nonpathogenic SIV infection of African green monkeys (AGM) exhibits high viral loads in blood and the gut mucosae, but lacks virus in lymphoid follicles. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection, but the underlying mechanisms for NK cell surveillance and modulation of HIV/SIV reservoirs is unclear. Our recent research indicates that SIV can be effectively cleared from lymphoid follicles in nonpathogenic AGM but not pathogenic RM hosts and is dependent on an IL-15- dependent redistribution of NK cells to lymph node follicles and increased CXCR5 expression on AGM NK (Huot et al. Nature Medicine 2017). In this innovative proposal we will utilize three SIV-infected nonhuman primate models to test the central hypothesis that NK cells critically contribute to the reduction of SIV reservoirs. Specifically we will: (1) Determine mechanisms associated with NK cell-mediated control of SIV reservoirs; and (2) Determine mechanisms associated with NK cell failure to control SIV reservoirs in lymph nodes and associated pathogenesis. Application of these data could contribute substantially to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.

尽管 cART 有效抑制了 HIV 感染患者的血浆病毒血症，但复制能力病毒仍然可以从多种解剖部位回收。 HIV 和致病性 SIV 感染的主要储存库恒河猴 (RM) 中的淋巴结滤泡（通过 TFH 细胞中的复制和 FDC 捕获病毒）通常禁止接触细胞毒性 CD8+ T 细胞。有趣的是，非洲绿的非致病性SIV感染猴子（AGM）在血液和肠粘膜中表现出高病毒载量，但在淋巴滤泡中缺乏病毒。自然杀伤 (NK) 细胞对 HIV/SIV 感染提供快速的早期反应，并在很大程度上有助于疾病调节和疫苗保护，但 NK 细胞监视和保护的基本机制 HIV/SIV 储存库的调节尚不清楚。我们最近的研究表明SIV可以被有效清除来自非致病性 AGM 而非致病性 RM 宿主的淋巴滤泡，并且依赖于 IL-15- NK 细胞依赖于淋巴结滤泡重新分布以及 AGM NK 上 CXCR5 表达增加（Huot 等人，《自然医学》，2017 年）。在这项创新提案中，我们将利用三种感染 SIV 的非人类动物灵长类动物模型检验 NK 细胞对减少 SIV 至关重要的中心假设水库。具体来说，我们将：（1）确定与 NK 细胞介导的控制相关的机制。 SIV 储库； (2) 确定与 NK 细胞无法控制 SIV 储存库相关的机制淋巴结和相关发病机制。这些数据的应用可以大大有助于未来的 HIV/SIV 疫苗、免疫治疗或利用有效抗病毒药物的储库清除策略 NK细胞的潜力。