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

• 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
• 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

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.

尽管接受cART治疗的HIV感染患者的血浆病毒血症得到有效抑制， 病毒仍然可以从各种解剖部位恢复。艾滋病毒和致病性SIV感染的主要宿主 在恒河猴（RM）中，淋巴结滤泡（通过在TFH细胞中复制和FDC捕获病毒） 一般禁止接触细胞毒性CD 8 + T细胞。有趣的是，非洲绿色的非致病性SIV感染 猴（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）细胞提供对HIV/SIV感染的快速早期反应，并在很大程度上有助于 疾病调节和疫苗保护，但NK细胞监测和 HIV/SIV储库的调节尚不清楚。我们最近的研究表明，SIV可以有效清除 来自非致病性AGM而非致病性RM宿主的淋巴滤泡，并依赖于IL-15- NK细胞向淋巴结滤泡的依赖性再分布和AGM NK上CXCR 5表达增加 (Huot等人。Nature Medicine 2017）。在这个创新的建议中，我们将利用三个SIV感染的非人类 灵长类动物模型，以检验NK细胞对SIV减少起关键作用的中心假设 水库具体而言，我们将：（1）确定与NK细胞介导的控制相关的机制， （2）确定与NK细胞不能控制SIV储库相关的机制 淋巴结中的淋巴结转移和相关的发病机制。这些数据的应用可以大大有助于 未来的HIV/SIV疫苗，免疫治疗剂或利用强效抗病毒药物的储库清除策略 NK细胞的潜力。