Innate Immunity and SIV Infection

先天免疫和 SIV 感染

• 批准号: 8066581
• 负责人: Aftab A. Ansari
• 金额: $ 15.5万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-10 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066581
• 关键词: Acquired Immunodeficiency Syndrome; Activities of Daily Living; Acute; Adoptive Transfer; Alleles; Animals; Antibodies; Appearance; Autologous; Biological Assay; Blood; Cell Lineage; Cell physiology; Cells; Cercocebus atys; Chronic; Containment; Data; Development; Disease Progression; Disease Resistance; Dose; Effectiveness; Event; Family; Frequencies; Functional disorder; Genes; Genetic; Genetic Epistasis; Genetic Polymorphism; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; HLA-Bw4; HLA-C Antigens; Haplotypes; Homing; Human; Immune; Immune response; Immune system; Immunoglobulins; In Vitro; Individual; Infection; Infectious Agent; Infusion procedures; Inherited; Integrins; JAK3 gene; Janus kinase 3; KIR3DS1; Killer Cells; Kinetics; Lead; Ligands; Ligation; Link; Macaca; Macaca mulatta; Mamu-A 01 antigen; Masks; Modeling; Molecular Genetics; Monkeys; Mucous Membrane; Natural Immunity; Natural Killer Cells; Outcome; Plasma; Play; Procedures; Process; Production; Reagent; Receptor Gene; Role; SIV; Specificity; Staging; Therapeutic; Time; Variant; Viral Load result; Viremia; Work; arm; base; chemokine; cytokine; genetic element; genome wide association study; human leukocyte antigen gene; immune function; imprint; in vivo; inhibitor/antagonist; insight; nonhuman primate; public health relevance; receptor; research study; tool

DESCRIPTION (provided by applicant): Several lines of evidence suggest that innate immune responses particularly within the gut associated lymphoid tissues (GALT) play a critical role during the acute infection period that delivers an imprint on the level of viremia, setting of the viral load set point and rate of disease progression both in HIV-1 infected humans and the SIV non-human primate model of human AIDS. This concept is supported by the findings from studies that document a) an important role of the cellular lineages that comprise the innate immune system during acute infection, b) the findings from studies of whole genome association that the rate of disease progression is linked with several genes among them is the association with the HLA-C region known to interact with killer cell immunoglobulin inhibitory receptors (KIRs) expressed by NK cells c) Specific KIR alleles influence the effectiveness of NK cell activity in the containment of HIV replication d) our data of a strong association of KIR3DL.11 allele with spontaneous viral load control in SIVmac251 infected Mamu-A01+ rhesus macaques c) our lab derived preliminary data of an association between differences in the kinetics of marked rapid increases during the acute infection period in the frequency and absolute numbers of HLA-E tetramer+ cells that express the gut homing marker alpha4/beta7 in SIV disease-resistant sooty mangabeys. The fact that the kinetics are also faster in SIV-infected long term non-progressor rhesus macaques as compared with MHC haplotype identical SIV-infected regular progressor rhesus macaques underscores the importance of this finding. We submit that a more detailed study of the kinetics of the appearance of sub-lineages of NK cells, the family of KIRs that are expressed and the cytokine/chemokine profile of each of these subsets is warranted. Our ability to functionally deplete this cell lineage in vivo during acute and/or chronic infection using a JAK3 inhibitor combined with our ability to in vitro expand and infuse large number of defined autologous NK cells and track them in vivo provide us with unique and powerful tools to do the subtract/add cell lineage experiments that we submit will provide important clues as to the role this cell lineage plays during the acute and chronic infection period. We submit that the studies outlined will provide important insights on mechanisms by which the innate immune system influences events during the acute infection period and provide avenues that can be exploited for therapeutic benefit of HIV-1 infected humans. PUBLIC HEALTH RELEVANCE: Early events following HIV infection in humans and in the SIV infected monkey model of human AIDS are poorly understood. It is the working hypothesis of this proposal that precise definition of these early events are important since they lay down the ground work with how the level of viremia and rate of disease progression proceeds. Studies are therefore focused on defining these early events in SIV infected monkeys.

描述（由申请人提供）：多项证据表明，先天免疫反应，特别是肠道相关淋巴组织 (GALT) 内的先天免疫反应，在急性感染期间发挥着关键作用，对病毒血症水平、病毒载量设定产生影响HIV-1感染者和人类艾滋病的SIV非人类灵长类动物模型中疾病进展的设定点和速率。这一概念得到了研究结果的支持，这些研究记录了 a) 构成先天免疫系统的细胞谱系在急性感染期间的重要作用，b) 全基因组关联研究的结果，即疾病进展的速度与多种因素有关。其中的基因与 HLA-C 区域相关，已知该区域与 NK 细胞表达的杀伤细胞免疫球蛋白抑制受体 (KIR) 相互作用 c) 特定的 KIR 等位基因影响 NK 细胞活性在遏制 HIV 复制方面的有效性 d) 我们的数据在 SIVmac251 感染的 Mamu-A01+ 恒河猴中，KIR3DL.11 等位基因与自发病毒载量控制之间存在很强的关联 c) 我们的实验室得出了急性感染期间频率和频率显着快速增加的动力学差异之间关联的初步数据抗 SIV 病的乌白眉猴中表达肠道归巢标记 α4/β7 的 HLA-E 四聚体+细胞的绝对数量。与 MHC 单倍型相同的 SIV 感染的常规进展恒河猴相比，感染 SIV 的长期非进展恒河猴的动力学也更快，这一事实强调了这一发现的重要性。我们认为，有必要对 NK 细胞亚谱系的出现动力学、表达的 KIR 家族以及每个亚群的细胞因子/趋化因子谱进行更详细的研究。我们能够在急性和/或慢性感染期间使用 JAK3 抑制剂在体内功能性地消除这种细胞谱系，再加上我们在体外扩增和输注大量确定的自体 NK 细胞并在体内追踪它们的能力，为我们提供了独特而强大的工具我们提交的减法/加法细胞谱系实验将为了解该细胞谱系在急性和慢性感染期间所起的作用提供重要线索。我们认为，概述的研究将为先天免疫系统影响急性感染期间事件的机制提供重要见解，并提供可用于治疗 HIV-1 感染者的途径。公共卫生相关性：人类和感染 SIV 的人类艾滋病猴模型中 HIV 感染后的早期事件知之甚少。该提案的工作假设是，这些早期事件的精确定义非常重要，因为它们为病毒血症水平和疾病进展速度的进展奠定了基础。因此，研究的重点是确定感染 SIV 的猴子中的这些早期事件。