Innate Immunity and SIV Infection

描述（由申请人提供）：一些证据表明，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HIV-1感染者和人类艾滋病的SIV非人类灵长类动物模型中，在急性感染期间对病毒血症水平、病毒载量设定点设置和疾病进展速度产生影响，发挥关键作用。这一概念得到了以下研究结果的支持：a)在急性感染期间，构成先天免疫系统的细胞谱系发挥了重要作用；b)全基因组关联研究发现，疾病进展速度与几个基因相关，其中与已知与NK细胞表达的杀伤细胞免疫球蛋白抑制受体（KIRs）相互作用的HLA-C区域相关c)特异性KIR等位基因影响NK细胞活性抑制HIV复制的有效性d)我们的KIR3DL强关联的数据。c)我们的实验室获得了初步数据，表明在SIV抗病的黑白鸦中，表达肠道归巢标记alpha4/beta7的HLA-E四聚体+细胞的频率和绝对数量在急性感染期间显着快速增加的动力学差异之间存在关联。与MHC单倍型相同的siv感染的正常进展性恒河猴相比，siv感染的长期非进展性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细胞亚谱系的外观动力学、表达的KIRs家族以及这些亚群的细胞因子/趋化因子谱进行更详细的研究。我们在急性和/或慢性感染期间使用JAK3抑制剂在体内功能性耗尽该细胞系的能力，结合我们在体外扩增和注入大量定义的自体NK细胞并在体内跟踪它们的能力，为我们提供了独特而强大的工具来进行我们提交的减/加细胞系实验，这将为该细胞系在急性和慢性感染期间发挥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在急性感染期间影响事件的机制提供重要见解，并为HIV-1感染者的治疗效益提供途径。公共卫生相关性：人类和猴免疫缺陷病毒感染的人类艾滋病猴模型中HIV感染后的早期事件尚不清楚。这一建议的工作假设是，这些早期事件的精确定义是重要的，因为它们为研究病毒血症水平和疾病进展速度奠定了基础。因此，研究的重点是确定SIV感染猴子的这些早期事件。

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.