Innate Immunity and SIV Infection

描述（由申请方提供）：多项证据表明，先天性免疫应答（特别是肠道相关淋巴组织（GALT）内的先天性免疫应答）在急性感染期间发挥关键作用，其对HIV-1感染者和SIV非人灵长类动物人类AIDS模型的病毒血症水平、病毒载量设定点和疾病进展速率产生影响。这一概念得到了研究结果的支持，这些研究记录了a）在急性感染期间构成先天免疫系统的细胞谱系的重要作用，B）来自全基因组关联研究的发现，即疾病进展的速率与几个基因相关，其中包括与已知与杀伤细胞免疫球蛋白抑制受体（KIR）相互作用的HLA-C区的关联c）特异性KIR等位基因影响NK细胞活性在遏制HIV复制中的有效性d）我们的数据表明，在SIVmac 251感染的Mamu-A01+恒河猴中，KIR3DL.11等位基因与自发病毒载量控制密切相关c）我们的实验室获得了HLA-E四聚体+的频率和绝对数量在急性感染期间显著快速增加的动力学差异之间的关联的初步数据。表达肠道归巢标记α 4/β 7的细胞在SIV抗病性白眉猴中。与MHC单倍型相同的SIV感染的常规进展恒河猴相比，SIV感染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，需要对NK细胞亚系出现的动力学、表达的KIR家族以及这些亚群中每一个的细胞因子/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JAK 3抑制剂在体内功能性地耗尽该细胞谱系的能力与我们体外扩增和输注大量限定的自体NK细胞并在体内追踪它们的能力相结合，为我们提供了独特且强大的工具来进行减去/消除。我们提交的细胞谱系实验将为这种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，所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，并提供可用于HIV-1感染者治疗益处的途径。公共卫生相关性：人类感染HIV后的早期事件和SIV感染猴模型中的人类艾滋病知之甚少。该建议的工作假设是，这些早期事件的精确定义是重要的，因为它们奠定了病毒血症水平和疾病进展速度的基础。因此，研究集中在定义SIV感染猴的这些早期事件。

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.