Innate Immunity and SIV Infection

描述(由申请人提供)：多行证据表明，先天性免疫反应，特别是在肠道相关淋巴组织(GALT)内的先天性免疫反应在急性感染期发挥关键作用，这对HIV-1感染者和SIV非人类灵长类艾滋病模型的病毒血症水平、病毒载量设定点和疾病进展速度都有影响。这一概念得到了研究结果的支持，这些研究记录了a)在急性感染期间组成先天性免疫系统的细胞谱系的重要作用，B)全基因组关联研究发现，疾病进展速度与几个基因有关，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(KIR)相互作用的HLA-C区域有关c)特定的KIR等位基因影响NK细胞在遏制HIV复制方面的有效性d)我们的数据表明KIR3DL.11等位基因与SIVmac251感染的Mamu-A01+恒河猴的自发病毒载量控制有很强的相关性c)我们的实验室获得了初步数据，表明在急性感染期KIR频率和表达肠道归巢标记α4/β7的人类白细胞抗原-E四聚体+细胞的绝对数。与MHC单倍型相同的SIV感染的正常进展性猕猴相比，SIV感染的长期非进展性猕猴的动力学也更快，这一事实强调了这一发现的重要性。我们认为，有必要对NK细胞亚系的出现、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。我们在急性和/或慢性感染期间使用JAK3抑制剂在体内功能性地耗尽这一细胞谱系的能力，加上我们在体外扩增和注入大量已定义的自体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减法/相加细胞谱系实验，我们提交的实验将为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在急性感染期间影响事件的机制提供重要的见解，并为艾滋病毒-1感染者的治疗提供可利用的途径。公共卫生相关性：人类感染艾滋病毒后的早期事件以及人类艾滋病的SIV感染猴子模型中的早期事件知之甚少。这一建议的工作假设是，对这些早期事件的准确定义是重要的，因为它们为病毒血症水平和疾病进展率如何进展奠定了基础。因此，研究的重点是确定感染SIV的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.