IFN-a and pDC in HIV infection: impact on T cell development and reconstitution

性状（由申请方提供）：尽管干扰素-1（IFN-？）是一种以其抗病毒作用而闻名的细胞因子，它在低生理浓度下对适应性和先天性免疫系统的正常功能也很重要，而在高浓度下则具有免疫抑制作用。在这方面，IFN-γ水平升高？与HIV-1感染的控制无关，可能是导致HIV-1发病的免疫激活的标志。我们的初步数据表明，HIV-1诱导的IFN-γ？产生通过损害IL-7/IL 7 R途径抑制人T细胞发育的早期阶段。此外，我们发现在正常胸腺组织中，成熟胸腺细胞和浆细胞样树突状细胞（pDC）组成性表达IFN-γ。其次级反应蛋白MxA处于低水平。相反，外周淋巴器官中的淋巴细胞和pDC（来自同一供体）不组成性表达IFN-γ。这些结果支持的概念，在胸腺，低水平的IFN-γ？对T细胞发育的正常功能很重要。然而，高水平的IFN-γ？和延长HIV-1诱导的IFN-？可能干扰正常的T细胞发育，从而干扰外周T细胞重建。因此，虽然IFN-γ？能在体外抑制HIV-1的复制，而IFN-？尽管HIV-1治疗在体内显示出混合的结果，但其免疫抑制作用可能超过其抗病毒活性，从而促进HIV-1发病。根据我们的初步数据，我们的中心假设是，高水平的干扰素？？其在HIV-1感染期间伴随免疫激活，损害T细胞（再生）生成，并且pDC在该过程中起重要作用。我们将使用我们建立的方法以及新的方法和独特的试剂来测试我们的假设。实验将用HIV诱导的IFN-γ进行。在人源化小鼠模型和体外T细胞发育测定中，如以下具体目的中所提出的：1.探讨HIV-1诱导IFN-γ产生的机制。抑制T细胞发育和重建。2.探讨浆细胞样树突状细胞（pDC）在胸腺中的作用。3.为了研究IFN-γ的作用机制，诱导的MxA或其它次级应答蛋白抑制嗜CCR 5和CXCR 4的HIV-1的复制。目前的建议是一个独特的合作方法来阐明IFN-γ的作用？和pDC在HIV-1感染中的T细胞发育和重建中的作用。从拟议的实验中获得的信息将对免疫调节疗法治疗HIV-1感染患者产生影响。公共卫生相关性：虽然干扰素-？？(IFN-??)是一种以其抗病毒作用而闻名的细胞因子，它在低生理浓度下对适应性和先天性免疫系统的正常功能也很重要，而在高浓度下是免疫抑制性的。在这方面，IFN-γ水平升高？与HIV-1感染的控制无关，可能是导致HIV-1发病的免疫激活的标志。目前的建议是一个独特的合作方法来阐明IFN-γ的作用？和pDC在HIV-1感染中的T细胞发育和重建中的作用。深入了解IFN-γ的分子机制？诱导的T细胞发育阻断将促进免疫调节治疗干预的发展，以抵消受损的T细胞发育和再生。

DESCRIPTION (provided by applicant): Although Interferon-1 (IFN-?) is a cytokine known for its antiviral effects, it may be also be important for normal functioning of the adaptive and innate immune system at low, physiologic concentrations, while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. Our preliminary data show that HIV-1-induced IFN-?? production inhibits early stages of human T cell development by impairing the IL-7/IL7R pathway. In addition we found that in normal thymus tissue, mature thymocytes and plasmacytoid dendritic cells (pDC) constitutively express IFN-?? and its secondary response protein MxA at low levels. In contrast, lymphocytes and pDC in peripheral lymphoid organs (from the same donor) do not constitutively express IFN-??. These results support the notion that in the thymus, low levels of IFN-?? are important for normal functioning of T cell development. However, high levels of IFN-?? and prolonged HIV-1-induced IFN-?? are likely to disturb normal T cell development and thereby peripheral T cell reconstitution. Thus, although IFN-?? can suppress HIV-1 replication in vitro, and IFN-?? therapy has shown mixed results in vivo, it is likely that its immunosuppressive effects outweigh its antiviral activity thereby contributing to HIV-1 pathogenesis. Based on our preliminary data our central hypothesis is that high levels of IFN-?? which accompany immune, activation during HIV-1 infection, impair T cell (re)generation and that pDC play an essential role in this process. We will use our established methods as well as novel approaches and unique reagents to test our hypothesis. Experiments will be performed with HIV-induced IFN-?? in humanized mouse models and in vitro T cell development assays as proposed in the following specific aims: 1. To investigate the mechanisms by which HIV-1 induced IFN-?? inhibits T-cell development and reconstitution. 2. To characterize the role of plasmacytoid dendritic cells (pDC) in the thymus. 3. To investigate the mechanisms by which IFN-?? induced MxA or other secondary response proteins suppress replication of CCR5- and CXCR4-tropic HIV-1. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Information gained from the proposed experiments will have implications for the treatment of HIV-1 infected patients with immunomodulatory therapies. PUBLIC HEALTH RELEVANCE: Although Interferon-?? (IFN-??) is a cytokine known for its antiviral effects, it may also be important for normal functioning of the adaptive and innate immune system at low, physiologic, concentrations while it is immunosuppressive at high concentrations. In this respect, elevated levels of IFN-?? are not correlated with control of HIV-1 infection and are likely a sign of immune activation that contributes to HIV-1 pathogenesis. The present proposal represents a unique collaborative approach to elucidate the role of IFN-?? and pDC in T cell development and reconstitution in HIV-1 infection. Insight into the molecular mechanisms underlying the IFN-?? induced block of T cell development will enhance the development of immunomodulatory therapeutic interventions to counteract impaired T cell development and regeneration.