Impact of Tuberculosis on HIV Disease

描述（由申请人提供）：结核病（TB）是世界范围内人类免疫缺陷病毒-1 （HIV）感染期间最常见的合并感染，并且与HIV相关的发病率和死亡率相关。与其他艾滋病毒相关的机会性感染（OI）不同，结核病发生在艾滋病毒感染的整个过程中，其对病毒活性的影响不能仅通过抗结核治疗来逆转。HL-51636的研究系统地检查了艾滋病毒扩展的基础，并在艾滋病毒/结核病双重感染的局部地点进行了研究。在这些位点上，MTB诱导HIV在巨噬细胞和t细胞中复制，并且这个HIV室有助于系统HIV载量和异质性。细胞因子/趋化因子和HIV/MTB双重感染位点的细胞组成是TB对HIV疾病影响的重要因素。HIV/TB感染胸膜部位的环境特点是TGF-2、IL-6、M-CSF-1和MCP-1活性过高，此外还有TH1谱，以及记忆和调节性t细胞（T-reg）的大量扩增。与非T-reg相比，PFMC T-reg具有生存优势，可抑制对HIV的效应t细胞免疫反应，尤其适合于生产性HIV感染。此外，在MTB刺激下，巨噬细胞将HIV感染传播给CD4 t细胞，反式激活HIV生产，并支持T-reg扩增。最近的研究已经确定了三种化合物，它们可能针对HIV/TB中过量的细胞因子/趋化因子谱，因此可能作为抗结核治疗的短期辅助药物有用。这些包括;1. 红霉素衍生物，其中一些可能对耐多药结核病有用；CDK9 （P-TEFb）的抑制剂，靛柔比星单肟，和3。抗肿瘤药物伊马替尼，可对抗促生存因子M-CSF，可能有助于hiv感染巨噬细胞的凋亡。我们假设HIV/TB共感染位点的细胞组成和细胞因子/趋化因子环境有助于增加HIV复制并通过巨噬细胞和T-reg扩散到CD4 t细胞。这些单核细胞亚群破坏抗HIV t细胞免疫反应，并有助于HIV储存库。通过新的辅助抗HIV疗法调节HIV和宿主分子的界面可能允许在双重感染位点控制HIV和MTB感染的共同发病机制。具体目标是：1。探讨巨噬细胞和DC增强HIV/TB双重感染患者PFMC中mtb特异性CD4+ T细胞感染的机制，并探讨巨噬细胞和DC在T-reg扩增中的作用。2. 确定T-reg在HIV/TB感染胸膜部位扩增对HIV免疫应答的作用，以及它们在HIV/TB期间对病毒动力学的贡献，包括生产感染和潜伏期。3. 确定特定的辅助疗法，如EM-703、IM或伊马替尼，在巨噬细胞中具有抗HIV活性和/或抑制T-reg，是否对HIV/TB合并胸膜结核患者有用。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is the most common co-infection during Human Immunodeficiency Virus-1 (HIV) infection worldwide, and is associated with significant HIV-related morbidity and mortality. Unlike other HIV associated opportunistic infections (OI), TB occurs throughout the course of HIV infection, and its impact on viral activity is not reversible by anti-TB treatment alone. Studies by HL-51636 have examined the basis of HIV expansion systemically and at local sites of dual HIV/TB infection. At these sites MTB induces HIV replication in both macrophages and T-cells, and this HIV compartment contributes to systemic HIV load and heterogeneity. Cytokines/chemokine and the cellular composition at sites of dual HIV/MTB infection are important factors in the impact of TB on HIV disease. The milieu at pleural sites of HIV/TB infection is characterized by excessive TGF-2, IL-6, M-CSF-1, and MCP-1 activity in addition to a TH1 profile, and a massive expansion of memory and regulatory T-cells (T-reg). PFMC T-reg have survival advantage over non T-reg, suppress effector T-cell immune responses to HIV, and are particularly poised to productive HIV infection. Further, upon MTB stimulation macrophages both transmit HIV infection to, trans-activate HIV production in CD4 T-cells, and support T-reg expansion. Recent studies have identified three compounds that potentially target the excessive cytokine/chemokine profile of HIV/TB, and therefore may be useful as short-term adjuncts to anti-TB treatment. These include; 1. Derivatives of erythromycin, some of which may be useful in MDR TB, 2. an inhibitor of CDK9 (of P-TEFb), Indirubicin Monoxime, and 3. the anti-neoplastic agent Imatinib, which counter-acts the pro-survival factor M-CSF, and may be conducive to apoptosis of HIV-infected macrophages. We hypothesize that the cellular composition and cytokine/chemokine milieu at sites of HIV/TB co- infection is conducive to increased HIV replication and spread to CD4 T-cells by macrophages and T-reg. These mononuclear cell subsets undermine anti-HIV T-cell immune responses and contribute to HIV reservoirs. Modulation of the interface of HIV and host molecules by novel adjunctive anti-HIV therapies may allow control of the co-pathogenesis of HIV and MTB infection at sites of dual infection. The Specific Aims are: 1. To determine the mechanism(s) of enhanced HIV infection of MTB-specific CD4+ T cells by macrophages and DC in PFMC from HIV/TB dually infected patients, and to examine the role of macrophages and DC in expansion of T-reg. 2. To determine the role of T-reg expanded at pleural sites of HIV/TB infection on immune responses to HIV, and their contribution to viral dynamics including productive infection and latency during HIV/TB. 3. To determine whether specific adjunctive therapies such as EM-703, IM, or Imatinib that have been shown to have anti-HIV activity in macrophages and/or inhibit T-reg are useful in HIV/TB patients with pleural TB.