Impact of Tuberculosis on HIV Disease

描述(申请人提供)：结核病(TB)是全球人类免疫缺陷病毒-1(HIV)感染过程中最常见的混合感染，与艾滋病毒相关的发病率和死亡率显著相关。与其他艾滋病毒相关机会性感染(OI)不同，结核病在艾滋病毒感染的整个过程中都会发生，其对病毒活动的影响不是单靠抗结核治疗就能逆转的。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/结核病双重感染的地方进行了研究。在这些部位，MTB诱导巨噬细胞和T细胞中的HIV复制，而这个HIV隔间有助于全身HIV负荷和异质性。细胞因子/趋化因子和HIV/MTB双重感染部位的细胞成分是结核病对HIV疾病影响的重要因素。HIV/TB感染胸膜部位的环境特征是除了TH1外，还有过度的转化生长因子-2、IL-6、M-CSF-1和MCP-1活性，以及记忆和调节性T细胞(T-reg)的大规模扩张。与非T-reg相比，pFMC T-reg具有生存优势，可抑制效应者T细胞对HIV的免疫反应，尤其适合于产生HIV感染。此外，在MTB刺激下，巨噬细胞将HIV感染传递给CD4T细胞，反式激活CD4T细胞中的HIV产生，并支持T-reg的扩张。最近的研究已经确定了三种化合物，它们可能针对艾滋病毒/结核病的过度细胞因子/趋化因子图谱，因此可能作为抗结核病治疗的短期辅助药物。这些药物包括：1.红霉素的衍生物，其中一些可能对耐多药结核病有用；2.CDK9的抑制剂(P-TEFb)，青紫素单肟，以及3.抗肿瘤药物伊马替尼，它能对抗促进生存因子M-CSF，并可能有助于艾滋病毒感染的巨噬细胞的凋亡。我们推测，HIV/TB混合感染部位的细胞成分和细胞因子/趋化因子环境有助于增加HIV的复制，并通过巨噬细胞和T-reg传播到CD4T细胞。这些单个核细胞亚群破坏了抗艾滋病毒T细胞免疫反应，并促进了艾滋病毒的蓄积。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部位控制HIV和MTB感染的共同致病。1.研究HIV/TB双重感染患者巨噬细胞和DC对结核分枝杆菌特异性CD_4~+T细胞感染的增强机制(S)，并探讨巨噬细胞和DC在T-reg扩增中的作用。2.确定在HIV/TB感染的胸膜部位扩增的T-reg在HIV免疫应答中的作用，以及它们在HIV/TB的产生性感染和潜伏期等病毒动力学中的作用。3.确定EM-703、IM或Imatinib等已被证明具有抗巨噬细胞HIV活性和/或抑制T-reg的特定辅助疗法是否对患有胸膜结核的HIV/TB患者有效。 公共卫生相关性：结核病是全世界艾滋病毒感染过程中最常见的混合感染，与艾滋病毒相关的发病率和死亡率显著相关。这项研究将确定结核病影响艾滋病毒的机制，这些机制可能受到辅助治疗的调节。

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. PUBLIC HEALTH RELEVANCE: TB is the most common co-infection during HIV infection worldwide, and is associated with significant HIV-related morbidity and mortality. This research will identify mechanisms by which TB impacts HIV that may be modulated by adjunctive therapies.