Impact of Tuberculosis on HIV Disease

结核病（TB）是全球范围内HIV-1期间最常见的合并感染，并且与显著的HIV相关发病率和死亡率相关。在双重感染受试者中，HIV载量和异质性在局部和全身都增加。结核分枝杆菌（MTB）感染通过宿主细胞因子、趋化因子及其受体的失调支持HIV复制和传播。宿主分子如TNF α和MCP-1和TGF-β MTB感染位点部分通过核因子κ B的活化诱导HIV-1在单核细胞中复制。宿主P-TEF-β（细胞周期蛋白T1）的调节组分对HIV达特活性至关重要，在巨噬细胞中可由细菌LPS诱导，因此在合并感染（如TB）期间可活化。此外，MTB激活来自具有潜伏HIV-1感染的HIV感染受试者的肺泡巨噬细胞以进行病毒表达。此外，本发明还提供了一种方法， 在MTB感染部位的巨噬细胞上CCR 5的表达上调。此外，HIV- 1抑制性趋化因子的浓度在TB期间和在MTB感染部位是有限的。该提议的假设是MTB通过上调P-TEF-[3]诱导巨噬细胞中的HIV转录，并且由巨噬细胞在MTB感染位点产生的宿主分子（TNF-α、MCP-1和TGF-β）有利于MTB的转录激活。 HIV和抗逆转录病毒疗法能够在HIV/TB期间抑制来自巨噬细胞的病毒表达。具体目标是：1）确定单核吞噬细胞中MTB对HIV的转录激活的基础;检测肺泡巨噬细胞和单核细胞中MTB对HIV的增强作用中P-TEF-I和转录因子的激活作用; 2）为了确定在患有胸膜TB的HIV/TB患者中在活动性MTB感染部位有效的HIV转录激活机制，并评估过量的细胞因子和趋化因子在 3）确定在HIV/TB期间抗逆转录病毒治疗是否有效地控制HIV病毒设定点、病毒异质性、潜伏性和生产性感染的CD 4细胞的频率以及巨噬细胞释放病毒粒子。在目标1中，分子测定将是 应用于评估从健康受试者获得的人肺泡巨噬细胞中HIV的转录激活。来自患有胸膜TB的HIV/TB患者的单核细胞将用作这两种病原体在活动性TB部位相互作用的模型（目的2）。为了实现目标3，将对入组抗逆转录病毒安慰剂对照试验的艾滋病毒/肺结核患者进行纵向评估。

Tuberculosis (TB) is the most common co-infection during HIV-1 worldwide, and is associated with significant HIV-related morbidity and mortality. In dually infected subjects, HIV load and heterogeneity are increased both locally and systemically. Mycobacterium tuberculosis (MTB) infection supports HIV replication and dissemination through dysregulations of host cytokines, chemokines and their receptors. Host molecules such as TNFalpha and MCP-1 and TGF-beta sites of MTB infection induce HIV-1 replication in mononuclear cells in part through activation of nuclear factor kappaB. The regulatory component of host P-TEF-beta (Cyclin T1), which is critical to HIV tat activity is inducible in macrophages by bacterial LPS, and therefore its activation during co-infections such as TB. Furthermore, MTB activates alveolar macrophages from HIV-infected subjects with latent HIV-1 infection to viral expression. In addition, the expression of CCR5 is upregulated on macrophages at sites of MTB infection. Furthermore, the concentrations of the HIV- 1 inhibitory chemokines are limited during TB and at sites of MTB infection. The Hypothesis of this proposal is that MTB induces HIV transcription in macrophages by upregulation of P-TEF-[3, and that host molecules produced by macrophages at sites of MTB infection (TNF-alpha, MCP-1, and TGF-beta) are conducive to transcriptional activation of HIV, and antiretroviral therapies are able to contain viral expression from macrophages during HIV/TB. The Specific Aims are: 1) To determine the basis of transcriptional activation of HIV by MTB in mononuclear phagocytes; to examine the role of activation of P-TEF-I], and transcription factors in augmentation of HIV by MTB in alveolar macrophages and monocytes; 2) To determine mechanisms of transcriptional activation of HIV operative at sites of active MTB infection in HIV/TB patients with pleural TB, and to assess the role of excess cytokines and chemokines in viral production, and the role of new rounds of HIV infection in enhanced HIV activity in situ; 3) To determine whether HIV viral set point, viral heterogeneity, frequency of latently and productively infected CD4 cells and release of virions by macrophages are effectively controlled by antiretroviral therapy during HIV/TB. In Aim 1, molecular assays will be applied to assessment of transcriptional activation of HIV in human alveolar macrophages obtained from healthy subjects. Mononuclear cells from HIV/TB patients with pleural TB will be used as a model of interaction of these two 9athogens at sites of active TB (Aim 2). For purposes of Aim 3, HIV/TB patients with pulmonary TB enrolled in a placebo-controlled trial of ARV will be assessed longitudinally.