Monocyte subpopulation in HIV+LTB+ individuals and development of active TB

结核分枝杆菌（Mtb）感染了世界三分之一的人口， 每年死亡人数（1，2）。大约90%的感染者有潜伏性结核感染（LTBI）， 保护性免疫，并保持良好，但10%的发展原发性结核病（结核病）感染后不久，或 多年后结核病复发（3）。艾滋病毒感染显著增加了对结核病的易感性， LTBI患者患活动性结核病的风险高800倍（www.cdc.gov/tb/）。结核病是主要的 艾滋病毒感染者的死亡原因，每年有50多万合并感染者死亡 （www.avert.org/tuberculosis.htm）。我们已发表的研究表明，在健康供体中，Mtb H37 Rv生长 5.6-与CD 14 loCD 16 + MDM相比，在CD 14 hiCD 16-MDM中更快1倍。我们发现， CD 14 hiCD 16-MDM中的Mtb是由于c-Maf表达增加，这增加了IL-10的产生， 促进Mtb H37 Rv生长。在初步研究中，我们发现，在对结核分枝杆菌的反应中，来自HIV+和 HIV-LTBI患者产生等量的T细胞细胞因子。相比之下，HIV+中的CD 14+单核细胞 与来自HIV-LTBI+的CD 14+细胞相比，个体对Mtb的应答表达更多的c-maf和IL-10。 个体根据我们的初步数据，我们假设艾滋病毒感染增加了c- maf和IL-10表达CD 14+细胞，导致Mtb生长增强，增加了 进展为活动性结核病。我们的具体目标是1。确定艾滋病毒感染是否会促进 CD 14 hiCD 16-MDM中的Mtb。2.确定有利于Mtb在巨噬细胞中生长增加的机制 HIV+LTBI+人群。

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes almost 1.3 million deaths per year (1,2). Approximately 90% of infected persons have latent tuberculosis infection (LTBI), have protective immunity and remain well, but 10% develop primary tuberculosis (TB) soon after infection or reactivation TB many years later (3). HIV infection markedly increases susceptibility to TB, and HIV-infected persons with LTBI have an 800-fold greater risk of developing active TB (www.cdc.gov/tb/). TB is the leading cause of death in HIV-infected persons and more than half a million coinfected people die annually (www.avert.org/tuberculosis.htm). Our published studies demonstrate that in healthy donors, Mtb H37Rv grew 5.6-fold more rapidly in CD14hiCD16- MDMs, compared to CD14loCD16+ MDMs. We found increased growth of Mtb in CD14hiCD16- MDMs is due to increased expression of c-Maf, which increases production of IL-10 that promote Mtb H37Rv growth. In preliminary studies we found that in response to Mtb, PBMC from HIV+ and HIV- individuals with LTBI produced equal amounts of T-cell cytokines. In contrast CD14+ monocytes in HIV+ individuals expressed more c-maf and IL-10 in response to Mtb, compared to CD14+ cells from HIV-LTBI+ individuals. Based on our preliminary data we hypothesize that HIV infection increases the number of c- maf and IL-10 expressing CD14+ cells which leads to enhanced Mtb growth, increasing the risk for progression to active TB. Our specific aims are 1. Determine whether HIV infection enhances the growth of Mtb in CD14hiCD16- MDMs. 2. Identify the mechanisms which favor increased growth of Mtb in macrophage subpopulations of HIV+LTBI+ persons.