Co-factors in HIV Mucosal Infection

描述(申请人提供)：在世界范围内，异性传播是HIV-1感染的主要原因。显然，控制HIV-1的异性传播将是朝着消除这一全球流行病迈出的重要一步。为了实现这一目标，描述影响病毒传播的细胞和分子事件将是重要的。虽然炎症性和溃疡性传播感染都会增强HIV-1的性传播，但导致这种增强的潜在机制尚未完全阐明。感染易感性的增加可能是由于许多因素，包括宫颈阴道上皮屏障完整性的破坏，HIV-1靶细胞的招募，如朗格汉斯/树突状细胞(LC/DC)，巨噬细胞(M？)和T淋巴细胞到炎症部位，通过性传播感染直接激活靶细胞。STI病原体的一个共同特征是编码模式识别受体Toll样受体(Toll-like Receptor，TLR)家族成员的配体，这些配体激活的TLR既能激活HIV-1靶细胞，又能诱导局部炎症反应。配体激活的核受体(NR)包括过氧化物酶体增殖物激活受体(PPAR)、肝X受体(LXR)、糖皮质激素受体(GR)，是TLR诱导的M？、LC/DC和上皮细胞炎症基因表达的有效抑制因子。此外，维甲酸受体(RAR)和PPAR配体已被证明可以抑制HIV-1基因的表达。我们最初的目标是确定淋球菌暴露或TLR信号在增强宫颈阴道粘膜中发现的靶细胞的HIV-1感染方面的作用。我们的主要和长期目标是研究配体激活的NR作为HIV-1传播抑制剂的潜在作用。我们将验证配体激活的NR通过以下方式发挥作用的假设：1)直接抑制HIV-1转录，2)限制STI或TLR诱导的有利于HIV-1复制的炎性微环境。为了实现这些目标，我们将1)评估NR/TLR串扰对原代LC、DC、MF和T细胞中HIV-1复制和炎症基因表达的影响，2)确定TLR调控HIV-1转录的机制(S)以及NR信号如何调控它，以及3)在阴道和宫颈组织外植体以及人体阴道器官模型中检测NR/TLR串扰对靶细胞HIV-1感染和炎症的影响。 与公共卫生相关：在世界范围内，导致艾滋病的艾滋病毒-1的大多数新感染发生在与受感染男子发生过性行为的妇女中。艾滋病毒-1传播给妇女的能力在那些同时感染其他性传播疾病的妇女中更大。这在一定程度上是因为这些其他疾病会引起炎症。我们正在研究一类新的药物，我们认为这种药物通过阻断炎症和艾滋病毒-1的生长能力来抑制艾滋病毒-1感染。我们将使用纯化的细胞和一个独特的实验室衍生的女性生殖道组织模型来测试这些药物抑制HIV-1传播的能力。

DESCRIPTION (provided by applicant): Worldwide, heterosexual transmission accounts for most HIV-1 infections. Clearly, controlling heterosexual transmission of HIV-1 would be a significant step toward eliminating this global epidemic. To achieve this goal, it will be important to delineate the cellular and molecular events that affect virus transmission. Although both inflammatory and ulcerative sexually transmitted infections (STIs) enhance sexual transmission of HIV-1, the underlying mechanisms leading to this enhancement have not been fully elucidated. Enhanced susceptibility to infection may be due to a number of factors, including the disruption of the integrity of the cervicovaginal epithelial barrier, recruitment of HIV-1 target cells such as Langerhans/dendritic cells (LC/DC), macrophages (M?) and T lymphocytes to sites of inflammation, and direct activation of target cells by STIs. A common feature of STI pathogens is that they encode ligands for members of the Toll-like receptor (TLR) family of pattern recognition receptors and these ligand-activated TLRs can both activate HIV-1 target cells and induce local inflammatory responses. Ligand-activated nuclear receptors (NR), including peroxisome proliferator activated receptor (PPAR), liver X receptor (LXR), glucocorticoid receptor (GR), are potent inhibitors of TLR-induced inflammatory gene expression in M?, LC/DC, and epithelial cells. In addition, retinoic acid receptor (RAR) and PPAR ligands have been shown to repress HIV-1 gene expression. Our initial goal is to determine the role of Neisseria gonorrhoeae exposure or TLR-signaling in augmenting HIV-1 infection of target cells that are found in the cervicovaginal mucosae. Our major and long-term goal is to examine the potential role of ligand-activated NR as inhibitors of HIV-1 transmission. We will test the hypothesis that ligand-activated NR act by: 1) directly repressing HIV-1 transcription, and 2) by limiting the STI or TLR-induced inflammatory microenvironment that favors HIV-1 replication. To achieve these goals, we will 1) evaluate the impact of NR/TLR crosstalk on HIV-1 replication and inflammatory gene expression in primary LC, DC, MF and T cells, 2) determine the mechanism(s) of TLR-modulated HIV-1 transcription and how it is regulated by NR signaling, and 3) examine the effects of NR/TLR crosstalk on HIV-1 infection of target cells and inflammation in vaginal and cervical tissue explants and in an organotypic model of the human vagina. PUBLIC HEALTH RELEVANCE: World-wide, most new infections with HIV-1, the virus that causes AIDS, occur in women who have had intercourse with infected men. The ability of HIV-1 to be transmitted to women is greater in those women who are also infected with other sexually transmitted diseases. This is partly due to the fact that these other diseases cause inflammation. We are studying a novel class of drugs that we believe inhibit HIV-1 infection by blocking both inflammation and the ability of HIV-1 to grow. We will test these drugs for their ability to inhibit HIV-1 transmission using purified cells and a unique laboratory-derived tissue model of the female reproductive tract.