Genital Ulcer Disease and HIV Transmission

生殖器溃疡疾病（GUD）是人类免疫缺陷病毒1型（HIV-1）双向传播的重要危险因素。许多生物学和分子机制可能解释了这种风险的增加，包括保护性上皮/粘膜屏障的破坏，激活的炎症细胞的募集，以及生殖器溃疡处HIV-1复制的增加。体外研究提供的证据表明，至少有一种HIV-1共受体（CCR5）在苍白球绦虫刺激人类单核细胞后上调。然而，体内数据的缺乏证实了许多这些分子的发现。鉴于艾滋病毒感染仍然是一个令人担忧的全球公共卫生问题，并且与GUD合并感染是常见的，进一步阐明细胞和分子水平上这种相互关系的研究对于我们了解和可能预防艾滋病毒传播至关重要。妊娠和/或孕激素水平升高在改变艾滋病毒传播中的潜在作用尚未得到调查，但可能是一个主要的混杂因素。为此，本提案的具体目的是：1)表征GUD中的炎症环境，并确定对HIV-1未感染的GUD妇女中HIV-1共受体表达的影响；2)确定GUD对HIV-1感染妇女中HIV-1表达的影响；3)确定妊娠对GUD环境下炎症环境及HIV-1共受体表达的影响。对这些目标的追求将进一步阐明GUD与HIV-1传播之间相互关系的细胞和分子基础，特别是在妇女中。

Genital ulcer disease (GUD) is a significant risk factor for the bidirectional transmission of the human immunodeficiency virus type-1 (HIV-1). A number of biologic and molecular mechanisms have been proposed which likely account for this increased risk, including disruption of the protective epithelial/mucosal barrier, recruitment of activated inflammatory cells, and increased replication of HIV-1 at the genital ulcer. In vitro studies have provided evidence that at least one HIV-1 coreceptor (CCR5) is upregulated after stimulation of human monocytes with T. pallidum. There is, however, a paucity of in vivo data confirming many of these molecular findings. Given that HIV infection remains an alarming global public health problem, and that co-infection with GUD is common, studies to further elucidate this interrelationship at the cellular and molecular levels is vital to our understanding of and possible prevention of HIV transmission. The potential role pregnancy and/or elevated progesterone levels play in altering HIV transmission has not been investigated, yet may be a major confounder. To this end, the Specific Aims of this proposal are: 1) To characterize the inflammatory milieu in GUD and determine the effect on HIV-1 coreceptor expression in HIV-1 uninfected women with GUD; 2) To determine the effect of GUD on HIV-1 expression in HIV- 1 infected women; and 3) To determine the influence of pregnancy on the inflammatory milieu and HIV-1 coreceptor expression in the setting of GUD. The pursuit of these aims will further elucidate the cellular and molecular bases of the interrelationship between GUD and HIV-1 transmission, particularly in women.