Genital Ulcer Disease and HIV Transmission

生殖器溃疡是人类免疫缺陷病毒1型(HIV-1)双向传播的重要危险因素。已经提出了许多可能导致这种风险增加的生物学和分子机制，包括保护性上皮/粘膜屏障的破坏，激活的炎症细胞的招募，以及生殖器溃疡中HIV-1复制的增加。体外研究表明，梅毒螺旋体刺激人单核细胞后，至少有一个HIV-1辅助受体(CCR5)上调。然而，证实其中许多分子发现的体内数据很少。鉴于艾滋病毒感染仍然是一个令人震惊的全球公共卫生问题，而且与GUD合并感染很常见，在细胞和分子水平上进一步阐明这种相互关系的研究对于我们理解和可能预防艾滋病毒传播至关重要。怀孕和/或黄体酮水平升高在改变艾滋病毒传播方面的潜在作用尚未被调查，但可能是一个主要的混淆因素。为此，这项建议的具体目的是：1)表征GUD的炎症环境，并确定GUD对未感染HIV-1的GUD妇女HIV-1协同受体表达的影响；2)确定GUD对HIV-1感染妇女HIV-1表达的影响；以及3)确定GUD背景下怀孕对炎症环境和HIV-1协同受体表达的影响。追求这些目标将进一步阐明GUD和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.