Effect of sex hormones on HIV infection of cervical and rectal mucosal tissue

性激素对宫颈和直肠粘膜组织HIV感染的影响性激素对女性生殖道的粘膜环境有深远的影响，但它们如何影响艾滋病毒的阴道传播仍不清楚。 如果它们对直肠微环境和直肠传播有影响。数据显示，在使用激素避孕的妇女中，艾滋病毒感染增加，主要是Depo-Provera，这表明高孕酮水平可能导致艾滋病毒传播增强。事实上，服用口服激素避孕药或Depo-Provera的患者生殖器粘膜中激活的CCR5 T细胞数量增加。进一步支持这一观点的是，非人类灵长类动物的数据显示，服用Depo-Provera的动物和黄体期动物的阴道SIV传播率增加，这是以高孕酮水平为特征的。最近的数据表明，肛交在女性中比之前认为的更普遍，因此可能会影响对性激素在异性传播艾滋病毒过程中影响的数据的解释。虽然激素在艾滋病毒阴道传播中的作用的证据是令人信服的，但性激素很可能也会影响直肠粘膜微环境。事实上，性激素参与了肠道组织炎症的调节。因此，确定它们在艾滋病毒直肠传播和阴道传播中的作用是很重要的。我们假设孕激素/孕酮水平的增加与子宫外膜、宫颈和直肠乙状结肠粘膜对HIV的易感性增加有关，这是由于(I)HIV靶细胞数量和表型的变化，(Ii)限制HIV感染的基线先天免疫因素的抑制，(Iii)抑制病毒诱导的保护粘膜免受感染的反应。我们将通过确定女性宫颈和直肠乙状结肠组织对体外IV感染的敏感性是否与全身孕激素/孕酮水平(外源性和内源性)相关，以及这是否也与组织免疫功能的变化相平行来探索这一点。这些研究将确定宫颈和直肠乙状结肠组织中孕激素/孕酮水平(全身组织)与HIV感染之间是否存在联系。此外，我们将通过集中于免疫环境来研究孕激素/孕酮在这两个部位的作用机制，并潜在地确定影响女性感染艾滋病毒的潜在因素。

DESCRIPTION (provided by applicant): Effect of sex hormones on HIV infection of cervical and rectal mucosal tissue Sex hormones have a profound effect on the mucosal environment of the female genital tract, however, it is still not clear how they influence vaginal transmission of HIV and if they have an impact on the rectal microenvironment and rectal transmission. The data demonstrating increased HIV acquisition in women using hormonal contraception, primarily Depo-Provera, suggest that high progestin level may lead to enhanced HIV transmission. In fact, patients on oral hormonal contraceptives or Depo-Provera have an increased number of activated CCR5+ T cells in the genital mucosa. Further supporting this idea are data in non-human primates demonstrating increased vaginal SIV transmission in Depo-Provera treated animals and in animals during luteal phase of the menstrual cycle which is characterized by high progesterone levels. Recent data demonstrate that anal intercourse is more prevalent among women than previously thought, and therefore can impact interpretation of data on effect of sex hormones during heterosexual HIV transmission. While the evidence for a role of hormones in HIV vaginal transmission is compelling, it is likely that sex hormones influence the rectal mucosal microenvironment as well. In fact, sex hormones are involved in regulation of inflammation in the gut tissue. Therefore, it is important to establish their role in rectal HIV transmission, as well as vaginal transmission. We hypothesize that increased progestins/progesterone levels are associated with increased susceptibility of ecto-, endocervical and rectosigmoid mucosa to HIV due to (i) changes in HIV target cell numbers and phenotype, (ii) suppression of baseline innate immune factors that limit HIV infection, (iii) suppression of virus-induced responses that protect against infection in the mucosa. We will explore this by determining if the susceptibility of cervical vs. rectosigmoid tissues to in vitro IV infection correlates with systemic progestin/progesterone levels (exogenous vs. endogenous) in women and whether this also parallels changes in tissue immune function. These studies will determine if there is a link between progestins/progesterone levels (systemic, tissue) and HIV infection in both the cervical and rectosigmoid tissues. Furthermore, we will address the mechanism of progestin/progesterone action at both sites by focusing on the immune environment and potentially identify underlying factors that influence a woman's susceptibility to HIV infection.