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

描述（由申请人提供）：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具有深远的影响，然而，尚不清楚它们如何影响HIV的阴道传播。 艾滋病病毒是否对直肠微环境和直肠传播有影响。数据显示，使用激素避孕药（主要是Depo-Provera）的妇女感染艾滋病毒的人数增加，这表明高水平的抗艾滋病毒蛋白可能导致艾滋病毒传播增加。事实上，口服激素避孕药或Depo-Provera的患者生殖器粘膜中活化的CCR 5 + T细胞数量增加。进一步支持这一观点的是在非人灵长类动物中的数据，其表明在Depo-Provera治疗的动物中和在月经周期的黄体期期间的动物中阴道SIV传播增加，所述黄体期的特征在于高孕酮水平。最近的数据表明，肛交在妇女中比以前认为的更普遍，因此可能影响对异性性传播艾滋病毒期间性激素影响数据的解释。虽然激素在HIV阴道传播中的作用的证据是令人信服的，但性激素也可能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，重要的是要确定它们在直肠艾滋病毒传播以及阴道传播中的作用。我们假设孕激素/孕酮水平的增加与外、宫颈内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）抑制限制HIV感染的基线先天免疫因子，（iii）抑制病毒诱导的保护粘膜免受感染的反应。我们将通过确定宫颈与直肠乙状结肠组织对体外IV感染的易感性是否与女性全身孕酮/孕酮水平（外源性与内源性）相关以及这是否也与组织免疫功能的变化平行来探讨这一点。这些研究将确定孕激素/孕酮水平（全身、组织）与宫颈和直肠乙状结肠组织中的HIV感染之间是否存在联系。此外，我们将通过关注免疫环境来解决这两个位点的孕酮/孕酮作用机制，并可能确定影响女性对HIV感染易感性的潜在因素。

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.