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

性激素对宫颈及直肠粘膜组织HIV感染的影响

• 批准号: 8708757
• 负责人: Natalia Teleshova
• 金额: $ 55.82万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708757
• 关键词: Address; African; Animals; Anus; Binding; Biological; Biopsy; Blood; CCL20 gene; CCR5 gene; CD14 gene; CD209 gene; Cell Count; Cells; Cervical; Client; Contraceptive Agents; Couples; Data; Defensins; Depo Provera; Developed Countries; Down-Regulation; Environment; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Frequencies; Gagging; Gene Expression; Gene Expression Profile; Genital system; Gonadal Steroid Hormones; HIV; HIV Infections; HIV-1; Heterosexuals; Hormonal Oral Contraceptives; Hormones; Human; Hysterectomy; ICAM1 gene; Immune; Immunologics; Immunosuppression; In Vitro; Infection; Inflammation; Injectable; Interferons; Intrauterine Devices; Kenya; Knowledge; Lactoferrin; Lead; Life; Link; Luteal Phase; Measures; Mediating; Memory; Menstrual cycle; Molecular Profiling; Monitor; Mucous Membrane; Natural Killer Cells; PI3 gene; Patients; Phenotype; Play; Predisposition; Premenopause; Probability; Progesterone; Progestins; RNA; RNA Sequences; Recruitment Activity; Regulation; Reporting; Risk; Role; Route; SIV; SLPI gene; Sampling; Sex Behavior; Site; South Africa; Specimen; Surveys; T-Lymphocyte; Techniques; Time; Tissues; Vagina; Viral; Virus; Woman; Youth; aged; antimicrobial; base; chemokine; cytokine; cytotoxic; experience; girls; hormonal contraception; immune function; implantable device; in vivo; macrophage; mucosal site; nonhuman primate; public health relevance; receptor; rectal; research study; response; sex; transmission process; vaginal transmission

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.

描述（由申请人提供）：性激素对宫颈和直肠粘膜组织性荷尔蒙的艾滋病毒感染的影响对女性生殖道的粘膜环境具有深远的影响，但是，仍然不清楚它们如何影响阴道的传播 艾滋病毒，如果它们对直肠微环境和直肠传播产生影响。数据表明，使用激素避孕药（主要是depo-provera）在女性中获得HIV增加的数据表明，高孕激素水平可能导致HIV传播增强。实际上，口服激素避孕药或Depo-Provera的患者在生殖器粘膜中活化的CCR5+ T细胞数量增加。进一步支持这一想法的是非人类灵长类动物的数据，表明在月经周期的黄体期，在depo-provera治疗的动物和动物中的阴道SIV传播增加，其特征是孕酮高。最近的数据表明，女性的肛交比以前认为的更为普遍，因此可以影响对异性疾病传播期间性激素影响的数据解释。尽管激素在HIV阴道传播中作用的证据令人信服，但性激素可能也会影响直肠粘膜微环境。实际上，性激素参与肠道组织中炎症的调节。因此，重要的是要在直肠艾滋病毒传播以及阴道传播中确定其作用。我们假设孕激素/孕激素水平升高与（i）HIV靶细胞数量和表型的变化引起的外核，遗传和直肠粘膜粘膜的易感性增加有关，（ii）抑制基线的先天免疫因子，这些因素限制了HIV感染，（III）对病毒诱导的反应的抑制作用，这些因素对MOSC诱导的感染抑制。我们将通过确定宫颈与直肠静脉注射感染的敏感性是否与女性全身孕激素/孕激素水平（外源性与内源性）相关，以及这是否同样在组织免疫功能上会发生变化。这些研究将确定在宫颈和直肠组织组织中是否存在孕激素/孕酮水平（全身，组织）和HIV感染之间的联系。此外，我们将通过关注免疫环境并潜在地识别影响女性对HIV感染易感性的潜在因素来解决两个部位孕激素/孕酮作用的机制。