Innate immunity predictors of HIV: the role of contraception, pregnancy and HSV-2

HIV 的先天免疫预测因素：避孕、怀孕和 HSV-2 的作用

• 批准号: 8897178
• 负责人: RAINA N. FICHOROVA
• 金额: $ 48.48万
• 依托单位: FAMILY HEALTH INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8897178
• 关键词: Advocate; Affect; African; Age; Biological; Biological Markers; Biological Response Modifiers; Blood; CCL23 gene; Cervical; Cervix Uteri; Clinical; Combined Oral Contraceptives; Complex; Conflict (Psychology); Consultations; Contraceptive Agents; Contraceptive methods; Counseling; Environment; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Equilibrium; Estrogens; Exposure to; Female; Genital system; Goals; Guidelines; HIV; HIV Infections; HIV risk; HIV-1; Health Policy; High Prevalence; Hormonal; Hormones; Human Herpesvirus 2; IL6 gene; IL8 gene; Immune; Immune system; Immunity; Immunologics; Immunosuppressive Agents; Incidence; Infection; Inflammation; Inflammation Mediators; Inflammatory; Injectable; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-6; Interleukin-7; Laboratories; Measures; Mediator of activation protein; Medroxyprogesterone 17-Acetate; Menstrual cycle; Natural Immunity; Outcome; Participant; Phase; Policy Maker; Pregnancy; Progesterone; Progestins; Prospective Studies; Public Health; RANTES; Research; Research Design; Risk; Risk Factors; Role; SHBG gene; SLPI gene; Sampling; Serum; Sex Hormone-Binding Globulin; Site; Specific qualifier value; Specimen; Swab; Testing; Time; Translating; Uganda; Vascular Endothelial Growth Factors; Vulnerable Populations; Woman; World Health Organization; Zimbabwe; activin A; beta-Defensins; condoms; evidence base; experience; health practice; hormonal contraception; immune activation; longitudinal analysis; novel; prevent; public health relevance; reproductive; reproductive hormone; seroconversion; transmission process; unintended pregnancy

DESCRIPTION (provided by applicant): Hormonal contraception (HC), including the injectable progestin depot medroxyprogesterone acetate (DMPA) and combined oral contraceptives (COCs), and pregnancy have been associated with increased risk of HIV in some, but not all, large prospective studies. In February 2012, due to the conflicting epidemiologic study results and lack of sufficient mechanistic information, the World Health Organization held a technical consultation to evaluate the existing evidence on hormonal contraception and HIV infection. The WHO decided not to change the guidelines for access to HC for women at risk of HIV but recommended that women who specifically use progestin-only injectable contraception and seek to prevent unintended pregnancy and HIV should be strongly advised to also use condoms for dual protection. Policy makers and women's advocate groups have expressed concern that the WHO statement is insufficient and difficult to translate into effective counseling for women. In addition, genital HSV-2 infection is known to significantly increase a woman's risk of acquiring HIV, but the mechanism and the impact of hormones on this relationship are not understood. A more complete mechanistic understanding of how HC and HSV-2 may modify the female immune system to increase the risk of HIV is key to clarifying the results of the epidemiologic studies and to establishing more accurate and effective public health policy and practice. The aims of the proposed research are two-fold: 1) to understand the associations between systemic hormonal levels, circulating regulators of inflammation and immunity and soluble innate immunity mediators in the cervix, their relationship with HIV acquisition risk, and how these relationships are altered by exposure to hormonal contraception (DMPA and COC) and pregnancy; and 2) to define the effects of pregnancy and hormonal contraception on the innate immune system preceding, at the time of, and during established (> 6 months) HSV-2 infection to better understand the effect of hormonal contraception and pregnancy on HSV-2 associated HIV risk. We will use ~4,000 longitudinal paired serum and cervical specimens from 1,200 women from Uganda and Zimbabwe who used DMPA, COCs and no hormonal contraception and participated in the HC-HIV study with well-specified HIV and HSV-2 seroconversion dates and who experienced substantial HSV-2, HIV-1 and pregnancy incidence. We will use ELISA and the Meso Scale Discovery multiplex platform to measure levels of endogenous hormones and regulators of inflammation and immunity in cervical samples and paired blood serum. We will use cross-sectional and longitudinal analyses to determine how hormonal contraception, pregnancy and menstrual cycle modify innate immunity, how systemic regulators affect the cervical immune environment, and how the immune regulators are associated with HSV-2 infection (incident and prevalent) and subsequent HIV acquisition risk. This research provides a unique opportunity to elucidate and validate the complex associations between endogenous and exogenous hormones, HSV-2 and HIV-1 through analysis of underlying shared biological mechanisms.

描述（由申请人提供）：荷尔蒙避孕药（HC），包括可注射的孕激素乙酸酯乙酸酯（DMPA）（DMPA）和综合口服避孕药（COC）和妊娠与某些但并非全部的大型前瞻性研究在某些但并非全部与HIV的风险增加有关。 2012年2月，由于流行病学研究的结果矛盾，缺乏足够的机械信息，世界卫生组织进行了技术咨询，以评估现有的有关激素避孕和HIV感染的证据。世卫组织决定不更改患有艾滋病毒风险的妇女的HC的准则，但建议强烈建议使用专门使用仅孕激素注射的避孕药并寻求防止意外怀孕和艾滋病毒的妇女使用避孕套来进行双重保护。政策制定者和妇女倡导者团体表示关注，WHO声明不足以容易地转化为妇女的有效咨询。此外，已知生殖器HSV-2感染会显着增加女性获得的风险 艾滋病毒，但尚不清楚激素对这种关系的机制和影响。对HC和HSV-2如何改变女性免疫系统以增加艾滋病毒风险的更完整的机械理解是阐明流行病学研究结果并建立更准确有效的公共卫生政策和实践的关键。拟议研究的目的是两倍：1）了解系统的激素水平，循环炎症，免疫和免疫的调节因子和子宫颈中可溶性的先天免疫介体，它们与HIV审查风险的关系以及这些关系如何通过暴露于荷尔蒙避孕药（DMPA和COC）和怀孕（DMPA和COC）和怀孕来改变这些关系。 2）定义妊娠和荷尔蒙避孕对先天免疫系统的影响，在既定（> 6个月）HSV-2感染之前和期间，以更好地了解激素避孕和怀孕对HSV-2相关HIV风险的影响。我们将使用来自乌干达和津巴布韦的1,200名妇女的纵向配对的血清和宫颈检查，这些妇女使用了DMPA，COCS和无激素避孕药，并与良好的HSV-HIV研究一起参加了HC-HIV研究，并参加了良好的HSV-2血清转化日期，并经历了HSV-2，HSV-2，HSV-2，HSV-2，HSV-2，HIV-1和怀孕。我们将使用ELISA和MESO量表发现多路复用平台来测量内源激素的水平以及宫颈样品和配对血清中炎症和免疫力的调节剂。我们将使用横截面和纵向分析来确定激素避孕，妊娠和月经周期如何改变先天免疫，系统性调节剂如何影响宫颈免疫环境以及免疫调节剂与HSV-2感染（事件和普遍）以及随后的HIV恢复风险。这项研究提供了一个独特的机会，可以通过分析基础共享的生物学机制来阐明和验证内源性激素和外源激素，HSV-2和HIV-1之间的复杂关联。