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

描述(由申请人提供)：在一些(但不是全部)大型前瞻性研究中，激素避孕(HC)，包括注射孕激素库醋酸甲羟孕酮(DMPA)和联合口服避孕药(COCs)，以及怀孕与艾滋病毒风险的增加有关。2012年2月，由于流行病学研究结果相互矛盾，缺乏足够的机械性信息，世界卫生组织举行了一次技术磋商，以评估关于激素避孕和艾滋病毒感染的现有证据。世界卫生组织决定不改变针对有艾滋病毒风险的女性获得HC的指南，但建议专门使用仅含孕激素的注射避孕药并寻求防止意外怀孕和艾滋病毒的女性也应被强烈建议使用避孕套进行双重保护。政策制定者和妇女权益倡导团体表示担心，世卫组织的声明不够充分，很难转化为对妇女的有效咨询。此外，众所周知，生殖器HSV-2感染会显著增加女性感染HSV-2的风险 HIV，但荷尔蒙对这种关系的机制和影响尚不清楚。更全面地了解HC和HSV-2如何改变女性免疫系统以增加感染艾滋病毒的风险，是澄清流行病学研究结果和建立更准确和有效的公共卫生政策和实践的关键。拟议研究的目的有两个：1)了解宫颈系统激素水平、炎症和免疫循环调节因子和可溶性先天免疫介质之间的关系，以及它们与艾滋病毒感染风险的关系，以及这些关系如何因接受激素避孕(DMPA和COC)和怀孕而改变；2)确定怀孕和激素避孕对HSV-2感染之前、感染时和感染期间(&gt；6个月)先天免疫系统的影响，以更好地了解激素避孕和怀孕对HSV-2相关艾滋病毒风险的影响。我们将使用来自乌干达和津巴布韦的1200名妇女的约4,000份纵向配对血清和宫颈样本，这些妇女使用DMPA、COCS和不使用激素避孕药，并参与了HC-HIV研究，这些妇女具有明确的HIV和HSV-2血清转换日期，并且经历了相当大的HSV-2、HIV-1和怀孕发病率。我们将使用ELISA和Meso Scale Discovery多重平台来检测宫颈样本和配对血清中内源性激素以及炎症和免疫调节因子的水平。我们将使用横断面和纵向分析来确定激素避孕、怀孕和月经周期如何改变先天免疫，系统调节因子如何影响宫颈免疫环境，以及免疫调节因子如何与HSV-2感染(事件和流行)和随后的艾滋病毒感染风险相关。这项研究提供了一个独特的机会，通过分析潜在的共同生物学机制来阐明和验证内源和外源激素、HSV-2和HIV-1之间的复杂联系。

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.