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

描述（由申请人提供）：激素避孕（HC），包括注射用长效醋酸甲羟孕酮（DMPA）和复方口服避孕药（COCs），在一些但不是所有的大型前瞻性研究中，妊娠与HIV风险增加相关。2012年2月，由于流行病学研究结果相互矛盾，缺乏足够的机制信息，世界卫生组织举行了一次技术磋商，以评估激素避孕和艾滋病毒感染的现有证据。世卫组织决定不改变有艾滋病毒风险的妇女获得HC的指导方针，但建议特别使用仅孕激素注射避孕药并寻求预防意外怀孕和艾滋病毒的妇女也应该使用避孕套进行双重保护。决策者和妇女倡导团体对世卫组织的声明不够充分和难以转化为对妇女的有效咨询表示关切。此外，生殖器HSV-2感染是众所周知的显着增加妇女的风险获得 艾滋病毒，但机制和激素对这种关系的影响尚不清楚。更完整地了解HC和HSV-2如何改变女性免疫系统以增加HIV风险的机制是澄清流行病学研究结果和建立更准确有效的公共卫生政策和实践的关键。拟议研究的目的有两个方面：1）了解全身激素水平，炎症和免疫的循环调节因子以及宫颈中可溶性先天免疫介质之间的关系，它们与艾滋病毒感染风险的关系，以及这些关系如何通过暴露于激素避孕药而改变（DMPA和COC）和妊娠;和2）确定怀孕和激素避孕对先天免疫系统的影响，在怀孕时，以及在确定的HSV-2感染期间（> 6个月），以更好地了解激素避孕和妊娠对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名妇女的约4，000份纵向配对血清和宫颈标本，这些妇女使用DMPA、COC，未使用激素避孕药，参加了HC-HIV研究，具有明确的HIV和HSV-2血清转换日期，并经历了大量HSV-2、HIV-1和妊娠发病率。我们将使用ELISA和Meso Scale Discovery多重平台来测量宫颈样本和配对血清中内源性激素和炎症和免疫调节剂的水平。我们将使用横断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，全身调节剂如何影响宫颈免疫环境，以及免疫调节剂如何与HSV-2感染（事件和流行）和随后的HIV获得风险相关。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，阐明和验证内源性和外源性激素，HSV-2和HIV-1之间的复杂关联。

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.