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

基本信息

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
项目类别：
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

项目摘要

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）：在一些（但不是全部）大型前瞻性研究中，激素避孕（HC），包括注射孕激素长效醋酸甲羟孕酮（DMPA）和复方口服避孕药（COC）以及怀孕与艾滋病毒风险增加有关研究。 2012年2月，由于流行病学研究结果相互矛盾且缺乏足够的机制信息，世界卫生组织举行了一次技术磋商会，评估有关激素避孕和HIV感染的现有证据。世卫组织决定不改变有艾滋病毒风险的女性获得医疗服务的指南，但建议专门使用纯孕激素注射避孕剂并寻求预防意外怀孕和艾滋病毒的女性也应使用避孕套进行双重保护。政策制定者和妇女权益团体对世卫组织的声明不够充分且难以转化为对妇女的有效咨询表示担忧。此外，已知生殖器 HSV-2 感染会显着增加女性感染 HSV-2 的风险。 HIV，但其机制以及激素对这种关系的影响尚不清楚。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 HIV 的风险是澄清流行病学研究结果以及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）了解全身激素水平、炎症和免疫的循环调节因子以及子宫颈中可溶性先天免疫介质之间的关联，它们与艾滋病毒感染风险的关系，以及这些关系是如何改变的通过接触激素避孕药（DMPA 和 COC）和怀孕； 2) 明确 HSV-2 感染前、感染时和感染期间（> 6 个月）妊娠和激素避孕对先天免疫系统的影响，以更好地了解激素避孕和妊娠对 HSV-2 的影响相关的艾滋病毒风险。我们将使用来自乌干达和津巴布韦 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 且未使用激素避孕，并参加了 HC-HIV 研究，具有明确的 HIV 和 HSV-2 血清转化日期，并且经历了相当长的一段时间。 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以及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、怀孕和月经周期如何改变先天免疫，系统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）和随后的艾滋病毒感染风险。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性和外源性激素、HSV-2 和 HIV-1 之间的复杂关联。