Anti-HIV activity in genital tract secretions of postmenopausal women

绝经后妇女生殖道分泌物的抗艾滋病毒活性

• 批准号: 8319127
• 负责人: Mimi Ghosh
• 金额: $ 9.02万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319127
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; Aging; Anti-Retroviral Agents; Area; Ascaridil; Biological; CCL20 gene; Cathepsins; Cathepsins B; Cervical; Data; Developed Countries; Development; Dimensions; Drug usage; Effectiveness; Epidemic; Estrogens; Female; Genital system; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; HIV Seropositivity; HIV-1; Health Care Costs; Heterosexuals; Highly Active Antiretroviral Therapy; Hormone Responsive; Human; Immune; Immune system; Immunity; Infection; Life; Measures; Menopause; Outcome; PI3 gene; Peptide Hydrolases; Pharmaceutical Preparations; Planet Mars; Postmenopause; Predisposition; Premenopause; Probability; Progesterone; Research; Risk; SLPI gene; Series; Sexually Transmitted Diseases; Source; Testing; Therapeutic Intervention; United States National Institutes of Health; Vagina; Woman; antimicrobial; beta-defensin-2; design; immune function; innate immune function; men; older women; reproductive; sexually active; transmission process

DESCRIPTION (provided by applicant): Heterosexual transmission is now the predominant source of new HIV infections and the number of infections in women is on the rise. In developed countries, the effectiveness of HAART therapy has allowed HIV-positive men and women to live longer. It has been predicted that by 2015, approximately 50% of people in the USA living with HIV will be above 50 years old (http://www.sfaf.org/hiv-info/hot-topics/hivision/hiv-and-aging-vienna- satellite-2010-07-19-executive-summary.pdf). This will result in a massive increase in health care costs in order to provide for antiretroviral drugs as well as to manage the multitude of adverse effects that occur with long-term usage of these drugs (http://www.gmhc.org/files/editor/file/a_pa_aging10_emb2.pdf). Although it is known that aging results in loss of sex hormones and reduction of certain immune functions (reviewed in Wira et al, Am J Reprod Immunol. 2011 Mar;65(3):196-211),there remains a major gap in our understanding regarding the extent of loss of innate immune functions in the female reproductive tract (FRT). As multiple innate immune factors of the FRT are hormone-responsive, the loss of estrogen (and/or progesterone) with aging can result in a loss of protective mechanisms that make women more susceptible to sexually transmitted infections, such as HIV. In case of HIV-positive women, this can result in an increased probability of sexually transmitting HIV to a non-infected partner. Our proposal will examine the hypothesis that significant changes occur in the reproductive tract of postmenopausal women resulting in an increased susceptibility to acquiring sexually transmitted HIV. Specifically we will determine the levels of protective endogenous anti-HIV factors (SLPI, Elafin, MIP3a/CCL20 and human beta defensin 2 (HBD2)) in genital tract secretions of pre- and postmenopausal women and correlate these values with anti-HIV activity in the same secretions. We will also examine the biological activity of the endogenous anti-HIV factors by correlating with the levels of proteases known as Cathepsins (specifically B, D, and G) that are known to activate/deactivate the aforementioned anti-HIV factors. The proposed adds a new dimension to a grossly under-studied area of HIV research and will provide us with a unique outlook on susceptibility of postmenopausal women to sexually transmitted HIV. The outcomes will be significant because the data from this study can be used to develop therapeutic interventions specifically designed to boost genital tract immunity in older women. PUBLIC HEALTH RELEVANCE: Women are disproportionately affected by the HIV/AIDS epidemic, and aging women may develop increased susceptibility to HIV due to loss of immune functions as a result of sex hormone decline at menopause. Our proposal will examine innate immune functions in the genital tract of postmenopausal women to determine whether a less robust immune system might make these women more susceptible to acquiring as well as transmitting HIV.

描述（由申请人提供）：异性传播现在是新的艾滋病毒感染的主要来源，妇女感染人数正在上升。在发达国家，高效抗逆转录病毒疗法的有效性使艾滋病毒阳性的男性和女性活得更长。 据预测，到2015年，美国约50%的HIV感染者将超过50岁（http：www.sfaf.org/hiv-info/hot-topics/hivision/hiv-and-aging-vienna- satellite-2010-07-19-executive-summary.pdf）。 这将导致保健费用大幅度增加，以便提供抗逆转录病毒药物，并管理长期使用这些药物所产生的多种不良影响（http：//www.gmhc.org/files/editor/file/a_pa_aging10_emb2.pdf）。尽管已知衰老导致性激素的损失和某些免疫功能的降低（综述于Wira等人，Am J Reprod Immunol.2011年3月;65（3）：196-211），但我们对女性生殖道（FRT）中先天免疫功能损失程度的理解仍存在重大差距。由于FRT的多种先天免疫因子是免疫反应性的，随着年龄的增长雌激素（和/或孕酮）的损失可能导致保护机制的丧失，使女性更容易受到性传播感染，如艾滋病毒。对于艾滋病毒抗体阳性的妇女，这可能会增加通过性行为将艾滋病毒传染给未感染伴侣的可能性。我们的提案将检验绝经后妇女生殖道发生重大变化导致性传播艾滋病毒易感性增加的假设。具体而言，我们将确定绝经前和绝经后妇女生殖道分泌物中保护性内源性抗HIV因子（SLPI、Elafin、MIP 3a/CCL 20和人β防御素2（HBD 2））的水平，并将这些值与相同分泌物中的抗HIV活性相关联。我们还将通过与已知激活/失活上述抗HIV因子的蛋白酶（称为组织蛋白酶（特别是B、D和G））的水平相关来检查内源性抗HIV因子的生物活性。这项提议为艾滋病毒研究的一个严重不足的领域增加了一个新的维度，并将为我们提供绝经后妇女对性传播艾滋病毒易感性的独特前景。结果将是重要的，因为这项研究的数据可用于开发专门用于提高老年妇女生殖道免疫力的治疗干预措施。 公共卫生相关性：妇女受艾滋病毒/艾滋病流行病的影响特别大，由于更年期性激素下降导致免疫功能丧失，老年妇女可能更容易感染艾滋病毒。我们的建议将检查绝经后妇女生殖道的先天免疫功能，以确定免疫系统是否不太强大，是否会使这些妇女更容易获得和传播艾滋病毒。