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: 8456086
• 负责人: Mimi Ghosh
• 金额: $ 7.55万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456086
• 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.

描述（申请人提供）：目前，异性传播是新发艾滋病毒感染的主要来源，女性感染人数呈上升趋势。在发达国家，HAART疗法的有效性使艾滋病毒阳性男性和女性的寿命更长。 据预测，到 2015 年，美国大约 50% 的艾滋病毒感染者将超过 50 岁（http://www.sfaf.org/hiv-info/hot-topics/hivision/hiv-and-老化-维也纳-卫星-2010-07-19-executive-summary.pdf)。 这将导致医疗保健费用大幅增加，以便提供抗逆转录病毒药物以及控制长期使用这些药物所产生的多种不良反应 (http://www.gmhc.org/files /editor/file/a_pa_aging10_emb2.pdf）。尽管众所周知，衰老会导致性激素的丧失和某些免疫功能的降低（Wira 等人，Am J ReprodImmunol. 2011 Mar;65(3):196-211 进行了综述），但我们的研究仍然存在重大差距。了解女性生殖道（FRT）先天免疫功能丧失的程度。由于 FRT 的多种先天免疫因子具有激素反应性，因此随着年龄的增长雌激素（和/或黄体酮）的丧失可能会导致保护机制的丧失，从而使女性更容易受到性传播感染，例如艾滋病毒。对于艾滋病毒呈阳性的女性，这可能会导致通过性行为将艾滋病毒传播给未感染伴侣的可能性增加。我们的提案将检验以下假设：绝经后妇女的生殖道发生显着变化，导致感染性传播艾滋病毒的可能性增加。具体来说，我们将测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、MIP3a/CCL20 和人 β 防御素 2 (HBD2)）的水平，并将这些值与绝经后妇女的抗 HIV 活性相关联。相同的分泌物。我们还将通过与组织蛋白酶（特别是 B、D 和 G）的蛋白酶水平相关来检查内源性抗 HIV 因子的生物活性，已知组织蛋白酶可激活/失活上述抗 HIV 因子。该提议为艾滋病毒研究领域中一个严重不足的领域增加了一个新的维度，并将为我们提供关于绝经后妇女对性传播艾滋病毒易感性的独特看法。结果将非常重要，因为这项研究的数据可用于开发专门用于增强老年女性生殖道免疫力的治疗干预措施。