Anti-HIV activity in genital tract secretions of postmenopausal women

描述(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，女性感染人数正在上升。在发达国家，HAART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，美国大约50%的艾滋病毒携带者将超过50岁((http://www.sfaf.org/hiv-info/hot-topics/hivision/hiv-and-aging-vienna-卫星-2010-07-19-执行摘要pdf)。这将导致医疗费用的大幅增加，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(在Wira等人的评论中，Am J Reprod免疫学。2011年3月；第65(3)：196-211)，关于女性生殖道先天免疫功能丧失的程度，我们的理解仍然存在重大差距。由于FRT的多种先天免疫因素是激素反应的，随着年龄的增长雌激素(和/或黄体酮)的丧失可能导致保护机制的丧失，使女性更容易受到艾滋病毒等性传播感染的影响。对于艾滋病毒阳性的妇女，这可能导致将艾滋病毒性传播给未感染的伴侣的可能性增加。我们的提案将检验这样一种假设，即绝经后妇女的生殖道发生显着变化，导致获得性传播艾滋病毒的易感性增加。具体地说，我们将测定绝经前和绝经后女性生殖道分泌物中保护性内源性抗艾滋病毒因子(SLPI、Elafin、MIP3a/CCL20和人β防御素2(HBD2))的水平，并将这些值与相同分泌物中的抗艾滋病毒活性相关联。我们还将通过与已知激活/停用上述抗HIV因子的被称为组织蛋白(特别是B、D和G)的蛋白酶水平的相关性来检查内源性抗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层面，并将为我们提供关于绝经后妇女经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以用于开发专门为提高老年妇女生殖道免疫力而设计的治疗干预措施。

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.