Anti-HIV activity in genital tract secretions of postmenopausal women

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，妇女感染的人数正在上升。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- execut-summary .pdf）。这将导致保健费用大幅增加，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众多不良影响（http://www.gmhc.org/files/editor/file/a_pa_aging10_emb2.pdf）。虽然已知衰老会导致性激素的丧失和某些免疫功能的降低（review in Wira et al ., Am J rebd Immunol. 2011 Mar;65(3):196-211），但我们对女性生殖道（FRT）先天免疫功能丧失的程度仍有很大的了解差距。由于FRT的多种先天免疫因子是激素反应性的，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，使妇女更容易受到性传播感染，如艾滋病毒。对于艾滋病毒呈阳性的妇女，这可能导致通过性行为将艾滋病毒传染给未感染的伴侣的可能性增加。我们的建议将检验这样一个假设，即绝经后妇女的生殖道发生重大变化，从而增加了获得性传播艾滋病毒的易感性。具体来说，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， 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hiv活性联系起来。我们还将通过与组织蛋白酶（特别是B、D和G）水平的相关性来研究内源性抗hiv因子的生物活性，这些组织蛋白酶被称为组织蛋白酶（特别是B、D和G），已知可以激活/灭活上述抗hiv因子。该建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的易感性的独特观点。这项研究的结果将具有重大意义，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。

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.