Host Factors Influencing HIV Viral Load and Infectivity in Semen

描述（由申请人提供）：暴露于艾滋病毒感染的精液中是世界上大多数病毒传播的原因，然而，决定精液中艾滋病毒载量和传染性的因素尚不清楚。我们最近在精液中发现了一种新的淀粉样蛋白纤维，它来自于精液凝胶，它增强了HIV感染靶细胞的能力。这些原纤维的作用类似于精液病毒感染性增强子（SEVI），这是在精液中发现的第一个淀粉样原纤维。引人注目的是，我们发现，在感染艾滋病毒的男性中，精液中精液凝胶的水平有显著差异，而且这种水平与精液中的艾滋病毒载量直接相关，而与血液中的艾滋病毒载量无关。相反，精液病毒载量与SEVI或其蛋白前体前列腺酸性磷酸酶（PAP）的水平无关。我们假设精液中的HIV病毒载量部分是由HIV与精囊内产生的这些精胶质淀粉样原纤维的相互作用驱动的。如果正确的话，这个模型可以解释在HIV感染的男性中观察到的精液HIV病毒载量和传染性的显著差异。这些发现还可以确定生物医学干预的新目标，以大大减少男性-女性和男性-男性传播艾滋病毒感染。我们建议进行一系列的临床和转化研究来检验和完善我们的假设，即精液中源自淀粉样蛋白原纤维影响HIV病毒载量和传染性。在具体目标1中，我们将使用泌尿外科手术患者的精囊组织进一步研究精蛋白和精蛋白衍生的淀粉样原纤维的生物学特性。我们将评估这些患者精囊液中精胶质淀粉样纤维水平和HIV增强活性，并确定特定因素（如PSA水平或组织炎症变化）是否可能影响淀粉样纤维表达。在特异性目标2中，我们将对感染HIV的精液供者进行横断面和纵向研究，以确定精囊来源的淀粉样蛋白原纤维（促进靶细胞的感染）和生殖器炎症（增加靶细胞的可用性）是否影响精液中的HIV病毒载量。在特异性目标3中，我们将使用HIV感染男性的病例对照研究方法检查精液淀粉样蛋白水平是否影响HIV传播风险。具体来说，我们将比较将艾滋病毒传播给性伴侣（传播者）的男性与其他男性的精液中的淀粉样蛋白水平，这些男性的性伴侣也接触过他们的精液，但其伴侣未被感染（非传播者）。在该项目完成后，我们将测试基于存在于精囊中的宿主衍生淀粉样原纤维的HIV感染和HIV传播新模型的预测。通过完善我们对艾滋病毒传播生物学的基本理解，包括新宿主因子的作用，我们希望推动预防艾滋病毒传播的新方法，这些方法可以与抗逆转录病毒治疗协同使用。

DESCRIPTION (provided by applicant): Exposure to HIV-infected semen accounts for most viral transmissions worldwide, however the factors that determine the HIV viral load and infectivity of semen are not well understood. We have recently discovered a new type of amyloid fibril in the semen, derived from the semenogelins, which enhances the ability of HIV to infect target cells. These fibrils act similarly to semen enhancer of viral infectivity (SEVI), the first amyloid fibril identified in semen. Strikingly we have found that the levels of semenogelins in semen differ markedly between HIV infected men, and that levels correlate directly with the semen HIV viral load, independent of the blood HIV viral load. Conversely, semen viral load did not correlate with levels of SEVI or its protein precursor, prostatic acid phosphatase (PAP). We hypothesize that the semen HIV viral load is driven in part by the interaction of HIV with these semenogelin amyloid fibrils produced within the seminal vesicles. If correct, this model could explain the marked variability in semen HIV viral load and infectivity that is observed among HIV-infected men. These findings could also identify novel targets for biomedical interventions to greatly reduce male-female and male-male transmission of HIV infection. We propose to conduct a series of clinical and translational studies to test and refine our hypothesis that semenogelin- derived amyloid fibrils influence HIV viral load and infectivity in semen. In Specifi Aim 1, we will further investigate the biology of the semenogelins and semenogelin-derived amyloid fibrils using seminal vesicle tissue obtained from patients undergoing urologic surgery. We will assess semenogelin amyloid fibril levels and HIV enhancing activity of seminal vesicle fluid from these patients, and determine whether specific factors (such as PSA levels, or inflammatory changes in the tissue) may influence amyloid fibril expression. In Specific Aim 2, we will perform both cross-sectional and longitudinal studies with HIV-infected semen donors to determine whether seminal vesicle-derived amyloid fibrils (promoting infection of target cells) and genital inflammation (increasing target cell availability) influence the semen HIV viral load. In Specific Aim 3, we will examine whether semen amyloid fibril levels affect HIV transmission risk using a case-control study approach with HIV-infected men. Specifically we will compare semen amyloid levels between men who have transmitted HIV to their sexual partners (transmitters) with those from other men who also had partners exposed to their semen, but whose partners remained uninfected (non-transmitters). At the completion of this project, we will have tested the predictions of a new model of HIV infectivity and HIV transmission based on host-derived amyloid fibrils present in seminal vesicles. By refining our fundamental understanding of HIV transmission biology including the role of novel host factors, we hope to propel new approaches for preventing HIV transmission that can be used synergistically with antiretroviral therapy.