Host Factors Influencing HIV Viral Load and Infectivity in Semen

描述(申请人提供)：暴露在感染艾滋病毒的精液中是世界上大多数病毒传播的原因，然而决定艾滋病毒病毒载量和精液传染性的因素还不是很清楚。我们最近在精液中发现了一种新型的淀粉样原纤维，它来自精原蛋白，它增强了HIV感染靶细胞的能力。这些纤维的作用类似于病毒感染性精液增强剂(SEVI)，SEVI是在精液中发现的第一种淀粉样原纤维。令人惊讶的是，我们发现精液中的精胶蛋白水平在感染艾滋病毒的男性之间存在显著差异，而且这种水平与精液中的艾滋病毒病毒载量直接相关，与血液中的艾滋病毒病毒载量无关。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)水平无关。我们推测，精液中的HIV病毒载量部分是由HIV与精囊中产生的这些精胶蛋白淀粉样纤维相互作用所驱动的。如果正确，这个模型可以解释在感染艾滋病毒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，以极大地减少艾滋病毒感染的男性-女性和男性-男性传播。我们建议进行一系列临床和翻译研究，以测试和完善我们的假设，即精胶蛋白衍生的淀粉样纤维影响精液中的HIV病毒载量和传染性。在具体目标1中，我们将使用从泌尿外科手术患者获得的精囊组织进一步研究精胶蛋白和精胶蛋白衍生的淀粉样纤维的生物学。我们将评估这些患者的精原蛋白淀粉样原纤维水平和精囊液中HIV增强活性，并确定特定因素(如PSA水平或组织中的炎症变化)是否会影响淀粉样原纤维的表达。在具体目标2中，我们将对感染艾滋病毒的精液捐赠者进行横断面和纵向研究，以确定精囊来源的淀粉样纤维(促进靶细胞感染)和生殖器炎症(增加靶细胞的可获得性)是否影响精液HIV病毒载量。在具体目标3中，我们将通过对感染艾滋病毒的男性进行病例对照研究，检查精液淀粉样蛋白纤维水平是否影响艾滋病毒传播风险。具体地说，我们将比较将艾滋病毒传播给他们的性伴侣(传播者)的男性与其他男性之间的精液淀粉样蛋白水平，这些男性的伴侣也接触了他们的精液，但其伴侣仍未感染(非传播者)。在这个项目完成时，我们将测试一种基于精囊中存在的宿主来源的淀粉样纤维的艾滋病毒传染性和艾滋病毒传播的新模型的预测。通过完善我们对艾滋病毒传播生物学的基本理解，包括新宿主因素的作用，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.