Host Factors Influencing HIV Viral Load and Infectivity in Semen

描述（由申请人提供）：暴露于HIV感染的精液是全球大多数病毒传播的原因，但决定HIV病毒载量和精液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纤维，它来源于精液凝胶，可以增强HIV感染靶细胞的能力。这些纤维的作用类似于精液病毒感染性增强剂（SEVI），这是精液中发现的第一种淀粉样纤维。引人注目的是，我们发现精液中的精液凝胶蛋白水平在HIV感染的男性之间存在显著差异，并且该水平与精液HIV病毒载量直接相关，而与血液HIV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HIV病毒载量部分是由HIV与精囊内产生的精液凝胶淀粉样纤维相互作用驱动的。如果正确的话，这个模型可以解释在HIV感染者中观察到的精液HIV病毒载量和传染性的显著变化。这些发现还可以确定生物医学干预的新目标，以大大减少艾滋病毒感染的男性与女性和男性与男性之间的传播。我们建议进行一系列的临床和转化研究，以检验和完善我们的假设，即精液凝胶衍生的淀粉样纤维影响精液中的HIV病毒载量和感染性。 在具体目标1中，我们将使用从接受泌尿外科手术的患者获得的精囊组织进一步研究精液凝胶和精液凝胶衍生的淀粉样纤维的生物学。我们将评估这些患者精囊液中精液凝固蛋白淀粉样纤维水平和HIV增强活性，并确定特定因素（如PSA水平或组织中的炎症变化）是否可能影响淀粉样纤维表达。在具体目标2中，我们将对HIV感染的精液供体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（增加靶细胞可用性）是否影响精液HIV病毒载量。在具体目标3中，我们将使用HIV感染男性的病例对照研究方法来检查精液淀粉样纤维水平是否影响HIV传播风险。具体来说，我们将比较那些将艾滋病毒传播给他们的性伴侣（传播者）的男性与那些也有伴侣接触他们精液的男性之间的精液淀粉样蛋白水平，但他们的伴侣没有被感染（非传播者）。 在这个项目完成后，我们将测试一个新的模型的预测艾滋病毒感染性和艾滋病毒传播的基础上，主机衍生的淀粉样蛋白纤维存在于精囊。通过完善我们对艾滋病毒传播生物学的基本理解，包括新的宿主因子的作用，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疗法协同使用。

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.