Host Factors Influencing HIV Viral Load and Infectivity in Semen

影响精液中 HIV 病毒载量和传染性的宿主因素

• 批准号: 9068200
• 负责人: Christopher D Pilcher
• 金额: $ 61.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-25 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068200
• 关键词: Accounting; Affect; Age; Alcohol consumption; Amyloid; Amyloid Fibrils; Anatomy; Biological Markers; Biology; Biology of HIV Transmission; Blood; Case-Control Studies; Cells; Clinical Research; Couples; Deposition; Diagnosis; Enhancers; Epididymis; Event; Exposure to; Female; Genital system; HIV; HIV Infections; HIV drug resistance; In Vitro; Individual; Infection; Inflammation; Inflammatory; Integration Host Factors; Interruption; Intervention; Laboratory Study; Left; Link; Liquid substance; Longitudinal Studies; Male Genital Organs; Malignant neoplasm of prostate; Measures; Mediating; Modeling; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Production; Property; Prostate; Prostate-Specific Antigen; Protein Precursors; Proteins; Radical Prostatectomy; Research; Risk; Role; Sampling; Semen Donor; Seminal Vesicles; Seminal fluid; Series; Sexual Partners; Source; Surface; Testing; Testis; Tissues; Urologic Surgical Procedures; Vaccines; Variant; Vasectomy; Viral; Viral Load result; Virion; Virus; Work; antiretroviral therapy; base; cytokine; in vivo; male; men; men who have sex with men; novel; novel strategies; older men; pandemic disease; prevent; prostatic fraction Acid phosphatase isoenzyme; reproductive tract; sexual HIV transmission; translational study; transmission process; viral transmission

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.

描述（由申请人提供）：世界范围内大多数病毒传播是由于接触感染艾滋病毒的精液而造成的，但是决定精液艾滋病毒病毒载量和感染性的因素尚不清楚。我们最近在精液中发现了一种新型淀粉样纤维，它源自精蛋白，可增强 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剂（SEVI），这是精液中发现的第一个淀粉样原纤维。令人惊讶的是，我们发现精液中精液蛋白的水平在 HIV 感染男性之间存在显着差异，并且该水平与精液 HIV 病毒载量直接相关，与血液 HIV 病毒载量无关。相反，精液病毒载量与 SEVI 或其蛋白质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 与精囊内产生的精蛋白淀粉样原纤维的相互作用驱动的。如果正确的话，该模型可以解释在艾滋病毒感染者中观察到的精液艾滋病毒病毒载量和感染性的显着变异。这些发现还可以确定生物医学干预措施的新目标，以大大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转化研究，以测试和完善我们的假设，即精液蛋白衍生的淀粉样原纤维影响精液中的 HIV 病毒载量和感染性。 在具体目标 1 中，我们将使用从泌尿外科手术患者获得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的精蛋白淀粉样原纤维水平和精囊液的 HIV 增强活性，并确定特定因素（例如 PSA 水平或组织中的炎症变化）是否可能影响淀粉样原纤维的表达。在具体目标 2 中，我们将对感染 HIV 的精液捐献者进行横断面和纵向研究，以确定精囊衍生的淀粉样原纤维（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原纤维水平是否会影响 HIV 传播风险。具体来说，我们将比较已将艾滋病毒传播给其性伴侣（传播者）的男性和其他也有性伴侣接触过精液但其伴侣仍未感染（非传播者）的男性的精液淀粉样蛋白水平。 该项目完成后，我们将测试基于精囊中存在的宿主衍生淀粉样原纤维的艾滋病毒感染性和艾滋病毒传播新模型的预测。通过完善我们对艾滋病毒传播生物学的基本理解，包括新型宿主因素的作用，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疗法协同使用。