The Role of gp120 on Cardiovascular Disease in People Living with HIV

项目摘要/摘要 慢性感染人类免疫缺陷病毒(HIV)的特点是，尽管使用了有效的 抗逆转录病毒治疗(ART)，通过存在低度炎症和免疫激活导致 多种年龄相关的非传染性并存，如心血管疾病(CVD)。艾滋病病毒的信封 糖蛋白120(Gp120)在病毒进入过程中起着至关重要的作用；然而，这种蛋白可以从病毒粒子或 细胞表面相关的包膜三聚体为可溶性gp120(Sgp120)，存在于血液和组织中。它 已有研究表明，sgp120通过以下途径参与HIV的发病和免疫功能障碍 诱导产生促炎细胞因子和趋化因子的免疫调节活性。有 也有报道称，患有未检测到病毒的抗逆转录病毒治疗患者血浆中sgp120水平显著升高。 载荷[1]。心血管疾病仍然是美国艾滋病毒携带者(PLWH)死亡的主要原因， 对夏威夷原住民和其他太平洋岛民等种族和少数民族造成不成比例的负担 (诺皮病)具有高心血管危险因素，包括肥胖、高血压、血脂异常和糖尿病。因此， Sgp120诱导的炎症可能是慢性炎症的一个额外来源。 使携带艾滋病毒的诺皮人的心血管疾病负担更重。 探讨sgp120在心血管疾病中的作用的一个限制因素是缺乏可靠的方法来定量检测sgp120在心血管疾病中的作用。 样本，如血浆。目前的sgp120酶联免疫吸附分析试剂盒不能检测到 由于抗体可能不会交叉反应，导致假阴性结果，因此基因上存在不同的sgp120变异。 为了获得更准确的sgp120检测结果，需要仔细扩大检测抗体的范围。 选择它们是为了确保它们能够识别和结合存在于PLWH中的不同的sgp120变体。缺乏一种 可靠和敏感的检测是了解sgp120在PLWH的CVD中所起作用的障碍。 这项建议的总体目标是了解gp120在慢性炎症中的作用。 PLWH首先提高了临床样本中sgp120的定量能力。我们建议使用和验证 一种新的测定PLWH血浆中sgp120的方法--建立基于微球的抑制试验和 比较sgp120变异检测与市售的ELISA试剂盒的改进情况。第二，我们将 利用免疫组织化学方法中用于抑制的相同抗体来鉴定细胞 淋巴组织和直肠组织中sgp120的来源。最后， 我们将评估sgp120与炎症标志物以及PLWH亚临床心血管疾病的关系。这个 这个项目的意义在于，sgp120的改进检测将促进我们对sgp120如何 在慢性或病毒抑制的艾滋病毒感染期间导致心血管疾病。

Project Summary/Abstract Chronic infection with human immunodeficiency virus (HIV) is characterized, despite the use of potent antiretroviral therapy (ART), by the presence of low-grade inflammation and immune activation leading to multiple age-related non-infectious comorbidities such as cardiovascular disease (CVD). The HIV envelope glycoprotein 120 (gp120) plays a vital role in viral entry; however, this protein can be shed from the virion or cell surface associated envelope trimer as soluble gp120 (sgp120) and is present in the blood and tissues. It has been suggested that sgp120 contributes to HIV pathogenesis and immune dysfunction through immunoregulatory activities that induce production of pro-inflammatory cytokines and chemokines. There have also been reports of significant levels of sgp120 in the plasma of individuals on ART with undetectable viral loads [1]. CVD remains the leading cause of death in people living with HIV (PLWH) in the United States with a disproportionate burden on racial and ethnic minorities such as Native Hawaiian and Other Pacific Islanders (NHOPI) with high CVD risk factors including obesity, hypertension, dyslipidemia, and diabetes. Therefore, sgp120 induced inflammation in predisposed NHOPI is likely to be an added source of chronic inflammation driving the higher burden of CVD in NHOPI living with HIV. A limiting factor in exploring the role of sgp120 in CVD is the lack of a reliable assays to quantitate sgp120 in samples such as plasma. Current sgp120 enzyme-linked immunosorbent assay (ELISA) kits cannot detect genetically diverse sgp120 variants because antibodies may not cross-react, leading to false-negative results. To obtain more accurate sgp120 measurements, detection antibodies need to be expanded and carefully selected to ensure they can recognize and bind to diverse sgp120 variants present in PLWH. The lack of a reliable and sensitive assay is a barrier to understanding the role that sgp120 plays in CVD in PLWH. The overall objective of this proposal is to understand the contributory role of gp120 in chronic inflammation in PLWH by first improving the ability to quantitate sgp120 in clinical samples. We propose to utilize and validate a novel approach to measuring sgp120 in the plasma of PLWH by creating a bead-based inhibition assay and compare improvements in sgp120 variant detection over commercially available ELISA kits. Second, we will utilize the same antibodies used in the inhibition in an immunohistochemistry approach to identify the cell source of sgp120 in lymphoid tissue within lymph nodes and rectal tissue of aviremic PLWH on ART. Finally, we will assess the relationship of sgp120 to inflammatory markers and to subclinical CVD in PLWH. The significance of this project is that improved detection of sgp120 will advance our understanding of how sgp120 contributes to CVD during chronic or virally suppressed HIV infection.