Soluble Insulin Receptor Dysfunction Correlates with HAND in HIV+ women on CART

描述(申请人提供)：由于联合抗逆转录病毒治疗(CART)的广泛使用，艾滋病毒感染患者的存活期延长，艾滋病毒相关神经认知障碍(HAND)的流行率有所增加。在接受CART治疗的HIV血清阳性患者中，大多数人手部症状较轻。尽管手部疾病的患病率增加，但我们缺乏良好的疾病生物标志物(Price，2010)。最近，在HIV感染者中发现了血糖代谢异常，并与手部相关。此外，来自我们自己的接受CART治疗的HIV血清阳性妇女队列的回顾数据显示，高血浆可溶性胰岛素受体(SIR)全长水平与手部的存在和严重程度有关。我们的长期目标是确定手部的生物标记物。目前这项研究的理论基础是我们的实验室和其他人之前观察到的血糖代谢异常与手有关。我们的中心假设是，这些异常有助于手的发育和进展。本研究的目的是确定在使用CART的HIV血清阳性妇女队列中，血浆SIR全长水平的变化是否与较轻的手型有关。我们提出了三个目标：1.确定在使用CART的HIV阳性妇女队列中，SIR胞外结构域(1)和全长(12)亚单位是否增加，2.确定高血浆SIR全长水平是否与HAND有关，以及3.确定胰岛素受体mRNA转录的选择性剪接是否与HAND HIV血清阳性妇女的血浆SIR全长水平相关。我们期望发现血浆SIR全长和HAND之间的联系，并且增加全长SIR与IR mRNA的选择性剪接增加有关。这项研究在测试全长血浆SIR可以作为手部存在和严重程度的血液生物标记物的可能性方面是新颖的。由于全长SIR可以帮助早期诊断和监测治疗反应，以及理解手部的致病过程，因此具有重要意义。 公共卫生相关性：我们发现，在接受联合抗逆转录病毒治疗(CART)的HIV血清阳性女性中，血浆可溶性胰岛素受体水平与HIV相关神经认知障碍(HAND)的存在和严重程度有关。我们建议进一步评估这种联系，并探索其潜在的机制。如果我们的发现是阳性的，我们将识别出一种血液生物标记物，用于CART上HIV血清阳性妇女的早期诊断和治疗。

DESCRIPTION (provided by applicant): The prevalence of HIV-associated neurocognitive disorders (HAND) has increased owing to the widespread use of combined antiretroviral treatment (CART) and resulting longer survival of HIV-infected patients. Among HIV-seropositive patients on CART, most suffer from the milder forms of HAND. Despite the increased prevalence of HAND, we lack good biomarkers for the disease (Price, 2010). Recently, blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HAND. In addition, retrospective data from our own cohort of HIV-seropositive women on CART show that high plasma soluble insulin receptor (sIR) full-length levels are associated with the presence and severity of HAND. Our long-term goal is to identify a biomarker for HAND. The rationale for the current study lies with previous observations by our lab and others that blood sugar metabolism abnormalities are associated with HAND. Our central hypothesis is that these abnormalities contribute to the development and progression of HAND. The objective of the present study is to determine if changes in plasma sIR full-length levels are associated with milder forms of HAND in a cohort of HIV-seropositive women using CART. We propose 3 aims: 1. To determine if sIR ectodomain (1) and full-length (12) subunits are increased in HIV-infection in a cohort of HIV- seropositive women using CART, 2. To determine if high plasma sIR full-length levels are associated with HAND, and 3. To determine if alternative splicing of the insulin receptor mRNA transcript correlates with plasma sIR full-length levels in HIV-seropositive women with HAND. We expect to find an association between plasma sIR full-length and HAND, and increased sIR full-length to be associated with increased alternative splicing of IR mRNA. This study is novel in testing the possibility that plasma sIR full-length could serve as a blood biomarker for presence and severity of HAND. It is significant since sIR full-length could assist in early diagnosis and monitoring treatment responses, as well as in understanding the pathogenic processes of HAND. PUBLIC HEALTH RELEVANCE: We found that plasma soluble insulin receptor levels are associated with the presence and severity of HIV- associated neurocognitive disorders (HAND) in HIV-seropositive women on combined antiretroviral treatment (CART). We propose to further evaluate this association and explore its underlying mechanisms. If our findings are positive, we will have identified a blood biomarker for the early diagnosis and treatment of HAND in HIV- seropositive women on CART.