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

描述（由申请人提供）：由于联合抗逆转录病毒治疗（CART）的广泛使用，艾滋病毒相关神经认知障碍（HAND）的患病率增加，导致艾滋病毒感染患者的生存期延长。在接受CART治疗的艾滋病毒血清阳性患者中，大多数人患有较轻形式的HAND。尽管HAND的患病率增加，但我们缺乏该疾病的良好生物标志物（Price，2010）。最近，在HIV感染者中发现了血糖代谢异常，并与HAND相关。此外，来自我们自己的CART HIV血清阳性女性队列的回顾性数据显示，高血浆可溶性胰岛素受体（sIR）全长水平与HAND的存在和严重程度相关。我们的长期目标是确定HAND的生物标志物。本研究的基本原理在于我们实验室和其他实验室先前的观察结果，即血糖代谢异常与HAND相关。我们的中心假设是，这些异常有助于手的发展和进展。本研究的目的是确定血浆sIR全长水平的变化是否与使用CART的HIV血清阳性女性队列中的轻度HAND相关。我们提出3个目标：1。为了确定在使用CART的HIV血清阳性妇女队列中，sIR胞外域（1）和全长（12）亚基是否在HIV感染中增加，2.确定高血浆sIR全长水平是否与HAND相关，以及3.确定HIV血清阳性女性HAND患者胰岛素受体mRNA转录本的选择性剪接是否与血浆sIR全长水平相关。我们期望发现血浆sIR全长和HAND之间的关联，并且增加的sIR全长与IR mRNA的增加的选择性剪接相关。这项研究是新的，在测试的可能性，血浆sIR全长可以作为血液生物标志物的存在和严重程度的手。这是重要的，因为sIR全长可以帮助早期诊断和监测治疗反应，以及在了解致病过程的手。 公共卫生相关性：我们发现血浆可溶性胰岛素受体水平与接受联合抗逆转录病毒治疗（CART）的HIV血清阳性妇女中HIV相关神经认知障碍（HAND）的存在和严重程度相关。我们建议进一步评估这种关联并探索其潜在机制。如果我们的研究结果是阳性的，我们将确定一个血液生物标志物，用于早期诊断和治疗艾滋病毒血清阳性妇女的手在CART。

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.