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

描述（由申请人提供）：由于抗逆转录病毒联合治疗（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，并导致艾滋病毒感染患者的生存时间延长。在接受CART治疗的艾滋病毒血清阳性患者中，大多数患有较轻形式的HAND。尽管HAND的患病率有所增加，但我们缺乏良好的生物标志物（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hiv血清阳性妇女CART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。当前研究的基本原理是基于我们实验室和其他人之前的观察，即血糖代谢异常与HAND有关。我们的中心假设是这些异常有助于HAND的发展和进展。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轻度形式的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外结构域(1)和全长亚基（12）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；确定胰岛素受体mRNA转录物的选择性剪接是否与hiv血清阳性HAND女性血浆sIR全长水平相关。我们希望发现血浆sIR全长与HAND之间的关联，而sIR全长的增加与IR mRNA选择性剪接的增加有关。这项研究在测试血浆sIR全长作为HAND存在和严重程度的血液生物标志物的可能性方面是新颖的。这是重要的，因为全长sIR可以帮助早期诊断和监测治疗反应，以及了解HAND的致病过程。

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.