Effect of Antiviral CNS Penetration on CSF/Blood Cytokines and Depression in HIV

描述(申请人提供)：针对艾滋病毒/艾滋病的高效抗逆转录病毒疗法(HAART)的引入提高了存活率。然而，抑郁症的患病率并没有明显变化。抑郁症与不良的临床结果有关。中枢神经系统(CNS)中较高浓度的抗HIV药物被认为是有益的神经反应的主要调节器。几项与医学相关的抑郁障碍的研究表明，炎性细胞因子作为抑郁症的煽动者发挥了作用。最近提出的抗逆转录病毒疗法(ART)的中枢神经系统渗透有效性(CPE)评分概念使抗逆转录病毒(ARV)药物在中枢神经系统的浓度估计得到改进，同时消除了获得每个患者的脑脊液药物浓度的挑战。利用CNS HIV抗逆转录病毒治疗效果研究(CHECH)队列研究的数据，我们建议调查更好的抗逆转录病毒药物治疗是否会减少抑郁，从而导致更好的HIV临床结果。我们将评估CPE对坚持使用ARV药物的影响。我们假设，更好的CPE将与更好的情绪和忠诚度相关。我们还建议评估ART的CPE对中枢神经系统和外周血炎症和营养环境的影响。我们将评估ART方案的CPE与抑郁症的脑脊液/血液促炎细胞因子水平之间的相关性，而不是与病毒载量抑制无关。我们假设CPE的增加会降低脑脊液和血液中的细胞因子(肿瘤坏死因子-α、白介素1、6和12以及单核细胞趋化蛋白-1)，从而改善抑郁症。我们还试图阐明抑郁症和脑脊液病毒学失败之间的联系。这项研究将提高我们对HIV的神经发病机制以及ARV治疗对其CPE的神经行为影响的理解。这将有助于改善艾滋病毒/艾滋病患者的治疗选择，从而改善临床结果。深入了解与抗逆转录病毒药物治疗相关的脑脊液/血液促炎细胞因子的变化，可能有助于开发具有改善情绪的额外效果的艾滋病毒治疗方法。

DESCRIPTION (provided by applicant): The introduction of highly active antiretroviral therapy (HAART) for HIV/AIDS has improved survival. However, the prevalence of depression has not significantly changed. Depression is associated with poor clinical outcomes. A higher concentration of anti-HIV medication in the central nervous system (CNS) is hypothesized to be the primary modulator of beneficial neurological response. Several studies in medically related depressive disorders have suggested a role for inflammatory cytokines as provocateurs of depression. The recently described concept of CNS penetration effectiveness (CPE) scores of antiretroviral therapy (ART) allows improved estimation of concentration of antiretroviral (ARV) medication in the CNS whilst eliminating the challenge of obtaining CSF drug concentrations on each patient. Utilizing data from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort study, we propose to investigate if better CPE of ART reduces depression thereby resulting in better HIV clinical outcomes. We will assess the effect of CPE on adherence to ARV medication. We hypothesize that better CPE will be associated with improved mood and adherence. We also propose to evaluate changes in the inflammatory and trophic environment of the CNS and peripheral blood produced by the CPE of ART. We will assess the association between CPE of ART regimens and levels of CSF/blood pro-inflammatory cytokine mediators of depression, independent of viral load suppression. We hypothesize that increased CPE will decrease CSF and blood cytokines (Tumor Necrosis Factor-alpha, Interleukins-1, 6, and 12 and monocyte chemo attractant protein-1), thereby improving depression. We also seek to elucidate the association between depression and CSF virologic failure. This study will improve our understanding of the neuropathogenesis of HIV and the neurobehavioral effects of ARV treatment with respect to their CPE. This will help improve therapeutic choices for patients with HIV/AIDS and thereby improve clinical outcomes. An insight into changes in CSF/blood pro-inflammatory cytokines associated with the CPE of ART may be helpful in developing HIV treatments that have an additional effect of improving mood.