The Role of Inflammation in CNS Mechanisms of Anhedonia and Psychomotor Slowing in Depressed PWH as Determined using a Next Generation TNF Antagonist

项目摘要 艾滋病毒感染者（PWH）患抑郁症的风险比普通人群高得多， 在威尔斯亲王医院，在治疗依从性、发病率和死亡率方面的结果更差。患抑郁症的风险是 随着炎症生物标志物的升高，PWH进一步增加，例如，急性期反应物C反应 蛋白质（CRP）和炎症细胞因子如肿瘤坏死因子（TNF），有助于抵抗 抗抑郁治疗此外，在PWH慢性抑郁症的背景下炎症增加， 其特征在于恶化的认知功能，包括受损的处理速度和运动活动。我们最近 对HIV阴性抑郁症（MD）患者的神经影像学研究表明，内源性 炎症的升高（如血浆CRP升高所反映的）与功能性降低有关。 连接（FC）内皮质纹状体奖励和运动电路涉及腹侧和背侧纹状体， 额叶皮层区域与快感缺乏和精神发育迟滞症状的关系。快感缺失， 心理减缓代表了积极的研究领域标准（RDoC）的基本方面， 负效价系统，并与PWH中过度代表的症状群密切相关， 冷漠，这被认为是由类似的内侧前额叶和皮质下回路驱动的。之前的工作 我们的研究小组还表明，用传统的TNF拮抗剂减轻炎症， 在HIV阴性的MD患者中存在快感缺失和精神发育迟滞，但仅在较高水平的患者中存在 的CRP。这些数据表明，TNF驱动的炎症在快感缺乏和运动障碍中起作用， 通过对PWH中皮质纹状体奖赏和运动回路的影响减缓。TNF及其可溶性 sTNF位于驱动慢性炎症的炎症级联反应的顶点，而 免疫学和神经“保护性”信号传导由跨膜（TM）TNF介导。虽然现有的TNF 抑制剂已经安全地用于PWH，与阻断病理性和保护性 TNF信号传导的各个方面，包括感染的可能性，限制了“第一代”抗TNF治疗的可行性， 研究炎症在PWH抑郁和神经认知症状中的作用。XPro 1595是一款“下一代 设计用于选择性中和炎性sTNF，同时保留保护性tmTNF的”第一代“TNF抑制剂 信号XPro 1595安全且耐受性良好，初步数据显示，XPro 1595不仅可降低血浆CRP， 脑脊液（CSF）中的炎性细胞因子和趋化因子，以及自由水扩散成像 神经炎症的指标。本提案的目标是使用生物标记驱动的方法， 确定用XPro 1595特异性抑制sTNF是否增加皮质纹状体奖赏和运动中的FC 回路（目的1），并改善快感缺乏和精神发育迟缓（目的2）与减少血浆 炎性标志物，以及额外的CSF、神经影像学、外周血免疫细胞和病毒学 炎症标志物和/或安全性（目的3），在PWH与MD和高炎症（血浆CRP>3 mg/L）。

PROJECT SUMMARY Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity and mortality. Risk for depression is further increased in PWH with elevated biomarkers of inflammation, e.g., the acute phase reactant C-reactive protein (CRP) and inflammatory cytokines like tumor necrosis factor (TNF), that contribute to resistance to antidepressant therapies. Moreover, increased inflammation in the context of chronic depression in PWH is characterized by worsened cognitive function including impaired processing speed and motor activity. Our recent neuroimaging studies in HIV-negative patients with major depression (MD) demonstrate that endogenous elevations in inflammation (as reflected by increased plasma CRP) are associated with decreased functional connectivity (FC) within corticostriatal reward and motor circuits involving the ventral and dorsal striatum and frontal cortical regions in relation to symptoms of anhedonia and psychomotor retardation. Anhedonia and psychomotor slowing represent fundamental aspects of research domain criteria (RDoC) of Positive and Negative Valence systems, and are closely aligned with a symptom cluster overrepresented in PWH referred to as apathy, which is thought to be driven by similar medial prefrontal and subcortical circuitry. Previous work from our group also suggests that reducing inflammation with a traditional TNF antagonist improves symptoms of anhedonia and psychomotor retardation in HIV-negative patients with MD, but only in patients with higher levels of CRP. These data suggest the hypothesis that inflammation driven by TNF plays a role in anhedonia and motor slowing through effects on corticostriatal reward and motor circuits in PWH. TNF and specifically its soluble species, sTNF, sits at the apex of the inflammatory cascade that drives chronic inflammation, whereas immunologic and neuro “protective” signaling is mediated by transmembrane (tm)TNF. Although existing TNF inhibitors have been safely used in PWH, the risk associated with blocking both the pathologic and protective aspects of TNF signaling, including liability for infection, limits viability of “first generation” anti-TNF therapies to examine the role of inflammation in depressive and neurocognitive symptoms in PWH. XPro1595 is a “next generation” TNF inhibitor designed to selectively neutralize inflammatory sTNF, while sparing protective tmTNF signaling. XPro1595 is safe and well-tolerated, and in preliminary data, reduces not only plasma CRP but also inflammatory cytokines and chemokines in cerebrospinal fluid (CSF), as well as free water diffusion imaging measures of neuroinflammation. The goals of this proposal are to use a biomarker-driven approach to determine whether specific inhibition of sTNF with XPro1595 increases FC in corticostriatal reward and motor circuits (Aim 1) and improves anhedonia and psychomotor slowing (Aim 2) in association with reduced plasma inflammatory markers, as well as additional CSF, neuroimaging, peripheral blood immune cell, and virologic markers of inflammation and/or safety (Aim 3), in PWH with MD and high inflammation (plasma CRP>3 mg/L).