SSRI Effects on Depression and Immunity in HIV/AIDS

 描述(申请人提供)：抑郁症是包括艾滋病毒/艾滋病在内的多种疾病的发病率和死亡率的已知风险因素。由于艾滋病毒血清阳性者中抑郁症的患病率是普通人群的两倍，因此有效地针对艾滋病毒携带者的抑郁症是一项重要的公共卫生需求。此外，由于抑郁症和HIV感染在免疫系统功能上都有一定的变化，即以全身炎症为标志的天然免疫抑制和细胞免疫过度激活，因此有可能通过治疗HIV/AIDS患者的抑郁来改善他们的免疫功能。尽管许多临床医生普遍认为选择性5-羟色胺再摄取抑制剂(SSRI)在治疗HIV/AIDS抑郁方面是安全有效的，但在抑郁的HIV血清阳性个体中抗抑郁药物的随机对照试验(RCT)很少，结果喜忧参半。此外，之前没有试验检测抑郁症和艾滋病毒/艾滋病共同存在的免疫失调的生物标记物。我们先前的工作一方面建立了抑郁、免疫失调和HIV疾病进展之间的联系，另一方面建立了SSRI治疗的免疫调节和抗病毒作用之间的联系。例如，我们发现抑郁症与医学上健康的个人和艾滋病毒感染患者的自然杀伤(NK)细胞溶解活性降低有关，我们还表明抑郁症与艾滋病毒疾病加速进展有关。我们还观察到抑郁的解决与NK细胞毒性的增加有关，我们证明了免疫细胞的体外SSRI治疗增强了NK细胞的杀伤活性。进一步，我们发现SSRI抑制了体内免疫细胞对HIV的感染性，并且SSRI治疗显著下调了巨噬细胞和T细胞上HIV受体和辅助受体(CD4、CXCR4、CXCR5)的表达。因此，我们的研究表明，SSRIs可能对外周免疫细胞有直接作用。综上所述，这项工作表明，SSRI治疗可以想见地降低精神疾病的发病率，并有助于扭转抑郁的艾滋病毒/艾滋病患者(PLWH)的免疫失调。为了实现我们成功治疗HIV/AIDS合并精神障碍和医学障碍的长期目标，这项研究旨在确定：1)SSRI治疗是否显著提高了先天免疫功能，减少了慢性炎症和免疫激活；2)抑郁症状的变化与HIV/AIDS免疫调节的变化有关。这项研究将是SSRI治疗艾滋病毒/艾滋病抑郁的第一次双盲、安慰剂对照试验，重点是先天免疫和炎症。如果成功，该项目将推动艾滋病毒护理领域的发展 通过首次证明，药物疗法对临床抑郁症的免疫益处以及病毒载量得到良好控制的人抑郁症状的解决：从而导致SSRIs作为CART的辅助手段的潜在新用途，这可能导致抑郁症PLWH的临床护理的改变，并为非抑郁症PLWH的SSRI免疫研究奠定基础。

 DESCRIPTION (provided by applicant): Depression is a known risk factor for morbidity and mortality in a wide range of diseases, including HIV/AIDS. Because the prevalence of depression in HIV seropositive individuals is double that of the general population, effectively targeting depression in people living with HIV is an important public health need. Moreover, because depression and HIV infection share certain alterations in immune system function, namely suppressed innate immunity and overactivated cellular immunity marked by systemic inflammation, it may be possible to improve immune function in patients with HIV/AIDS by treating their depression. Although many clinicians generally consider selective serotonin reuptake inhibitors (SSRIs) safe and effective in treating depression in HIV/AIDS, there have been very few randomized controlled trials (RCTs) of antidepressant medications among depressed HIV seropositive individuals, and results have been mixed. Moreover, no previous trials examined biomarkers of immune dysregulation common to both depression and HIV/AIDS. Our prior work has established links between depression, immune dysregulation, and HIV disease progression on the one hand, and immune regulating and antiviral effects of SSRI treatment on the other. For example, we found depression was associated with decreased natural killer (NK) cytolytic activity in both medically healthy individuals and in HIV- infected patients, and we showed that depression was associated with accelerated HIV disease progression. We also observed that resolution of depression was associated with increased NK cytotoxicity and we demonstrated that ex vivo SSRI treatment of immune cells enhances NK cytolytic activity. Further, we discovered that an SSRI inhibited HIV infectivity of immune cells e vivo, and that SSRI treatment significantly down-regulated the expression of HIV receptors and co-receptors (CD4, CXCR4, CXCR5) on macrophages and T-cells. Our studies thus indicate that SSRIs may have a direct action on peripheral immune cells. Taken together, this work suggests that SSRI treatment could conceivably reduce psychiatric morbidity and help reverse immune dysregulation in depressed, People Living with HIV/AIDS (PLWH). To pursue our long-term objective of successfully treating co-morbid mental and medical disorders in HIV/AIDS, this study aims to determine whether: 1) SSRI treatment significantly increases innate immunity and decreases chronic inflammation and immune activation, and 2) changes in depressive symptoms correlate with changes in immune regulation in HIV/AIDS. This study will be the first double-blind, placebo controlled trial of a SSRI for treating depression in HIV/AIDS with a focus on innate immunity and inflammation. If successful, this project will advance the field of HIV care by demonstrating for the first time, immune benefits of drug therapy for clinical depression and resolution of depressive symptoms among people with well-controlled viral load: thus leading to a potential new use of SSRIs as adjuncts to cART, which could lead to a change in clinical care of depressed PLWH, and set the stage for SSRI immune studies in non-depressed PLWH.