Depression Antidepressants and HIV infectivity

描述（由申请人提供）：抑郁症的医疗负担正在增加，世界卫生组织预测，到2020年，抑郁症将成为全球第二大致残原因。越来越多的研究表明，抑郁症是包括艾滋病毒/艾滋病在内的一系列人类疾病发病率和死亡率的潜在风险因素。尽管抑郁症影响艾滋病毒疾病进展和死亡率的潜在免疫机制仍有待确定，但大量证据表明，杀伤淋巴细胞在调节艾滋病毒感染中发挥关键作用，并在抑郁症中发生改变。在我们对抑郁症患者的研究中，我们发现与抑郁症相关的自然杀伤细胞（NK）溶解活性降低。在艾滋病毒感染者的研究中，我们已经表明抑郁症与NK细胞溶解活性降低和艾滋病毒疾病进展增加有关。我们最近证明，抑郁症的缓解与HIV中NK细胞毒性的恢复有关，我们发现用SSRI对淋巴细胞进行体外治疗可以增强NK细胞溶解活性。我们还观察到SSRI和糖皮质激素拮抗剂抑制HIV巨噬细胞的HIV感染。这项针对抑郁和非抑郁、HIV血清阴性个体的研究旨在检测抑郁是否与非细胞溶解、趋化因子和细胞因子、杀伤淋巴细胞功能改变以及与HIV感染相关的巨噬细胞和t细胞趋化因子受体敏感性有关。我们将通过比较暴露于SSRI和GC拮抗剂前后巨噬细胞和t细胞HIV受体反应中的杀伤淋巴细胞功能来研究血清素和糖皮质激素（GCs）的作用。以往对抑郁症和HIV的研究主要集中在杀伤淋巴细胞的细胞溶解功能上。该研究的一个独特优势是强调非细胞溶解功能以及抑郁症和抗抑郁药对这些具有HIV抑制活性的因子的影响。因此，本研究旨在确定抑郁症是否会增加对HIV感染的易感性，确定抗抑郁药物是否会降低对HIV感染的易感性，并确定可能导致抑郁症患者对HIV感染易感性的特定HIV抑制因子。这项研究也可能有助于确定是否有必要在抑郁的HIV感染者中进行抗抑郁临床试验，以加强临床管理，改善HIV感染的发病率和死亡率。

DESCRIPTION (provided by applicant): The medical burden of depression is increasing and the World Health Organization projects that by the year 2020, depression will be the second leading cause of disability worldwide. An increasing number of studies have implicated depression as a potential risk factor in the morbidity and mortality for a wide range of human diseases, including HIV/AIDS. Although the underlying immune mechanisms by which depression influences HIV disease progression and mortality remain to be determined, considerable evidence suggests that killer lymphocytes play key roles in regulating HIV infection and are altered in depression. In our studies of individuals who are depressed, but otherwise medically healthy, we have found depression-associated decreases in natural killer (NK) cytolytic activity. In studies of HIV-infected individuals, we have shown that depression is associated with a reduction in NK cytolytic activity and an increase in HIV disease progression. We have recently demonstrated that resolution of depression is associated with restoration of NK cytotoxicity in HIV, and we have found that ex vivo treatment of lymphocytes with an SSRI enhances NK cytolytic activity. We have also observed that an SSRI and a glucocorticoid antagonist inhibit HIV infectivity of macrophages in HIV. The proposed study of depressed and non depressed, HIV- seronegative individuals is designed to test whether depression is associated with non-cytolytic, chemokine and cytokine, functional alterations of killer lymphocytes, as well as chemokine receptor sensitivity of macrophages and T-cells that are relevant to HIV-infectivity. We will study the role of serotonin and glucocorticoids (GCs) by comparing killer lymphocyte function in macrophage and T-cell HIV receptor response before and after exposure to an SSRI and a GC antagonist. Previous studies of depression and HIV have focused on cytolytic function of killer lymphocytes. A unique strength of the proposed study is the emphasis on the non-cytolytic functions and the effects of depression and anti-depressants on these factors which have HIV suppressive activity. Thus, the proposed study is designed to determine if depression increases the susceptibility to HIV-infectivity, to determine if anti-depressants decrease the susceptibility to HIV-infectivity, and to determine specific HIV suppressive factors that may underlie susceptibility to HIV-infectivity in depression. This study also may help determine if anti-depressant clinical trials are warranted in depressed HIV-infected individuals in order to enhance clinical management and improve morbidity and mortality of HIV infection. PUBLIC HEALTH RELEVANCE The medical burden of depression is increasing and the World Health Organization projects that by the year 2020, depression will be the second leading cause of disability worldwide. An increasing number of studies have implicated depression as a potential risk factor in the morbidity and mortality for a wide range of human diseases, including HIV/AIDS. The proposed study is designed to determine if depression increases the susceptibility to HIV-infectivity, to determine if anti-depressants decrease the susceptibility to HIV-infectivity, and to determine specific HIV suppressive factors that may underlie susceptibility to HIV-infectivity in depression.