NEUROENDOCRINE

病毒感染可以激活HPA轴，大概是通过释放 然后增加下丘脑CRF分泌的细胞因子。 我们的试点数据 提供证据表明，艾滋病毒感染增加基础皮质醇分泌， 在艾滋病毒诱导的免疫反应发生之前的早期无症状阶段， 镇压 因此，我们假设艾滋病毒会导致 通过刺激下丘脑CRF释放的糖皮质激素分泌过多， 在边缘受体部位解除HPA轴的抑制。 因为我们发现 我们的HIV+患者肾上腺雄激素DHEA分泌减少 高皮质激素的HNRC受试者，我们还假设， 糖皮质激素的免疫抑制作用将较少受到 DHEA（具有抗糖皮质激素和神经保护特性） 在艾滋病毒感染期间。 因此，我们认为艾滋病毒引起的HPA异常 将在神经认知的发展中发挥重要作用 结构性脑缺陷，情绪失调， 适应艾滋病毒感染期间的心理社会压力。 我们将首先 确定HPA轴每个水平的特定异常， 是由艾滋病毒感染引起的，并确定了纵向的时间进程， HPA轴分泌从早期无症状阶段到AIDS的变化。 基础HPA分泌将在3小时内每隔20分钟测量一次 下午时段，提供24小时平均值的准确指数 分泌模式 然后我们将评估垂体促肾上腺皮质激素敏感性 (with 1 ug/kg CRF激发）和边缘系统对GC阴性的敏感性 反馈（使用皮质酮抑制试验）。 我们将研究交叉- 部分4组HIV+受试者，选择用于潜在采样 细胞免疫衰退进化的离散阶段点。 这些 HIV+组（每组N=30）为（1）1993 CDC A1;（2）A2，CD 4lesser 300， A3;（3）CDC B2-B3;（4）CDC C2-C3。 第五个对照组的30名艾滋病毒-将 也要检查。 我们还将进行一项纵向研究， 将每年评估HIV+A患者中HIV+轴中的HPA轴 CD 4水平完整（大于500）和较低（小于300）。 我们假设 基础皮质醇增多症，脱氢表雄酮消耗，减少ACTH反应， CRF，与GC负反馈的丢失将显著相关 高水平的HIV CNS感染，认知障碍增加，MRI 边缘脑缺陷，和神经行为障碍（即，心情 失调）。 我们还预测， 在DHEA分泌不足的情况下皮质醇增多将与 细胞免疫功能下降， 发展到艾滋病。 最后一个具体目标将检查艾滋病毒的影响， 根据我们的试点数据显示， HIV+患者对芬氟拉明的HPA反应 我们假设艾滋病病毒 将改变下丘脑CRF神经元的血清素释放， 神经内分泌失调和神经行为障碍（即， 抑郁症）。

Viral infections can activate the HPA axis, presumably by releasing cytokines which then increase hypothalamic CRF secretion. Our pilot data provide evidence that HIV infection increases basal cortisol secretion even in early asymptomatic stages prior to the onset of HIV-induced immuno- suppression. Therefore, we hypothesize that HIV will result in glucocorticoid hypersecretion by stimulating hypothalamic CRF release and disinhibiting the HPA axis at limbic receptor sites. Since we have found diminished secretion of the adrenal androgen DHEA in our HIV+ hypercortisolemic HNRC subjects, we also hypothesize that the neurotoxic and immunosuppressive effects of glucocorticoids will be less opposed by DHEA (which possesses antiglucocorticoid and neuroprotective properties) during HIV infection. We therefore expect HIV-induced HPA abnormalities will have an important role in the development of neurocognitive impairment, structural brain defects, mood dysregulation, and impaired adaptation to psychosocial stress during HIV infection. We will first determine the specific abnormalities at each level of the HPA axis which are caused by HIV infection and define the time course for the longitudinal changes in HPA axis secretion from early asymptomatic stages to AIDS. Basal HPA secretion will be measured at 20-minute intervals over a 3-hour afternoon period which provides an accurate index of the mean 24-hour secretion pattern. We will then assess pituitary corticotroph sensitivity (with a 1 ug/kg CRF challenge) and limbic sensitivity to GC negative feedback (using a corticosterone suppression test). We will study cross- sectionally 4 groups of HIV+ subjects, selected to sample potentially discrete stagepoints in evolution of cellular immune decline. These HIV+groups (N=30 each) will be (1) 1993 CDC A1; (2)A2 with CD4lesser300 and A3; (3) CDC B2-B3; (4) CDC C2-C3. A fifth comparison group of 30 HIV- will also be examined. We will also perform a longitudinal study whereby we will assess at yearly intervals the HPA axis in HIV+ axis in HIV+A patients with intact (more500) and low(lesser300) levels of CD4. We hypothesize that basal hypercortisolism, DHEA depletion, decreased ACTH responses to CRF, and loss of GC negative feedback will be significantly correlated with a high level of CNS infection by HIV, increasing cognitive impairment, MRI defects in limbic brain, and neurobehavioral disorders (i.e., mood dysregulation). We also predict that the magnitude of basal hypercortisolism in the presence of DHEA hyposecretion will be correlated with decreasing cellular immunity and highly predictive of immunologic progression to AIDS. A final specific aim will examine the effect of HIV infection on brain serotonin based on our pilot data revealing diminished HPA responses to fenfluramine in HIV+ patients. We hypothesize that HIV will alter serotonin release at hypothalamic CRF neurons resulting in neuroendocrine dysregulation and neurobehavioral disorders (i.e., depression).