Autonomic nervous system control of HIV-1 replication

目前，抗逆转录病毒药物是控制HIV致病的唯一有效手段，但现有的药物方案不能完全阻止病毒在体内的复制。因此，在高效抗逆转录病毒治疗(HAART)期间，确定支持残留艾滋病毒复制的生理过程至关重要。最近的数据表明，自主神经系统(ANS)交感神经部分的高水平活动是未经治疗和接受HAART的患者血浆病毒载量升高的体内危险因素。长期以来，神经系统调节某些病毒病原体(如疱疹病毒)的活动，但对其对HIV或SIV等慢病毒的影响知之甚少。ANS神经元支配淋巴器官，淋巴器官是HIV-1在体内复制的主要场所，T淋巴细胞携带β肾上腺素受体，允许神经调节细胞激活、细胞因子产生和细胞运输。在以前的研究中，我们发现ANS神经递质去甲肾上腺素通过改变细胞对感染的易感性和增强病毒基因的表达，在体外加速HIV-1的复制。拟议的研究试图确定这些影响的分子机制。具体地说，这些研究的目的是：1.确定ANS诱导HIV-1基因表达的转录调节因子。2.确定ANS对调节HIV-1复制的可溶性因子的影响。3.评估ANS神经元与淋巴组织中HIV/SIV复制之间的相互作用。这些研究将建立旨在阻止ANS支持HAART期间残留艾滋病毒复制的干预措施的病毒学框架。这些干预措施将通过反对支持正在进行的致病的生理过程来提高当前抗逆转录病毒治疗方案的疗效。

Antiretroviral medications currently represent the only effective means for controlling HIV pathogenesis, but existing drug regimens cannot fully stop viral replication in vivo. It is thus critical to identify physiologic processes that support residual HIV replication during highly active antiretroviral therapy (HAART). Recent data indicate that high levels of activity in the sympathetic division of the autonomic nervous system (ANS) represent an in vivo risk factor for elevated plasma viral load in untreated patients and those receiving HAART. The nervous system has long been known to regulate the activity of certain viral pathogens (e.g., herpes viruses), but little is known about its impact on lentiviruses such as HIV or SIV. ANS neurons innervate the lymphoid organs that serve as major sites of HIV-1 replication in vivo, and T lymphocytes bear beta adrenoreceptors that allow neural modulation of cellular activation, cytokine production, and cell trafficking. In previous studies, we found that the ANS neurotransmitter norepinephrine accelerates HIV-1 replication in vitro by altering cellular vulnerability to infection and enhancing viral gene expression. The proposed studies seek to define the molecular mechanisms of these effects. Specifically, these studies aim to: 1. Identify transcriptional mediators of ANS-induced HIV-1 gene expression. 2. Define ANS effects on soluble factors that modulate HIV-1 replication. 3. Assess interactions between ANS neurons and HIV/SIV replication in lymphoid tissues. These studies will establish a virologic framework for interventions aimed at blocking ANS support of residual HIV replication during HAART. Such interventions would enhance the efficacy of current antiretroviral treatment regimens by opposing physiologic processes that support ongoing pathogenesis.