| Human immunodeficiency virus (HIV) type-1, the etiologic agent of acquired immune deficiency syndrome (AIDS), can result in neurologic complications. A syndrome termed HIV-associated dementia (HAD) manifests itself through progressive motor, cognitive, and behavioral impairment. Pathologic examination has revealed a high level of cellular infiltrate into the brain and neuronal loss along with inflammation. It is estimated that HAD will affect 15-20% of HIV infected individuals. Furthermore, the syndrome appears to be refractory to highly active antiretroviral therapy (HAART), decreasing in incidence but increasing in prevalence. The neuronal cell death and dysfunction associated with HAD is thought to be caused by direct exposure to HIV proteins extracellularly and alterations to the microenvironment that are detrimental to neuron survival and function. Astrocytes play a multifaceted role in the maintenance of neurons by detoxification of the microenvironment. They also play a crucial role in the blood-brain barrier (BBB). Astrocytes are infected by HIV in a manner that is productive for a short time then enters a state of latency, forming a viral reservoir. Furthermore, astrocytes produce inflammatory molecules and alter their detoxification role as a result of exposure to HIV proteins such as gp120 and Tat. These studies demonstrate that there is indeed a potent combination of inflammatory cytokines and chemokines induced at the transcriptional level by HIV or its proteins. By use of microarray analysis, global alterations in astrocyte transcriptional regulation were detected in the presence of HIV proteins or by infection. Furthermore, these same conditions induced an upregulation and increased activation state of matrix metalloproteinases (MMP) by astrocytes, which can enzymatically disrupt the BBB. These studies also demonstrate that an endogenous protein, promyelocytic leukemia protein (PML), contributes to the latency of HIV in astrocytes. This is accomplished at a preintegration level within the HIV life cycle and by suppressing HIV transcription. The former is demonstrated by an increase in infection rate following PML downregulation. The latter is shown to occur via an interaction between the HIV transactivator protein Tat and PML, precluding proper transactivation of the HIV long terminal repeat (LTR). |
