Abstract
BackgroundAbnormal activation of the complement system contributes to some central nervous system diseases but the role of complement in HIV-associated neurocognitive disorder (HAND) is unclear.MethodsWe used real-time PCR and immunohistochemistry to detect complement expression in postmortem brain tissue from HAND patients and controls. To further investigate the basis for viral induction of gene expression in the brain, we studied the effect of HIV on C3 expression by astrocytes, innate immune effector cells, and targets of HIV. Human fetal astrocytes (HFA) were infected with HIV in culture and cellular pathways and factors involved in signaling to C3 expression were elucidated using pharmacological pathway inhibitors, antisense RNA, promoter mutational analysis, and fluorescence microscopy.ResultsWe found significantly increased expression of complement components including C3 in brain tissues from patients with HAND and C3 was identified by immunocytochemistry in astrocytes and neurons. Exposure of HFA to HIV in culture-induced C3 promoter activity, mRNA expression, and protein production. Use of pharmacological inhibitors indicated that induction of C3 expression by HIV requires NF-κB and protein kinase signaling. The relevance of NF-κB regulation to C3 induction was confirmed through detection of NF-κB translocation into nuclei and inhibition through overexpression of the physiological NF-κB inhibitor, I-κBα. C3 promoter mutation analysis revealed that the NF-κB and SP binding sites are dispensable for the induction by HIV, while the proximal IL-1β/IL-6 responsive element is essential. HIV-treated HFA secreted IL-6, exogenous IL-6 activated the C3 promoter, and anti-IL-6 antibodies blocked HIV activation of the C3 promoter. The activation of IL-6 transcription by HIV was dependent upon an NF-κB element within the IL-6 promoter.ConclusionsThese results suggest that HIV activates C3 expression in primary astrocytes indirectly, through NF-κB-dependent induction of IL-6, which in turn activates the C3 promoter. HIV induction of C3 and IL-6 in astrocytes may contribute to HIV-mediated inflammation in the brain and cognitive dysfunction.
Highlights
Abnormal activation of the complement system contributes to some central nervous system diseases but the role of complement in HIV-associated neurocognitive disorder (HAND) is unclear
HIV-infected patients are at high risk of central nervous system diseases termed HIV-associated neurocognitive disorders (HAND), which include in a decreasing order of severity HIV dementia (HAD), mild neurocognitive disorder (MND), and asymptomatic neurocognitive impairment (ANI) [1]
In our investigation of activation of primary human fetal astrocytes (HFA) by HIV, we found that HIV binding is sufficient to induce transcription and secretion of IL-6 and IL-8 [16]
Summary
Abnormal activation of the complement system contributes to some central nervous system diseases but the role of complement in HIV-associated neurocognitive disorder (HAND) is unclear. HIV-infected patients are at high risk of central nervous system diseases termed HIV-associated neurocognitive disorders (HAND), which include in a decreasing order of severity HIV dementia (HAD), mild neurocognitive disorder (MND), and asymptomatic neurocognitive impairment (ANI) [1]. ANI and MND are milder, chronic cognitive dysfunctions that generally do not progress to dementia [3] and are diagnosed solely by the extent of neurocognitive impairment (NCI) in neuropsychological tests [1, 4]. HIV generally does not target neurons [9], the virus was shown to cause neuropathogenesis through production of neurotoxic viral proteins and cellular mediators secreted by HIV-infected cells, primarily macrophages, microglia, and astrocytes (reviewed in [10]). Because astrocytes are the most numerous cells in the brain [15], their capacity to amplify neuropathogenic effects of HIV-infected macrophages and microglia in this manner may be significant
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