Abstract
BackgroundMore than 50% of patients undergoing lifelong suppressive antiviral treatment for HIV-1 infection develop minor HIV-1-associated neurocognitive disorders. Neurological complications during HIV-1 infection are the result of direct neuronal damage by proinflammatory products released from HIV-1-infected or -uninfected activated lymphocytes, monocytes, macrophages, microglia and astrocytes. The specific pro-inflammatory products and their roles in neurotoxicity are far from clear. We investigated proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of HIV-demented (HIV-D) and HIV-nondemented (HIV-ND) patients and studied their affect on neuroglial toxicity.Methods and resultsBioplex array showed elevated levels of signatory chemokines or cytokines (IL-6, IFN-γ, CXCL10, MCP-1 and PDGF) in the CSF of HIV-D patients (n = 7) but not in that of HIV-ND patients (n = 7). Among the signatory cytokines and chemokines, CXCL10 was distinctly upregulated in-vitro in HIV-1 (NLENG1)-activated human fetal astrocytes, HIV-1 (Ba-L)-infected macrophages, and HIV-1 (NLENG1)-infected lymphocytes. Virus-infected macrophages also had increased levels of TNF-α. Consistently, human fetal astrocytes treated with HIV-1 and TNF-α induced the signatory molecules. CXCL10 in combination with HIV-1 synergistically enhanced neuronal toxicity and showed chemotactic activity (~ 40 fold) for activated peripheral blood mononuclear cells (PBMC), suggesting the intersection of signaling events imparted by HIV-1 and CXCL10 after binding to their respective surface receptors, CXCR4 and CXCR3, on neurons. Blocking CXCR3 and its downstream MAP kinase (MAPK) signaling pathway suppressed combined CXCL10 and HIV-1-induced neurotoxicity. Bryostatin, a PKC modulator and suppressor of CXCR4, conferred neuroprotection against combined insult with HIV-1 and CXCL10. Bryostatin also suppressed HIV-1 and CXCL10-induced PBMC chemotaxis. Although, therapeutic targeting of chemokines in brain may have adverse consequences on the host, current findings and earlier evidence suggest that CXCL10 could strongly impede neuroinflammation.ConclusionWe have demonstrated induction of CXCL10 and other chemokines/cytokines during HIV-1 infection in the brain, as well as synergism of CXCL10 with HIV-1 in neuronal toxicity, which was dampened by bryostatin.
Highlights
HIV-1 infection programs aberrant host immune responses, including those in the brain that contribute to neuropathogenesis [1]
We have demonstrated induction of CXCL10 and other chemokines/cytokines during HIV-1 infection in the brain, as well as synergism of CXCL10 with HIV-1 in neuronal toxicity, which was dampened by bryostatin
Signatory proinflammatory chemokines and cytokines in HIV-1-infected demented patients We investigated the proinflammatory response in the cerebrospinal fluid (CSF) of HIV-D and HIV-ND patients using Bioplex array
Summary
HIV-1 infection programs aberrant host immune responses, including those in the brain that contribute to neuropathogenesis [1]. M-tropic HIV-1 infects macrophages and microglia in the brain, but both M-tropic and T-tropic HIV-1 populations were found on autopsy of central nervous tissues and cerebrospinal fluid (CSF) of HAD patients [2,3,4,5]. Neurotoxic inflammatory products have been implicated in neuronal damage [6,7,8,9,10]. These products include proinflammatory cytokines and chemokines derived from HIV-1 infected- or uninfected- activated lymphocytes, macrophages, microglia, and astrocytes. Neurological complications during HIV-1 infection are the result of direct neuronal damage by proinflammatory products released from HIV-1-infected or -uninfected activated lymphocytes, monocytes, macrophages, microglia and astrocytes. We investigated proinflammatory cytokines and chemokines in the cerebrospinal fluid (CSF) of HIV-demented (HIV-D) and HIV-nondemented (HIV-ND) patients and studied their affect on neuroglial toxicity
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