Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator

BACKGROUND: More 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 RESULTS: Bioplex 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. CONCLUSION: 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.