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.


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.


CONCLUSIONS
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.
Department of Pathology, Microbiology & Immunology, University of South Carolina, School of Medicine, Columbia, SC 29209, USA.
Rajeev
R
Mehla
Shalmali
S
Bivalkar-Mehla
Mitzi
M
Nagarkatti
Ashok
A
Chauhan
D015526:AIDS Dementia Complex / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001921:Brain / Q000473:pathology; D054713:Bryostatins / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D003601:Cytotoxicity Tests, Immunologic; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005333:Fetus; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D008875:Middle Aged; D009457:Neuroglia / Q000187:drug effects* / Q000821:virology; D009474:Neurons / Q000187:drug effects* / Q000821:virology; D011108:Polymers / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D054713:Bryostatins; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D004791:Enzyme Inhibitors; D011108:Polymers; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; C004216:bioplex