PMID- 30305110 OWN - NLM STAT- MEDLINE DCOM- 20190114 LR - 20200502 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 15 IP - 1 DP - 2018 Oct 10 TI - A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates. PG - 285 LID - 10.1186/s12974-018-1320-4 [doi] LID - 285 AB - BACKGROUND: The collective cognitive and motor deficits known as HIV-associated neurocognitive disorders (HAND) remain high even among HIV+ individuals whose antiretroviral therapy is optimized. HAND is worsened in the context of opiate abuse. The mechanism of exacerbation remains unclear but likely involves chronic immune activation of glial cells resulting from persistent, low-level exposure to the virus and viral proteins. We tested whether signaling through C-C chemokine receptor type 5 (CCR5) contributes to neurotoxic interactions between HIV-1 transactivator of transcription (Tat) and opiates and explored potential mechanisms. METHODS: Neuronal survival was tracked in neuronal and glial co-cultures over 72 h of treatment with HIV-1 Tat +/- morphine using cells from CCR5-deficient and wild-type mice exposed to the CCR5 antagonist maraviroc or exogenously-added BDNF (analyzed by repeated measures ANOVA). Intracellular calcium changes in response to Tat +/- morphine +/- maraviroc were assessed by ratiometric Fura-2 imaging (analyzed by repeated measures ANOVA). Release of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF from CCR5-deficient and wild-type glia was measured by ELISA (analyzed by two-way ANOVA). Levels of CCR5 and mu-opioid receptor (MOR) were measured by immunoblotting (analyzed by Student's t test). RESULTS: HIV-1 Tat induces neurotoxicity, which is greatly exacerbated by morphine in wild-type cultures expressing CCR5. Loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions. Unexpectedly, when CCR5 was lost from glia, morphine appeared to entirely protect neurons from Tat-induced toxicity. Maraviroc pre-treatment similarly eliminated neurotoxicity and attenuated neuronal increases in [Ca(2+)](i) caused by Tat +/- morphine. proBDNF/BDNF ratios were increased in conditioned media from Tat +/- morphine-treated wild-type glia compared to CCR5-deficient glia. Exogenous BDNF treatments mimicked the pro-survival effect of glial CCR5 deficiency against Tat +/- morphine. CONCLUSIONS: Our results suggest a critical role for glial CCR5 in mediating neurotoxic effects of HIV-1 Tat and morphine interactions on neurons. A shift in the proBDNF/BDNF ratio that favors neurotrophic support may occur when glial CCR5 signaling is blocked. Some neuroprotection occurred only in the presence of morphine, suggesting that loss of CCR5 may fundamentally change signaling through the MOR in glia. FAU - Kim, Sarah AU - Kim S AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, 1217 E. Marshall St, Richmond, VA, 23298-0709, USA. FAU - Hahn, Yun Kyung AU - Hahn YK AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, 1217 E. Marshall St, Richmond, VA, 23298-0709, USA. FAU - Podhaizer, Elizabeth M AU - Podhaizer EM AD - Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA. FAU - McLane, Virginia D AU - McLane VD AD - Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA. FAU - Zou, Shiping AU - Zou S AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, 1217 E. Marshall St, Richmond, VA, 23298-0709, USA. AD - Present Address: BioLegend, Inc., 210 Rustcraft Rd., Dedham, MA, 02026, USA. FAU - Hauser, Kurt F AU - Hauser KF AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, 1217 E. Marshall St, Richmond, VA, 23298-0709, USA. AD - Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA. AD - Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298, USA. FAU - Knapp, Pamela E AU - Knapp PE AD - Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, 1217 E. Marshall St, Richmond, VA, 23298-0709, USA. pamela.knapp@vcuhealth.org. AD - Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA. pamela.knapp@vcuhealth.org. AD - Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, 23298, USA. pamela.knapp@vcuhealth.org. LA - eng GR - F30 DA044875/DA/NIDA NIH HHS/United States GR - K02 DA027374/DA/NIDA NIH HHS/United States GR - T32 DA007027/DA/NIDA NIH HHS/United States GR - K02DA027374/DA/NIDA NIH HHS/United States GR - R01 DA045588/DA/NIDA NIH HHS/United States GR - R01 DA033200/DA/NIDA NIH HHS/United States GR - R01 DA034231/DA/NIDA NIH HHS/United States PT - Journal Article DEP - 20181010 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Analgesics, Opioid) RN - 0 (CCR5 Receptor Antagonists) RN - 0 (CCR5 protein, mouse) RN - 0 (Cytokines) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Narcotic Antagonists) RN - 0 (Opiate Alkaloids) RN - 0 (Receptors, CCR5) RN - 0 (Receptors, Opioid, mu) RN - 0 (tat Gene Products, Human Immunodeficiency Virus) RN - 36B82AMQ7N (Naloxone) RN - MD6P741W8A (Maraviroc) SB - IM MH - AIDS Dementia Complex MH - Analgesics, Opioid/*pharmacology MH - Animals MH - CCR5 Receptor Antagonists/pharmacology MH - Corpus Striatum/cytology MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Gene Expression Regulation/drug effects/*genetics MH - Glial Fibrillary Acidic Protein/genetics/metabolism MH - Maraviroc/pharmacology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Naloxone/pharmacology MH - Narcotic Antagonists/pharmacology MH - Neuroglia/drug effects/*metabolism MH - Neurons/physiology MH - Opiate Alkaloids/metabolism/*pharmacology MH - Receptors, CCR5/*deficiency/genetics MH - Receptors, Opioid, mu/metabolism MH - tat Gene Products, Human Immunodeficiency Virus/genetics/*metabolism PMC - PMC6180355 OTO - NOTNLM OT - Brain-derived neurotrophic factor OT - C-C chemokine receptor 5 OT - Human immunodeficiency virus OT - Maraviroc OT - Morphine OT - NeuroHIV COIS- ETHICS APPROVAL: Experiments were conducted in compliance with procedures reviewed and approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee. CONSENT FOR PUBLICATION: Not applicable COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/10/12 06:00 MHDA- 2019/01/15 06:00 PMCR- 2018/10/10 CRDT- 2018/10/12 06:00 PHST- 2018/05/21 00:00 [received] PHST- 2018/09/19 00:00 [accepted] PHST- 2018/10/12 06:00 [entrez] PHST- 2018/10/12 06:00 [pubmed] PHST- 2019/01/15 06:00 [medline] PHST- 2018/10/10 00:00 [pmc-release] AID - 10.1186/s12974-018-1320-4 [pii] AID - 1320 [pii] AID - 10.1186/s12974-018-1320-4 [doi] PST - epublish SO - J Neuroinflammation. 2018 Oct 10;15(1):285. doi: 10.1186/s12974-018-1320-4.