A Central Role for Glial CCR5 in Directing the Neuropathological Interactions of HIV-1 Tat and Opiates

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2018 Oct 12

PMID 30305110

Citations 31

Authors

Sarah Kim

Yun Kyung Hahn

Elizabeth M Podhaizer

Virginia D McLane

Shiping Zou

Kurt F Hauser

Pamela E Knapp

Affiliations

Soon will be listed here.

Abstract

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 μ-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] 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.

Citing Articles

Biosafety and mental health: Virus induced cognitive decline.

Du C, Li G, Han G Biosaf Health. 2025; 5(3):159-167.

PMID: 40078510 PMC: 11895046. DOI: 10.1016/j.bsheal.2023.04.002.

Recent advances in nanotherapeutics for HIV-associated neurocognitive disorders and substance use disorders.

Lomas C, Dubey R, Perez-Alvarez G, Lopez Hernandez Y, Atmar A, Arias A Nanomedicine (Lond). 2025; 20(6):603-619.

PMID: 39963928 PMC: 11902879. DOI: 10.1080/17435889.2025.2461984.

Sex Affects Cognitive Outcomes in HIV-1 Tat Transgenic Mice: Role of CCR5.

Simons C, Kim S, Hahn Y, Boake-Agyei A, Nass S, Vo P ASN Neuro. 2025; 17(1):2447338.

PMID: 39805095 PMC: 11877617. DOI: 10.1080/17590914.2024.2447338.

Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial cocultures through actions independent of opioid receptors.

Yarotskyy V, Nass S, Hahn Y, Contois L, Rory McQuiston A, Knapp P J Neurophysiol. 2024; 132(3):1056-1073.

PMID: 39110896 PMC: 11427067. DOI: 10.1152/jn.00444.2023.

Molecular Role of HIV-1 Human Receptors (CCL5-CCR5 Axis) in neuroAIDS: A Systematic Review.

Silva M, Marinho R, Rodrigues Y, Brasil T, Dos Santos P, Silva C Microorganisms. 2024; 12(4).

PMID: 38674726 PMC: 11051963. DOI: 10.3390/microorganisms12040782.

References

Elkabes S, Black I . Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci. 1996; 16(8):2508-21. PMC: 6578768. View

Szabo I, Wetzel M, Zhang N, Steele A, Kaminsky D, Chen C . Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J Leukoc Biol. 2003; 74(6):1074-82. DOI: 10.1189/jlb.0203067. View

Mahajan S, Schwartz S, Shanahan T, Chawda R, Nair M . Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor. J Immunol. 2002; 169(7):3589-99. DOI: 10.4049/jimmunol.169.7.3589. View

Sun S, Chen D, Lin F, Chen M, Yu H, Hou L . Role of interleukin-4, the chemokine CCL3 and its receptor CCR5 in neuropathic pain. Mol Immunol. 2016; 77:184-92. DOI: 10.1016/j.molimm.2016.08.006. View

Sorce S, Myburgh R, Krause K . The chemokine receptor CCR5 in the central nervous system. Prog Neurobiol. 2010; 93(2):297-311. DOI: 10.1016/j.pneurobio.2010.12.003. View

Bagasra O, Lavi E, Bobroski L, Khalili K, Pestaner J, Tawadros R . Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. AIDS. 1996; 10(6):573-85. DOI: 10.1097/00002030-199606000-00002. View

Yuan Y, Arnatt C, El-Hage N, Dever S, Jacob J, Selley D . A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities. Medchemcomm. 2013; 4(5):847-851. PMC: 3652433. DOI: 10.1039/C3MD00080J. View

Llibre J, Rivero A, Rojas J, Garcia Del Toro M, Herrero C, Arroyo D . Safety, efficacy and indications of prescription of maraviroc in clinical practice: Factors associated with clinical outcomes. Antiviral Res. 2015; 120:79-84. DOI: 10.1016/j.antiviral.2015.05.001. View

Levine A, Singer E, Shapshak P . The role of host genetics in the susceptibility for HIV-associated neurocognitive disorders. AIDS Behav. 2008; 13(1):118-32. PMC: 4433163. DOI: 10.1007/s10461-008-9360-x. View

10.

Victoria E, de Brito Toscano E, de Sousa Cardoso A, DA Silva D, de Miranda A, da Silva Barcelos L . Knockdown of C-C Chemokine Receptor 5 (CCR5) is Protective Against Cerebral Ischemia and Reperfusion Injury. Curr Neurovasc Res. 2017; 14(2):125-131. DOI: 10.2174/1567202614666170313113056. View

11.

Dean M, Carrington M, Winkler C, Huttley G, Smith M, Allikmets R . Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort,.... Science. 1996; 273(5283):1856-62. DOI: 10.1126/science.273.5283.1856. View

12.

Wiley C, Baldwin M, Achim C . Expression of HIV regulatory and structural mRNA in the central nervous system. AIDS. 1996; 10(8):843-7. DOI: 10.1097/00002030-199607000-00007. View

13.

Hahn Y, Paris J, Lichtman A, Hauser K, Sim-Selley L, Selley D . Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and β-arrestin 2 activity in the forebrain. Neurobiol Dis. 2016; 92(Pt B):124-36. PMC: 4907901. DOI: 10.1016/j.nbd.2016.01.014. View

14.

Takahashi K, Wesselingh S, Griffin D, McArthur J, Johnson R, Glass J . Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol. 1996; 39(6):705-11. DOI: 10.1002/ana.410390606. View

15.

Parkhurst C, Yang G, Ninan I, Savas J, Yates 3rd J, Lafaille J . Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell. 2013; 155(7):1596-609. PMC: 4033691. DOI: 10.1016/j.cell.2013.11.030. View

16.

Guo C, Li Y, Tian S, Wang X, Douglas S, Ho W . Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of beta-chemokines and CCR5 receptor. J Investig Med. 2002; 50(6):435-42. PMC: 4037869. DOI: 10.1136/jim-50-06-03. View

17.

Fitting S, Knapp P, Zou S, Marks W, Bowers M, Akbarali H . Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na⁺ influx, mitochondrial instability, and Ca²⁺ overload. J Neurosci. 2014; 34(38):12850-64. PMC: 4166164. DOI: 10.1523/JNEUROSCI.5351-13.2014. View

18.

RESNICK L, Berger J, Shapshak P, Tourtellotte W . Early penetration of the blood-brain-barrier by HIV. Neurology. 1988; 38(1):9-14. DOI: 10.1212/wnl.38.1.9. View

19.

Powderly W . Current approaches to treatment for HIV-1 infection. J Neurovirol. 2000; 6 Suppl 1:S8-S13. View

20.

Bednar M, Sturdevant C, Tompkins L, Arrildt K, Dukhovlinova E, Kincer L . Compartmentalization, Viral Evolution, and Viral Latency of HIV in the CNS. Curr HIV/AIDS Rep. 2015; 12(2):262-71. PMC: 4431548. DOI: 10.1007/s11904-015-0265-9. View