Abstract
Recruitment of immune cells such as monocytes/macrophages and dendritic cells (DCs) across the blood–brain barrier (BBB) has been documented in diseases involving neuroinflammation. Neuroinvasion by HIV leads to neurocognitive diseases and alters the permeability of the BBB. Likewise, many HIV patients use drugs of abuse such as morphine, which can further compromise the BBB. While the role of monocytes and macrophages in neuroAIDS is well established, research demonstrating the presence and role of DCs in the CNS during HIV infection has not been developed yet. In this respect, this study explored the presence of DCs in the brain parenchyma of rhesus macaques infected with a neurovirulent form of SIV (SIV mac239 R71/17E) and administered with morphine. Cells positive for DC markers including CD11c (integrin), macDC-SIGN (dendritic cell-specific ICAM-3 grabbing nonintegrin), CD83 (a maturation factor), and HLA-DR (MHC class II) were consistently found in the brain parenchyma of SIV-infected macaques as well as infected macaques on morphine. Control animals did not exhibit any DC presence in their brains. These results provide first evidence of DCs’ relevance in NeuroAIDS vis-à-vis drugs of abuse and open new avenues of understanding and investigative HIV-CNS inflictions.
This is a preview of subscription content, log in via an institution to check access.
References
Annunziata P (2003) Blood–brain barrier changes during invasion of the central nervous system by HIV-1. Old and new insights into the mechanism. J Neurol 250:901–906
Bailey SL, Schreiner B, McMahon EJ, Miller SD (2007) CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 8:172–180
Bokhari SM, Hegde R, Callen S, Yao H, Adany I, Li Q, Li Z, Pinson D, Yeh HW, Cheney PD, Buch S (2011) Morphine potentiates neuropathogenesis of SIV infection in rhesus macaques. J Neuroimmune Pharmacol 6:626–639
Buckner CM, Calderon TM, Willams DW, Belbin TJ, Berman JW (2011) Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood–brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol 267:109–123
Changyong C, Sun M, Li H, Brockmeyer N, Wu NP (2010) Simian virus 40 inhibits differentiation and maturation of rhesus macaque DC-SIGN(+) dendritic cells. Eur J Med Res 15:377–382
Cloak CC, Chang L, O'Neil SP, Ernst TM, Anderson DC, Donahoe RM (2011) Neurometabolite abnormalities in simian immunodeficiency virus-infected macaques with chronic morphine administration. J Neuroimmune Pharmacol 6:371–380
Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121
de Witte L, de Vries RD, van der Vlist M, Yuksel S, Litjens M, de Swart RL, Geijtenbeek TB (2008) DC-SIGN and CD150 have distinct roles in transmission of measles virus from dendritic cells to T-lymphocytes. PLoS Pathog 4:e1000049
Dhillon NK, Williams R, Callen S, Zien C, Narayan O, Buch S (2008) Roles of MCP-1 in development of HIV-dementia. Front Biosci 13:3913–3918
Donahoe RM, O'Neil SP, Marsteller FA, Novembre FJ, Anderson DC, Lankford-Turner P, McClure HH (2009) Probable deceleration of progression of Simian AIDS affected by opiate dependency: studies with a rhesus macaque/SIVsmm9 model. J Acquir Immune Defic Syndr 50:241–249
Eden A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslen M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783
Eugenin EA, Osiecki K, Lopez L, Goldstein H, Calderon TM, Berman JW (2006) CCL2/monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood–brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J Neurosci 26:1098–1106
Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, Figdor CG (2000) Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100:575–585
Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11:328–334
Hatterer E, Touret M, Belin MF, Honnorat J, Nataf S (2008) Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS One 3:e3321
Higgins JR, Sutjipto S, Marx PA, Pedersen NC (1992) Shared antigenic epitopes of the major core proteins of human and simian immunodeficiency virus isolates. J Med Primatol 21:265–269
Hu SSW, Lokensgard JR, Peterson PK (2005) Morphine potentiates HIV-1 gp120-induced neuronal apoptosis. J Infect Dis 191:886–889
Ifergan I, Kebir H, Bernard M, Wosik K, Dodelet-Devillers A, Cayrol R, Arbour N, Prat A (2008) The blood–brain barrier induces differentiation of migrating monocytes into Th17-polarizing dendritic cells. Brain 131:785–799
Ilarregui JM, Croci DO, Bianco GA, Toscano MA, Salatino M, Vermeulen ME, Geffner JR, Rabinovich GA (2009) Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol 10:981–991
Jain P, Coisne C, Enzmann G, Rottapel R, Engelhardt B (2010) Alpha4beta1 integrin mediates the recruitment of immature dendritic cells across the blood–brain barrier during experimental autoimmune encephalomyelitis. J Immunol 184:7196–7206
Johnson MD, Kim P, Tourtellotte W, Federspiel CF (2004) Transforming growth factor beta and monocyte chemotactic protein-1 are elevated in cerebrospinal fluid of immunocompromised patients with HIV-1 infection. J NeuroAIDS 2:33–43
Kumar R, Orsoni S, Norman L, Verma AS, Tirado G, Giavedoni LD, Staprans S, Miller GM, Buch SJ, Kumar A (2006) Chronic morphine exposure causes pronounced virus replication in cerebral compartment and accelerated onset of AIDS in SIV/SHIV-infected Indian rhesus macaques. Virology 354:192–206
Lee EO, Kim SE, Park HK, Kang JL, Chong YH (2011) Extracellular HIV-1 Tat upregulates TNF-alpha dependent MCP-1/CCL2 production via activation of ERK1/2 pathway in rat hippocampal slice cultures: inhibition by resveratrol, a polyphenolic phytostilbene. Exp Neurol 229:399–408
Li ZCN, Shan L, Gong S, Yin Q, Jiang X (2009) Inducible expression of functional mu opioid receptors in murine dendritic cells. J Neuroimmune Pharmacol 4:359
Messmer DHI, Hitosugi N, Schmidt-Wolf IGH, Singhal PC (2006) Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol Med 12:284–290
Noel RJ Jr, Kumar A (2006) Virus replication and disease progression inversely correlate with SIV tat evolution in morphine-dependent and SIV/SHIV-infected Indian rhesus macaques. Virology 346:127–138
O'Brien M, Manches O, Sabado RL, Baranda SJ, Wang Y, Marie I, Rolnitzky L, Markowitz M, Margolis DM, Levy D, Bhardwaj N (2011) Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-alpha-producing and partially matured phenotype. J Clin Invest 121:1088–1101
Orenstein JM, Fox C, Wahl SM (1997) Macrophages as a source of HIV during opportunistic infections. Science 276:1857–1861
Perez-Casanova A, Husain K, Noel RJ Jr, Rivera-Amill V, Kumar A (2008) Interaction of SIV/SHIV infection and morphine on plasma oxidant/antioxidant balance in macaque. Mol Cell Biochem 308:169–175
Perez-Casanova A, Noel RJ Jr, Rivera-Amill V, Husain K, Kumar A (2007) Morphine-mediated deterioration of oxidative stress leads to rapid disease progression in SIV/SHIV-infected macaques. AIDS Res Hum Retroviruses 23:1004–1007
Pichyangkul S, Saengkrai P, Yongvanitchit K, Limsomwong C, Gettayacamin M, Walsh DS, Stewart VA, Ballou WR, Heppner DG (2001) Isolation and characterization of rhesus blood dendritic cells using flow cytometry. J Immunol Methods 252:15–23
Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S (2004) Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis. Am J Pathol 165:815–824
Raghavan R, Cheney PD, Raymond LA, Joag SV, Stephens EB, Adany I, Pinson DM, Li Z, Marcario JK, Jia F, Wang C, Foresman L, Berman NE, Narayan O (1999) Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus. Neuropathol Appl Neurobiol 25:285–294
Sabado RL, O'Brien M, Subedi A, Qin L, Hu N, Taylor E, Dibben O, Stacey A, Fellay J, Shianna KV, Siegal F, Shodell M, Shah K, Larsson M, Lifson J, Nadas A, Marmor M, Hutt R, Margolis D, Garmon D, Markowitz M, Valentine F, Borrow P, Bhardwaj N (2010) Evidence of dysregulation of dendritic cells in primary HIV infection. Blood 116:3839–3852
Sagar D, Lamontagne A, Foss CA, Khan ZK, Pomper MG, Jain P (2012) Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood–brain barrier through paracellular transmigration and ERK activation. J Neuroinflammation 9:245
Shapshak P, Kangueane P, Fujimura RK, Commins D, Chiappelli F, Singer E, Levine AJ, Minagar A, Novembre FJ, Somboonwit C, Nath A, Sinnott JT (2011) Editorial neuroAIDS review. AIDS 25:123–141
Soilleux EJ, Morris LS, Leslie G, Chehimi J, Luo Q, Levroney E, Trowsdale J, Montaner LJ, Doms RW, Weissman D, Coleman N, Lee B (2002) Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 71:445–457
Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, Brew B, Fuchs D, Tambussi G, Cinque P, Hecht FM, Price RW (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204:753–760
Suzuki S, Chuang AJ, Chuang LF, Doi RH, Chuang RY (2002) Morphine promotes simian acquired immunodeficiency syndrome virus replication in monkey peripheral mononuclear cells: induction of CC chemokine receptor 5 expression for virus entry. J Infect Dis 185:1826–1829
Tirado G, Kumar A (2006) Evolution of SIV envelope in morphine-dependent rhesus macaques with rapid disease progression. AIDS Res Hum Retroviruses 22:114–119
Wen H, Lu Y, Yao H, Buch S (2011) Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability. PLoS One 6:e21707
Xia H, Liu H, Zhang G, Zheng Y (2009) Phenotype and function of monocyte-derived dendritic cells from Chinese rhesus macaques. Cell Mol Immunol 6:159–165
Yu Kimata MT, Cella M, Biggins JE, Rorex C, White R, Hicks S, Wilson JM, Patel PG, Allan JS, Colonna M, Kimata JT (2002) Capture and transfer of simian immunodeficiency virus by macaque dendritic cells is enhanced by DC-SIGN. J Virol 76:11827–11836
Zhou LJ, Tedder TF (1995) Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol 154:3821–3835
Zink MC, Brice AK, Kelly KM, Queen SE, Gama L, Li M, Adams RJ, Bartizal C, Varrone J, Rabi SA, Graham DR, Tarwater PM, Mankowski JL, Clements JE (2010) Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA. J Infect Dis 202:161–170
Zink MC, Coleman GD, Mankowski JL, Adams RJ, Tarwater PM, Fox K, Clements JE (2001) Increased macrophage chemoattractant protein-1 in cerebrospinal fluid precedes and predicts simian immunodeficiency virus encephalitis. J Infect Dis 184:1015–1021
Zozulya AL, Ortler S, Lee J, Weidenfeller C, Sandor M, Wiendl H, Fabry Z (2009) Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci 29:140–152
Acknowledgments
This work was funded by the Public Health Service, National Institutes of Health through the following NIAID grants: AI077414 (PI: Pooja Jain) and AI093172-01 (PI: Zafar K. Khan). We also wish to thank the Philadelphia NeuroAIDS Training Grant: T32 MH079785, and the technical assistance provided by Ms. Anne Lamontagne.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Hollenbach, R., Sagar, D., Khan, Z.K. et al. Effect of morphine and SIV on dendritic cell trafficking into the central nervous system of rhesus macaques. J. Neurovirol. 20, 175–183 (2014). https://doi.org/10.1007/s13365-013-0182-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-013-0182-x