Interactive Effects of Morphine on HIV Infection: Role in HIV-Associated Neurocognitive Disorder

HIV epidemic continues to be a severe public health problem and concern within USA and across the globe with about 33 million people infected with HIV. The frequency of drug abuse among HIV infected patients is rapidly increasing and is another major issue since injection drug users are at a greater risk of developing HIV associated neurocognitive dysfunctions compared to non-drug users infected with HIV. Brain is a major target for many of the recreational drugs and HIV. Evidences suggest that opiate drug abuse is a risk factor in HIV infection, neural dysfunction and progression to AIDS. The information available on the role of morphine as a cofactor in the neuropathogenesis of HIV is scanty. This review summarizes the results that help in understanding the role of morphine use in HIV infection and neural dysfunction. Studies show that morphine enhances HIV-1 infection by suppressing IL-8, downregulating chemokines with reciprocal upregulation of HIV coreceptors. Morphine also activates MAPK signaling and downregulates cAMP response element-binding protein (CREB). Better understanding on the role of morphine in HIV infection and mechanisms through which morphine mediates its effects may help in devising novel therapeutic strategies against HIV-1 infection in opiate using HIV-infected population.

[1]  Sabita Roy,et al.  Morphine Negatively Regulates Interferon-γ Promoter Activity in Activated Murine T Cells through Two Distinct Cyclic AMP-dependent Pathways* , 2003, Journal of Biological Chemistry.

[2]  P. Simmonds,et al.  HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement. , 1998, Brain : a journal of neurology.

[3]  P. Pitha,et al.  Binding of Human Immunodeficiency Virus Type 1 to CD4 and CXCR4 Receptors Differentially Regulates Expression of Inflammatory Genes and Activates the MEK/ERK Signaling Pathway , 1998, Journal of Virology.

[4]  C. Hall,et al.  Human Immunodeficiency Virus-Related Cognitive Impairment and the Acquired Immunodeficiency Syndrome Dementia Complex , 1992, Seminars in neurology.

[5]  P. Peterson,et al.  Kappa-opioid receptor agonist inhibition of HIV-1 envelope glycoprotein-mediated membrane fusion and CXCR4 expression on CD4(+) lymphocytes. , 2002, Biochemical pharmacology.

[6]  P. Lusso HIV and chemokines: implications for therapy and vaccine. , 2002, Vaccine.

[7]  Dana Gabuzda,et al.  Regulation of Human Immunodeficiency Virus Type 1 Infectivity by the ERK Mitogen-Activated Protein Kinase Signaling Pathway , 1999, Journal of Virology.

[8]  J. Ambati,et al.  HIV‐1 Tat and opiate‐induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP‐1 and alternative chemokines , 2006, Glia.

[9]  Melina V Jones,et al.  Neurotoxicity and dysfunction of dopaminergic systems associated with AIDS dementia , 2000, Journal of psychopharmacology.

[10]  S. Mahajan,et al.  Morphine regulates gene expression of alpha- and beta-chemokines and their receptors on astroglial cells via the opioid mu receptor. , 2002, Journal of immunology.

[11]  Vanessa Rivera-Amill,et al.  Morphine and Rapid Disease Progression in Nonhuman Primate Model of AIDS: Inverse Correlation Between Disease Progression and Virus Evolution , 2010, Journal of Neuroimmune Pharmacology.

[12]  A. Bruce-Keller,et al.  Morphine and HIV‐Tat increase microglial‐free radical production and oxidative stress: possible role in cytokine regulation , 2009, Journal of neurochemistry.

[13]  T. Deuel,et al.  Polypeptide growth factors: roles in normal and abnormal cell growth. , 1987, Annual review of cell biology.

[14]  H. Enslen,et al.  Modulation of HIV‐1 infectivity by MAPK, a virion–associated kinase , 1998, The EMBO journal.

[15]  C. Heldin,et al.  Structural and functional studies on platelet‐derived growth factor. , 1992, The EMBO journal.

[16]  Honghong Yao,et al.  Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability. , 2011, Blood.

[17]  S. Meddows-Taylor,et al.  Reduced expression of interleukin-8 receptors A and B on polymorphonuclear neutrophils from persons with human immunodeficiency virus type 1 disease and pulmonary tuberculosis. , 1998, The Journal of infectious diseases.

[18]  H. Gendelman,et al.  The HIV-1 associated dementia complex: a metabolic encephalopathy fueled by viral replication in mononuclear phagocytes. , 1997, Current Opinion in Neurology.

[19]  H. Balfour,et al.  Morphine amplifies HIV-1 expression in chronically infected promonocytes cocultured with human brain cells , 1994, Journal of Neuroimmunology.

[20]  T. Murakami,et al.  Roles of chemokines and chemokine receptors in HIV-1 infection. , 2000, International journal of hematology.

[21]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[22]  M. Krangel,et al.  Biology and biochemistry of the chemokines: a family of chemotactic and inflammatory cytokines. , 1992, Critical reviews in immunology.

[23]  A. Fauci,et al.  Chemokines, cytokines and HIV: a complex network of interactions that influence HIV pathogenesis , 2000, Immunological reviews.

[24]  E. Benveniste,et al.  Immune function of astrocytes , 2001, Glia.

[25]  D. Yee,et al.  Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. , 2002, Cancer research.

[26]  T. Rogers,et al.  μ-opioid modulation of HIV-1 coreceptor expressionand HIV-1 replication , 2003 .

[27]  L. Montagnier,et al.  Apoptosis in AIDS. , 1993, Science.

[28]  J. Ambati,et al.  CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates , 2006, Journal of Neuroimmunology.

[29]  A. Garzino-Demo,et al.  Chemokine Receptors and Chemokines in HIV Infection , 1998, Journal of Clinical Immunology.

[30]  Stuart A. Lipton,et al.  Pathways to neuronal injury and apoptosis in HIV-associated dementia , 2001, Nature.

[31]  P. Cheney,et al.  Morphine Potentiates Neuropathogenesis of SIV Infection in Rhesus Macaques , 2011, Journal of Neuroimmune Pharmacology.

[32]  Michael E. Greenberg,et al.  CREB: A mediator of long-term memory from mollusks to mammals , 1994, Cell.

[33]  J. Gutkind The Pathways Connecting G Protein-coupled Receptors to the Nucleus through Divergent Mitogen-activated Protein Kinase Cascades* , 1998, The Journal of Biological Chemistry.

[34]  D. Donoghue,et al.  Structure and function of platelet-derived growth factor (PDGF) and related proteins. , 1989, Biochimica et biophysica acta.

[35]  A. Bruce-Keller,et al.  Morphine Exacerbates HIV-1 Tat-Induced Cytokine Production in Astrocytes through Convergent Effects on [Ca2+]i, NF-κB Trafficking and Transcription , 2008, PloS one.

[36]  Ulf Eriksson,et al.  Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke , 2008, Nature Medicine.

[37]  J. Zhang,et al.  Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro , 2001, Neuroscience.

[38]  D. Lysle,et al.  Suppression of natural killer cell activity by morphine is mediated by the nucleus accumbens shell , 2006, Journal of Neuroimmunology.

[39]  C Eisdorfer,et al.  Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality. , 2001, Journal of clinical epidemiology.

[40]  N. Haigwood,et al.  Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis , 1992, The Journal of experimental medicine.

[41]  S. Schwartz,et al.  Immunoregulatory effects of morphine on human lymphocytes , 1997, Clinical and diagnostic laboratory immunology.

[42]  Jie Chen,et al.  Overland heroin trafficking routes and HIV-1 spread in south and south-east Asia , 2000, AIDS.

[43]  M. Baggiolini,et al.  Interleukin‐8, a chemotactic and inflammatory cytokine , 1992, FEBS letters.

[44]  K. Marder,et al.  Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia , 2004, Neurology.

[45]  I. Schmidt-Wolf,et al.  Morphine Reciprocally Regulates IL-10 and IL-12 Production by Monocyte-Derived Human Dendritic Cells and Enhances T Cell Activation , 2006, Molecular medicine.

[46]  Dianne Langford,et al.  HIV and antiretroviral therapy in the brain: neuronal injury and repair , 2008, Nature Reviews Neuroscience.

[47]  A. Nath,et al.  Molecular Basis for Interactions of HIV and Drugs of Abuse , 2002, Journal of acquired immune deficiency syndromes.

[48]  M. Dorf,et al.  Astrocytes express functional chemokine receptors , 2000, Journal of Neuroimmunology.

[49]  A. Nath,et al.  Molecular targets of opiate drug abuse in neuro AIDS , 2005, Neurotoxicity Research.

[50]  A. Garzino-Demo,et al.  Beta-chemokines and protection from HIV type 1 disease. , 1998, AIDS research and human retroviruses.

[51]  Atta-ur-rahman,et al.  Interleukin-8: An autocrine inflammatory mediator. , 1999, Current pharmaceutical design.

[52]  Ravikumar Aalinkeel,et al.  Morphine modulates chemokine gene regulation in normal human astrocytes. , 2005, Clinical immunology.

[53]  Eric R. Kandel,et al.  Cell Adhesion Molecules, CREB, and the Formation of New Synaptic Connections , 1996, Neuron.

[54]  R. Savani,et al.  Morphine Enhances HIV Infection of Neonatal Macrophages , 2003, Pediatric Research.

[55]  Sulie L. Chang,et al.  HIV-1 gp120 up-regulation of the mu opioid receptor in TPA-differentiated HL-60 cells. , 2006, International immunopharmacology.

[56]  S. Woodman,et al.  Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation. , 2000, The American journal of pathology.

[57]  T. Eisenstein,et al.  Morphine treatment in vitro or in vivo decreases phagocytic functions of murine macrophages. , 1993, Life sciences.

[58]  S. Mahajan,et al.  Morphine Regulates Gene Expression of α- and β-Chemokines and Their Receptors on Astroglial Cells Via the Opioid μ Receptor1 , 2002, The Journal of Immunology.

[59]  Peter Simmonds,et al.  Impact of HIV on regional & cellular organisation of the brain. , 2006, Current HIV research.

[60]  C. Payá,et al.  Apoptosis in AIDS. , 1997, Advances in pharmacology.

[61]  Shuxian Hu,et al.  Morphine stimulates CCL2 production by human neurons , 2006, Journal of Neuroinflammation.

[62]  David Vlahov,et al.  The role of substance abuse in HIV disease progression: reconciling differences from laboratory and epidemiologic investigations. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[63]  M. Buchmeier,et al.  Dynamic regulation of alpha- and beta-chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease. , 1998, Journal of immunology.

[64]  J. Oppenheim,et al.  Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems , 2005, Journal of leukocyte biology.

[65]  Cynthia Torres,et al.  Modulation by Morphine of Viral Set Point in Rhesus Macaques Infected with Simian Immunodeficiency Virus and Simian-Human Immunodeficiency Virus , 2004, Journal of Virology.

[66]  A. Bruce-Keller,et al.  CCL5/RANTES Gene Deletion Attenuates Opioid-Induced Increases in Glial CCL2/MCP-1 Immunoreactivity and Activation in HIV-1 Tat-Exposed Mice , 2008, Journal of Neuroimmune Pharmacology.

[67]  C. Broder,et al.  Human immunodeficiency virus type-1 and chemokines: beyond competition for common cellular receptors. , 2001, Cytokine & growth factor reviews.

[68]  M. Mayo,et al.  Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis. , 2004, The American journal of pathology.

[69]  P. Portoghese,et al.  Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes. , 2001, Biochemical pharmacology.

[70]  V. Asensio,et al.  Chemokines and viral diseases of the central nervous system , 2001, Advances in Virus Research.

[71]  T. Eisenstein,et al.  μ-Opioid Induction of Monocyte Chemoattractant Protein-1, RANTES, and IFN-γ-Inducible Protein-10 Expression in Human Peripheral Blood Mononuclear Cells1 , 2000, The Journal of Immunology.

[72]  N. Desai,et al.  HIV infection and high-risk behaviors in opioid dependent patients: the Indian context. , 2004, Addictive behaviors.

[73]  N. Rothwell,et al.  Inflammation in central nervous system injury. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[74]  Honghong Yao,et al.  Morphine enhances Tat-induced activation in murine microglia , 2009, Journal of NeuroVirology.

[75]  J. Clements,et al.  Cerebrospinal fluid markers that predict SIV CNS disease , 2004, Journal of Neuroimmunology.

[76]  Sabita Roy,et al.  Opiate abuse, innate immunity, and bacterial infectious diseases , 2008, Archivum Immunologiae et Therapiae Experimentalis.

[77]  R. Vallejo,et al.  Opioid Therapy and Immunosuppression: A Review , 2004, American journal of therapeutics.

[78]  J. Reynolds,et al.  Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. , 2005, Current HIV research.

[79]  E. Major,et al.  Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[80]  J. Berman,et al.  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 , 2006, The Journal of Neuroscience.

[81]  Ji Ming Wang,et al.  Chemokines as Molecular Targets for Therapeutic Intervention , 1999, Journal of Clinical Immunology.

[82]  Frederick A. Schmitt,et al.  Acceleration of HIV dementia with methamphetamine and cocaine , 2011, Journal of NeuroVirology.

[83]  Nan Zhang,et al.  Role of MIP-1β and RANTES in HIV-1 infection of microglia: inhibition of infection and induction by IFNβ , 2000, Journal of Neuroimmunology.

[84]  K. Tanaka,et al.  Apoptosis induced in CD4+ cells expressing gp160 of human immunodeficiency virus type 1 , 1994, Journal of virology.

[85]  V. Metelev,et al.  Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. , 1995, Science.

[86]  W. Kelder,et al.  β‐Chemokines MCP‐1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus–associated dementia , 1998 .

[87]  J. Zamora,et al.  CD4 cell recovery during successful antiretroviral therapy in naive HIV-infected patients: the role of intravenous drug use , 2004, AIDS.

[88]  A. Verani,et al.  Chemokines as natural HIV antagonists. , 2002, Current molecular medicine.

[89]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[90]  Thomas Lehner,et al.  The role of CCR5 chemokine ligands and antibodies to CCR5 coreceptors in preventing HIV infection. , 2002, Trends in immunology.

[91]  T. Eisenstein,et al.  Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations , 1998, Journal of Neuroimmunology.

[92]  A. Nath,et al.  Synergistic increases in intracellular Ca2+, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat , 2005, Glia.

[93]  Shuxian Hu,et al.  Morphine potentiates HIV-1 gp120-induced neuronal apoptosis. , 2005, The Journal of infectious diseases.

[94]  A. Garzino-Demo,et al.  HIV Infection and Pathogenesis: What About Chemokines? , 1999, Journal of Clinical Immunology.

[95]  Shaily Malik,et al.  A Growth Factor Attenuates HIV-1 Tat and Morphine Induced Damage to Human Neurons: Implication in HIV/AIDS-Drug Abuse Cases , 2011, PloS one.

[96]  J. McArthur,et al.  HIV-associated neurocognitive disorders: is there a hidden epidemic? , 2010, AIDS.

[97]  D. Prough,et al.  Interleukin-8, neuroinflammation, and secondary brain injury. , 2000, Critical care medicine.

[98]  D. Ostrow,et al.  Substance abuse and HIV infection. , 1994, The Psychiatric clinics of North America.

[99]  A. Nath,et al.  HIV‐1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology , 2009, Glia.

[100]  J. Becker,et al.  Dementia in AIDS patients , 1993, Neurology.

[101]  K. Gupta,et al.  Morphine stimulates vascular endothelial growth factor-like signaling in mouse retinal endothelial cells. , 2006, Current neurovascular research.

[102]  Yangchao Chen,et al.  HIV-1 gp120 primes lymphocytes for opioid-induced, beta-arrestin 2-dependent apoptosis. , 2009, Biochimica et biophysica acta.

[103]  S. Barger,et al.  Pro‐inflammatory and pro‐oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17β‐estradiol , 2001, Journal of neurochemistry.

[104]  R. Donahoe Multiple ways that drug abuse might influence AIDS progression: clues from a monkey model , 2004, Journal of Neuroimmunology.

[105]  H. Balfour,et al.  Enhancement of HIV-1 replication by opiates and cocaine: the cytokine connection. , 1993, Advances in experimental medicine and biology.

[106]  V G Sasseville,et al.  Chemokine expression in simian immunodeficiency virus-induced AIDS encephalitis. , 1996, The American journal of pathology.

[107]  Honghong Yao,et al.  Morphine Induces Expression of Platelet-Derived Growth Factor in Human Brain Microvascular Endothelial Cells: Implication for Vascular Permeability , 2011, PloS one.