Morphine counteracts the antiviral effect of antiretroviral drugs and causes upregulation of p62/SQSTM1 and histone-modifying enzymes in HIV-infected astrocytes

  • Myosotys RodriguezEmail author
  • Jessica Lapierre
  • Chet Raj Ojha
  • Shashank Pawitwar
  • Mohan Kumar Muthu Karuppan
  • Fatah Kashanchi
  • Nazira El-HageEmail author


Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure. The effect of the protease inhibitor, lopinavir, alone or in combination with the protease inhibitor, abacavir, and the integrase inhibitor, raltegravir (LAR), with and without morphine co-exposure was also explored. Exposure with emtricitabine alone or ERA in HIV-infected astrocytes caused a significant decrease in viral replication and attenuated HIV-induced inflammatory molecules, while co-exposure with morphine negated the inhibitory effects of ERA, leading to increased viral replication and inflammatory molecules. Exposure with emtricitabine alone or in combination with morphine caused a significant disruption of mitochondrial membrane integrity. Genetic analysis revealed a significant increase in the expression of p62/SQSTM1 which correlated with an increase in the histone-modifying enzyme, ESCO2, after exposure with ERA alone or in combination with morphine. Furthermore, several histone-modifying enzymes such as CIITA, PRMT8, and HDAC10 were also increased with LAR exposure alone or in combination with morphine. Accumulation of p62/SQSTM1 is indicative of dysfunctional lysosomal fusion. Together with the loss of mitochondrial integrity and epigenetic changes, these effects may lead to enhanced viral titer and inflammatory molecules contributing to the neuropathology associated with HIV.


Antiretroviral drugs Opioid Autophagy Scaffold protein Arginine methyl transferase 



We gratefully acknowledge the support of the National Institutes of Health (NIH)-National Institute on Drug Abuse (NIDA) grants R01 DA036154; R01 DA036154-S1 (Diversity Supplement in support to J.L); R21 DA041287 to N.E.H. We also acknowledge the financial support of Presidential Fellowship provided to C.R.O. by University Graduate School, Florida International University.

Author contributions

M.R. performed and analyzed the experiments shown in Figs. 1, 2, 3, 4, and 5 and Supplementary Figs. S1S2 and wrote the manuscript. J.L. performed and analyzed the experiments shown in Fig. 4a–b, 5a, and Supplementary Fig. 2b and assisted in editing of the manuscript. C.R.O. provided assistance regarding the experiment shown in Fig. 3 and assisted in writing the “Introduction” and “Method” sections. S.P. provided assistance regarding the experiment shown in Fig. 4b. M.K. provided assistance regarding the experiment shown in Supplementary Fig. 2b. F.K. provided technical expertise and assisted in the editing of the manuscript. N.E.-H. designed, conceived, analyzed, and coordinated the study and wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13365_2018_715_MOESM1_ESM.jpg (113 kb)
ESM 1 (JPG 112 kb)
13365_2018_715_MOESM2_ESM.jpg (270 kb)
ESM 2 (JPG 269 kb)


  1. 2008. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet (London, England) 372, 293–299Google Scholar
  2. Akay C, Cooper M, Odeleye A, Jensen BK, White MG, Vassoler F, Gannon PJ, Mankowski J, Dorsey JL, Buch AM, Cross SA, Cook DR, Pena MM, Andersen ES, Christofidou-Solomidou M, Lindl KA, Zink MC, Clements J, Pierce RC, Kolson DL, Jordan-Sciutto KL (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39–53PubMedPubMedCentralCrossRefGoogle Scholar
  3. Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363–1381PubMedPubMedCentralGoogle Scholar
  4. Alcami J, Lain de Lera T, Folgueira L, Pedraza MA, Jacque JM, Bachelerie F, Noriega AR, Hay RT, Harrich D, Gaynor RB et al (1995) Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes. EMBO J 14:1552–1560PubMedPubMedCentralCrossRefGoogle Scholar
  5. Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry Biokhimiia 70:200–214PubMedCrossRefGoogle Scholar
  6. Apostolova N, Gomez-Sucerquia LJ, Gortat A, Blas-Garcia A, Esplugues JV (2011) Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy. Hepatology (Baltimore, Md) 54:1009–1019CrossRefGoogle Scholar
  7. Baloh RH (2008) Mitochondrial dynamics and peripheral neuropathy. Neuroscientist 14:12–18PubMedCrossRefGoogle Scholar
  8. Bertrand L, Toborek M (2015) Dysregulation of endoplasmic reticulum stress and autophagic responses by the antiretroviral drug efavirenz. Mol Pharmacol 88:304–315PubMedPubMedCentralCrossRefGoogle Scholar
  9. Blas-Garcia A, Apostolova N, Ballesteros D, Monleon D, Morales JM, Rocha M, Victor VM, Esplugues JV (2010) Inhibition of mitochondrial function by efavirenz increases lipid content in hepatic cells. Hepatology (Baltimore, Md.) 52:115–125CrossRefGoogle Scholar
  10. Bogoi RN, de Pablo A, Valencia E, Martin-Carbonero L, Moreno V, Vilchez-Rueda HH, Asensi V, Rodriguez R, Toledano V, Rodes B (2018) Expression profiling of chromatin-modifying enzymes and global DNA methylation in CD4+ T cells from patients with chronic HIV infection at different HIV control and progression states. Clin Epigenetics 10:20PubMedPubMedCentralCrossRefGoogle Scholar
  11. Boulanger MC, Liang C, Russell RS, Lin R, Bedford MT, Wainberg MA, Richard S (2005) Methylation of Tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression. J Virol 79:124–131PubMedPubMedCentralCrossRefGoogle Scholar
  12. Brinkman K, Smeitink JA, Romijn JA, Reiss P (1999) Mitochondrial toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet (London, England) 354:1112–1115CrossRefGoogle Scholar
  13. Canizares S, Cherner M, Ellis RJ (2014) HIV and aging: effects on the central nervous system. Semin Neurol 34:27–34PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chandra S, Mondal D, Agrawal KC (2009) HIV-1 protease inhibitor induced oxidative stress suppresses glucose stimulated insulin release: protection with thymoquinone. Exp Biol Med (Maywood, NJ) 234:442–453CrossRefGoogle Scholar
  15. Chang Y, Levy D, Horton JR, Peng J, Zhang X, Gozani O, Cheng X (2011) Structural basis of SETD6-mediated regulation of the NF-kB network via methyl-lysine signaling. Nucleic Acids Res 39:6380–6389PubMedPubMedCentralCrossRefGoogle Scholar
  16. Chen C, Li J, Bot G, Szabo I, Rogers TJ, Liu-Chen LY (2004) Heterodimerization and cross-desensitization between the mu-opioid receptor and the chemokine CCR5 receptor. Eur J Pharmacol 483:175–186PubMedCrossRefGoogle Scholar
  17. Chen L, Jarujaron S, Wu X, Sun L, Zha W, Liang G, Wang X, Gurley EC, Studer EJ, Hylemon PB, Pandak WM Jr, Zhang L, Wang G, Li X, Dent P, Zhou H (2009) HIV protease inhibitor lopinavir-induced TNF-alpha and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages. Biochem Pharmacol 78:70–77PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, Kwon DS, Rychert J, Lian J, Muller MI, Cutler S, McAndrew E, Jessen H, Pereyra F, Rosenberg ES, Altfeld M, Walker BD, Streeck H (2011) HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 85:733–741PubMedCrossRefGoogle Scholar
  19. Choi WS, Palmiter RD, Xia Z (2011) Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model. J Cell Biol 192:873–882PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cohen J, D'Agostino L, Wilson J, Tuzer F, Torres C (2017) Astrocyte senescence and metabolic changes in response to HIV antiretroviral therapy drugs. Front Aging Neurosci 9:281PubMedPubMedCentralCrossRefGoogle Scholar
  21. Decloedt EH, Rosenkranz B, Maartens G, Joska J (2015) Central nervous system penetration of antiretroviral drugs: pharmacokinetic, pharmacodynamic and pharmacogenomic considerations. Clin Pharmacokinet 54:581–598PubMedCrossRefGoogle Scholar
  22. Dever SM, Rodriguez M, Lapierre J, Costin BN, El-Hage N (2015) Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 6:653PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dever SM, Xu R, Fitting S, Knapp PE, Hauser KF (2012) Differential expression and HIV-1 regulation of mu-opioid receptor splice variants across human central nervous system cell types. J Neurovirol 18:181–190PubMedPubMedCentralCrossRefGoogle Scholar
  24. Dodson MW, Guo M (2007) Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson’s disease. Curr Opin Neurobiol 17:331–337PubMedCrossRefGoogle Scholar
  25. Du Y, Wooten MC, Wooten MW (2009) Oxidative damage to the promoter region of SQSTM1/p62 is common to neurodegenerative disease. Neurobiol Dis 35:302–310PubMedPubMedCentralCrossRefGoogle Scholar
  26. El-Hage N, Gurwell JA, Singh IN, Knapp PE, Nath A, Hauser KF (2005) Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia 50:91–106PubMedPubMedCentralCrossRefGoogle Scholar
  27. El-Hage N, Rodriguez M, Dever SM, Masvekar RR, Gewirtz DA, Shacka JJ (2015) HIV-1 and morphine regulation of autophagy in microglia: limited interactions in the context of HIV-1 infection and opioid abuse. J Virol 89:1024–1035PubMedCrossRefGoogle Scholar
  28. Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44PubMedCrossRefGoogle Scholar
  29. Ene L, Duiculescu D, Ruta SM (2011) How much do antiretroviral drugs penetrate into the central nervous system? J Med Life 4:432–439PubMedPubMedCentralGoogle Scholar
  30. Fiume G, Vecchio E, De Laurentiis A, Trimboli F, Palmieri C, Pisano A, Falcone C, Pontoriero M, Rossi A, Scialdone A, Fasanella Masci F, Scala G, Quinto I (2012) Human immunodeficiency virus-1 Tat activates NF-kappaB via physical interaction with IkappaB-alpha and p65. Nucleic Acids Res 40:3548–3562PubMedCrossRefGoogle Scholar
  31. Gangwani MR, Kumar A (2015) Multiple protein kinases via activation of transcription factors NF-kappaB, AP-1 and C/EBP-delta regulate the IL-6/IL-8 production by HIV-1 Vpr in astrocytes. PLoS One 10:e0135633PubMedPubMedCentralCrossRefGoogle Scholar
  32. Giunta B, Ehrhart J, Obregon DF, Lam L, Le L, Jin J, Fernandez F, Tan J, Shytle RD (2011) Antiretroviral medications disrupt microglial phagocytosis of beta-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders. Mol Brain 4:23PubMedPubMedCentralCrossRefGoogle Scholar
  33. Gurwell JA, Nath A, Sun Q, Zhang J, Martin KM, Chen Y, Hauser KF (2001) Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro. Neuroscience 102:555–563PubMedPubMedCentralCrossRefGoogle Scholar
  34. Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B (2011) Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS (London, England) 25:625–633CrossRefGoogle Scholar
  35. Hauser KF, Knapp PE (2014) Interactions of HIV and drugs of abuse: the importance of glia, neural progenitors, and host genetic factors. Int Rev Neurobiol 118:231–313PubMedPubMedCentralCrossRefGoogle Scholar
  36. Hauser KF, Stiene-Martin A, Mattson MP, Elde RP, Ryan SE, Godleske CC (1996) mu-Opioid receptor-induced Ca2+ mobilization and astroglial development: morphine inhibits DNA synthesis and stimulates cellular hypertrophy through a Ca(2+)-dependent mechanism. Brain Res 720:191–203PubMedPubMedCentralCrossRefGoogle Scholar
  37. Invernizzi CF, Xie B, Richard S, Wainberg MA (2006) PRMT6 diminishes HIV-1 Rev binding to and export of viral RNA. Retrovirology 3:93PubMedPubMedCentralCrossRefGoogle Scholar
  38. Iribarne C, Berthou F, Carlhant D, Dreano Y, Picart D, Lohezic F, Riche C (1998) Inhibition of methadone and buprenorphine N-dealkylations by three HIV-1 protease inhibitors. Drug metabolism and disposition: the biological fate of chemicals 26:257–260Google Scholar
  39. Jackson WT (2015) Viruses and the autophagy pathway. Virology 479-480:450–456PubMedPubMedCentralCrossRefGoogle Scholar
  40. Kanazawa S, Okamoto T, Peterlin BM (2000) Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 12:61–70PubMedCrossRefGoogle Scholar
  41. Kline ER, Bassit L, Hernandez-Santiago BI, Detorio MA, Liang B, Kleinhenz DJ, Walp ER, Dikalov S, Jones DP, Schinazi RF, Sutliff RL (2009) Long-term exposure to AZT, but not d4T, increases endothelial cell oxidative stress and mitochondrial dysfunction. Cardiovasc Toxicol 9:1–12PubMedCrossRefGoogle Scholar
  42. Kranick SM, Nath A (2012) Neurologic complications of HIV-1 infection and its treatment in the era of antiretroviral therapy. Continuum (Minneapolis, Minn) 18:1319–1337Google Scholar
  43. Kravcik S, Gallicano K, Roth V, Cassol S, Hawley-Foss N, Badley A, Cameron DW (1999) Cerebrospinal fluid HIV RNA and drug levels with combination ritonavir and saquinavir. J Acquir Immune Defic Syndr (1999) 21:371–375CrossRefGoogle Scholar
  44. Kumar A, Darcis G, Van Lint C, Herbein G (2015) Epigenetic control of HIV-1 post integration latency: implications for therapy. Clin Epigenetics 7:103PubMedPubMedCentralCrossRefGoogle Scholar
  45. Kumar GN, Rodrigues AD, Buko AM, Denissen JF (1996) Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277:423–431PubMedGoogle Scholar
  46. Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. Neuroreport 12:2085–2090PubMedCrossRefGoogle Scholar
  47. Kuusisto E, Salminen A, Alafuzoff I (2002) Early accumulation of p62 in neurofibrillary tangles in Alzheimer’s disease: possible role in tangle formation. Neuropathol Appl Neurobiol 28:228–237PubMedCrossRefGoogle Scholar
  48. Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard JP, Maachi M, Azoulay S, Briggs M, Caron M, Capeau J (2007) Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther 12:489–500PubMedGoogle Scholar
  49. Lahiri CD, Reed-Walker K, Sheth AN, Acosta EP, Vunnava A, Ofotokun I (2016) Cerebrospinal fluid concentrations of tenofovir and emtricitabine in the setting of HIV-1 protease inhibitor-based regimens. J Clin Pharmacol 56:492–496PubMedCrossRefGoogle Scholar
  50. Lapierre J, Rodriguez M, Ojha CR, El-Hage N (2018) Critical role of Beclin1 in HIV Tat and morphine-induced inflammation and calcium release in glial cells from autophagy deficient mouse. J Neuroimmune PharmacolGoogle Scholar
  51. Levy D, Kuo AJ, Chang Y, Schaefer U, Kitson C, Cheung P, Espejo A, Zee BM, Liu CL, Tangsombatvisit S, Tennen RI, Kuo AY, Tanjing S, Cheung R, Chua KF, Utz PJ, Shi X, Prinjha RK, Lee K, Garcia BA, Bedford MT, Tarakhovsky A, Cheng X, Gozani O (2011) Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat Immunol 12:29–36PubMedCrossRefGoogle Scholar
  52. Lohse N, Hansen AB, Pedersen G, Kronborg G, Gerstoft J, Sorensen HT, Vaeth M, Obel N (2007) Survival of persons with and without HIV infection in Denmark, 1995-2005. Ann Intern Med 146:87–95PubMedCrossRefGoogle Scholar
  53. Manda KR, Banerjee A, Banks WA, Ercal N (2011) Highly active antiretroviral therapy drug combination induces oxidative stress and mitochondrial dysfunction in immortalized human blood-brain barrier endothelial cells. Free Radic Biol Med 50:801–810PubMedCrossRefGoogle Scholar
  54. Maubert ME, Pirrone V, Rivera NT, Wigdahl B, Nonnemacher MR (2015) Interaction between tat and drugs of abuse during HIV-1 infection and central nervous system disease. Front Microbiol 6:1512PubMedGoogle Scholar
  55. Melik Parsadaniantz S, Rivat C, Rostene W, Reaux-Le Goazigo A (2015) Opioid and chemokine receptor crosstalk: a promising target for pain therapy? Nat Rev Neurosci 16:69–78PubMedCrossRefGoogle Scholar
  56. Merlin JS, Bulls HW, Vucovich LA, Edelman EJ, Starrels JL (2016) Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review. AIDS Care 28:1506–1515PubMedPubMedCentralCrossRefGoogle Scholar
  57. Moreau K, Luo S, Rubinsztein DC (2010) Cytoprotective roles for autophagy. Curr Opin Cell Biol 22:206–211PubMedPubMedCentralCrossRefGoogle Scholar
  58. Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II interferons in antiviral defense. Science 264:1918–1921PubMedCrossRefGoogle Scholar
  59. Murphy MP (2009) How mitochondria produce reactive oxygen species. The Biochemical journal 417:1–13PubMedCrossRefGoogle Scholar
  60. Nooka S, Ghorpade A (2017) HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses. Cell Death Discovery 3:17061PubMedPubMedCentralCrossRefGoogle Scholar
  61. Osborn L, Kunkel S, Nabel GJ (1989) Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A 86:2336–2340PubMedPubMedCentralCrossRefGoogle Scholar
  62. Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS (2008) Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A 105:3879–3884PubMedPubMedCentralCrossRefGoogle Scholar
  63. Papparella I, Ceolotto G, Berto L, Cavalli M, Bova S, Cargnelli G, Ruga E, Milanesi O, Franco L, Mazzoni M, Petrelli L, Nussdorfer GG, Semplicini A (2007) Vitamin C prevents zidovudine-induced NAD(P)H oxidase activation and hypertension in the rat. Cardiovasc Res 73:432–438PubMedCrossRefGoogle Scholar
  64. Piccinini M, Rinaudo MT, Anselmino A, Buccinna B, Ramondetti C, Dematteis A, Ricotti E, Palmisano L, Mostert M, Tovo PA (2005) The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function. Antiviral Therapy 10:215–223PubMedGoogle Scholar
  65. Pitha PM (2011) Innate antiviral response: role in HIV-1 infection. Viruses 3:1179–1203PubMedPubMedCentralCrossRefGoogle Scholar
  66. Ran X, Ao Z, Trajtman A, Xu W, Kobinger G, Keynan Y, Yao X (2017) HIV-1 envelope glycoprotein stimulates viral transcription and increases the infectivity of the progeny virus through the manipulation of cellular machinery. Sci Rep 7:9487PubMedPubMedCentralCrossRefGoogle Scholar
  67. Rao VR, Ruiz AP, Prasad VR (2014) Viral and cellular factors underlying neuropathogenesis in HIV associated neurocognitive disorders (HAND). AIDS Res Ther 11:13PubMedPubMedCentralCrossRefGoogle Scholar
  68. Robertson K, Liner J, Meeker RB (2012) Antiretroviral neurotoxicity. J Neurovirol 18:388–399PubMedPubMedCentralCrossRefGoogle Scholar
  69. Robertson KR, Su Z, Margolis DM, Krambrink A, Havlir DV, Evans S, Skiest DJ (2010) Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74:1260–1266PubMedPubMedCentralCrossRefGoogle Scholar
  70. Rodriguez M, Lapierre J, Ojha CR, Estrada-Bueno H, Dever SM, Gewirtz DA, Kashanchi F, El-Hage N (2017) Importance of autophagy in mediating human immunodeficiency virus (HIV) and morphine-induced metabolic dysfunction and inflammation in human astrocytes. Viruses 9Google Scholar
  71. Rosca A, Anton G, Ene L, Iancu I, Temereanca A, Achim CL, Ruta SM (2017) Immunoassay and molecular methods to investigate DNA methylation changes in peripheral blood mononuclear cells in HIV infected patients on cART. Journal of immunoassay & immunochemistry 38:299–307CrossRefGoogle Scholar
  72. Samji H, Cescon A, Hogg RS, Modur SP, Althoff KN, Buchacz K, Burchell AN, Cohen M, Gebo KA, Gill MJ, Justice A, Kirk G, Klein MB, Korthuis PT, Martin J, Napravnik S, Rourke SB, Sterling TR, Silverberg MJ, Deeks S, Jacobson LP, Bosch RJ, Kitahata MM, Goedert JJ, Moore R, Gange SJ (2013) Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One 8:e81355PubMedPubMedCentralCrossRefGoogle Scholar
  73. Seibenhener ML, Babu JR, Geetha T, Wong HC, Krishna NR, Wooten MW (2004) Sequestosome 1/p62 is a polyubiquitin chain binding protein involved in ubiquitin proteasome degradation. Mol Cell Biol 24:8055–8068PubMedPubMedCentralCrossRefGoogle Scholar
  74. Shah A, Gangwani MR, Chaudhari NS, Glazyrin A, Bhat HK, Kumar A (2016) Neurotoxicity in the post-HAART era: caution for the antiretroviral therapeutics. Neurotox Res 30:677–697PubMedPubMedCentralCrossRefGoogle Scholar
  75. Squitieri F, Cannella M, Sgarbi G, Maglione V, Falleni A, Lenzi P, Baracca A, Cislaghi G, Saft C, Ragona G, Russo MA, Thompson LM, Solaini G, Fornai F (2006) Severe ultrastructural mitochondrial changes in lymphoblasts homozygous for Huntington disease mutation. Mech Ageing Dev 127:217–220PubMedCrossRefGoogle Scholar
  76. Stiene-Martin A, Hauser KF (1991) Glial growth is regulated by agonists selective for multiple opioid receptor types in vitro. J Neurosci Res 29:538–548PubMedPubMedCentralCrossRefGoogle Scholar
  77. Swingler S, Morris A, Easton A (1994) Tumour necrosis factor alpha and interleukin-1 beta induce specific subunits of NFKB to bind the HIV-1 enhancer: characterisation of transcription factors controlling human immunodeficiency virus type 1 gene expression in neural cells. Biochem Biophys Res Commun 203:623–630PubMedCrossRefGoogle Scholar
  78. Trejbalova K, Kovarova D, Blazkova J, Machala L, Jilich D, Weber J, Kucerova D, Vencalek O, Hirsch I, Hejnar J (2016) Development of 5′ LTR DNA methylation of latent HIV-1 provirus in cell line models and in long-term-infected individuals. Clin Epigenetics 8:19PubMedPubMedCentralCrossRefGoogle Scholar
  79. Vaidya NK, Ribeiro RM, Perelson AS, Kumar A (2016) Modeling the effects of morphine on simian immunodeficiency virus dynamics. PLoS Comput Biol 12:e1005127PubMedPubMedCentralCrossRefGoogle Scholar
  80. Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733PubMedCrossRefGoogle Scholar
  81. Van Duyne R, Easley R, Wu W, Berro R, Pedati C, Klase Z, Kehn-Hall K, Flynn EK, Symer DE, Kashanchi F (2008) Lysine methylation of HIV-1 Tat regulates transcriptional activity of the viral LTR. Retrovirology 5:40PubMedPubMedCentralCrossRefGoogle Scholar
  82. Wang X, Gao Y, Tan J, Devadas K, Ragupathy V, Takeda K, Zhao J, Hewlett I (2012) HIV-1 and HIV-2 infections induce autophagy in Jurkat and CD4+ T cells. Cell Signal 24:1414–1419PubMedCrossRefGoogle Scholar
  83. Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, Casadesus G, Zhu X (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A 105:19318–19323PubMedPubMedCentralCrossRefGoogle Scholar
  84. Wang ZV, Hill JA (2015) Protein quality control and metabolism: bidirectional control in the heart. Cell Metab 21:215–226PubMedPubMedCentralCrossRefGoogle Scholar
  85. Xie B, Invernizzi CF, Richard S, Wainberg MA (2007) Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat interactions with both cyclin T1 and the Tat transactivation region. J Virol 81:4226–4234PubMedPubMedCentralCrossRefGoogle Scholar
  86. Zhang X, Cao R, Liu R, Zhao R, Huang Y, Gurley EC, Hylemon PB, Pandak WM, Wang G, Zhang L, Li X, Zhou H (2014) Reduction of the HIV protease inhibitor-induced ER stress and inflammatory response by raltegravir in macrophages. PLoS One 9:e90856PubMedPubMedCentralCrossRefGoogle Scholar
  87. Zhao L, Zhu Y, Wang D, Chen M, Gao P, Xiao W, Rao G, Wang X, Jin H, Xu L, Sui N, Chen Q (2010) Morphine induces Beclin 1- and ATG5-dependent autophagy in human neuroblastoma SH-SY5Y cells and in the rat hippocampus. Autophagy 6:386–394PubMedCrossRefGoogle Scholar
  88. Zhou D, Spector SA (2008) Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS (London, England) 22:695–699CrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2019

Authors and Affiliations

  • Myosotys Rodriguez
    • 1
    Email author
  • Jessica Lapierre
    • 1
  • Chet Raj Ojha
    • 1
  • Shashank Pawitwar
    • 1
  • Mohan Kumar Muthu Karuppan
    • 1
  • Fatah Kashanchi
    • 2
  • Nazira El-Hage
    • 1
    Email author
  1. 1.Department of Immunology and Nano-medicine, Herbert Wertheim College of MedicineFlorida International UniversityMiamiUSA
  2. 2.Laboratory of Molecular Virology, School of Systems BiologyGeorge Mason UniversityManassasUSA

Personalised recommendations