Abstract
Human immunodeficiency virus (HIV)-infected people's livelihoods are gradually being prolonged with the use of combined antiretroviral therapy (ART). Conversely, despite viral suppression by ART, the symptoms of HIV-associated neurocognitive disorder (HAND) endure. HAND persists because ART cannot really permanently confiscate the virus from the body. HAND encompasses a variety of conditions based on clinical presentation and severity level, comprising asymptomatic neurocognitive impairment, moderate neurocognitive disorder, and HIV-associated dementia. During the early stages of HIV infection, inflammation compromises the blood–brain barrier, allowing toxic virus, infected monocytes, macrophages, T-lymphocytes, and cellular products from the bloodstream to enter the brain and eventually the entire central nervous system. Since there are no resident T-lymphocytes in the brain, the virus will live for decades in macrophages and astrocytes, establishing a reservoir of infection. The HIV proteins then inflame neurons both directly and indirectly. The purpose of this review is to provide a synopsis of the effects of these proteins on the central nervous system and conceptualize avenues to be considered in mitigating HAND. We used bioinformatics repositories extensively to simulate the transcription factors that bind to the promoter of the HIV-1 protein and possibly could be used as a target to circumvent HIV-associated neurocognitive disorders. In the same vein, a protein–protein interaction complex was also deduced from a Search Tool for the Retrieval of Interacting Genes. In conclusion, this provides an alternative strategy that could be used to avert HAND.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
Not applicable.
Abbreviations
- AIDS:
-
Acquired immune deficiency syndrome
- ANI:
-
Asymptomatic neurocognitive impairment
- ART:
-
Antiretroviral therapy
- CNS:
-
Central nervous system
- CSF:
-
Cerebral spinal fluid
- ENV:
-
Envelope
- EPD:
-
Eukaryotic promoter database
- ERK:
-
Extracellular signal-regulated kinase ½
- GAG:
-
Group-specific antigen
- gp120:
-
Glycoprotein 120
- HAART:
-
Highly active antiretroviral therapy
- HAD:
-
HIV-associated dementia
- HAND:
-
HIV-associated neurocognitive disorders
- HIV:
-
Human immunodeficiency virus
- LTR:
-
HIV long terminal repeat
- MAPK:
-
Mitogen-activated kinase
- METH:
-
Methamphetamine
- MND:
-
Mild neurocognitive disorder
- Nef:
-
Negative regulatory factor
- NMDAR:
-
N-methyl-D-aspartate receptor
- POL:
-
DNA polymerase
- ProBDNF:
-
Pro-brain-derived neurotrophic factor
- PPI:
-
Protein–protein interaction
- P2X:
-
Purinergic receptor 2X
- P75NTR:
-
Neurotrophin receptor P75
- ROS:
-
Reactive oxygen species
- STRING:
-
Search tool for the retrieval of interacting genes
- Tat:
-
Trans-activating regulatory protein
- TUBB3:
-
Tubulin β-3
- TrkA:
-
Tropomyosin-related kinase A
- UNAIDS:
-
United Nations Program on HIV/AIDS
- Vpr:
-
Viral protein R
- WHO:
-
Word Health Organization
References
Abassi M, Morawski BM, Nakigozi G et al (2017) Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda. J Neurovirol 23:369–375. https://doi.org/10.1007/s13365-016-0505-9
Abers MS, Shandera WX, Kass JS (2014) Neurological and psychiatric adverse effects of antiretroviral drugs. CNS Drugs 28:131–145. https://doi.org/10.1007/s40263-013-0132-4
Aksenov MY, Aksenova MV, Mactutus CF, Booze RM (2012) D1/NMDA receptors and concurrent methamphetamine+ HIV-1 Tat neurotoxicity. J Neuroimmune Pharmacol 7:599–608. https://doi.org/10.1007/s11481-012-9362-3
Alirezaei M, Watry DD, Flynn CF et al (2007) Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci 27:11047–11055. https://doi.org/10.1523/JNEUROSCI.2733-07.2007
Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27:86–92. https://doi.org/10.1055/s-2006-956759
Anthony IC, Bell JE (2008) The neuropathology of HIV/AIDS. Int Rev Psychiatry 20:15–24. https://doi.org/10.1080/09540260701862037
Antinori A, Giancola ML, Grisetti S et al (2002) Factors influencing virological response to antiretroviral drugs in cerebrospinal fluid of advanced HIV-1-infected patients. AIDS 16:1867–1876. https://doi.org/10.1097/00002030-200209270-00003
Antinori A, Arendt G, Becker JT et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789–1799. https://doi.org/10.1212/01.WNL.0000287431.88658.8b
Athanasios A, Charalampos V, Vasileios T, Ashraf GM (2017) Protein-protein interaction (PPI) network: recent advances in drug discovery. Curr Drug Metab 18:5–10. https://doi.org/10.2174/138920021801170119204832
Avdoshina V, Biggio F, Palchik G et al (2010) Morphine induces the release of CCL5 from astrocytes: potential neuroprotective mechanism against the HIV protein gp120. Glia 58:1630–1639. https://doi.org/10.1002/glia.21035
Bachis A, Avdoshina V, Zecca L et al (2012) Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J Neurosci 32:9477–9484. https://doi.org/10.1523/JNEUROSCI.0865-12.2012
Bachis A, Wenzel E, Boelk A et al (2016) The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice. Neurobiol Aging 46:160–168. https://doi.org/10.1016/j.neurobiolaging.2016.07.001
Báez-Mendoza R, Schultz W (2013) The role of the striatum in social behavior. Front Neurosci 7:233. https://doi.org/10.3389/fnins.2013.00233
Bagetta G, Corasaniti MT, Berliocchi L et al (1995) HIV-1 gp120 produces DNA fragmentation in the cerebral cortex of rat. Biochem Biophys Res Commun 211:130–136. https://doi.org/10.1006/bbrc.1995.1787
Bansal AK, Mactutus CF, Nath A et al (2000) Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res 879:42–49. https://doi.org/10.1016/s0006-8993(00)02725-6
Barradas-Bautista D, Rosell M, Pallara C, Fernández-Recio J (2018) Structural prediction of protein-protein interactions by docking: application to biomedical problems. Adv Protein Chem Struct Biol 110:203–249. https://doi.org/10.1016/bs.apcsb.2017.06.003
Belmadani A, Zou JY, Schipma MJ et al (2001) Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+-mediated neurotoxicity. Neuroscience 104:769–781. https://doi.org/10.1016/s0306-4522(01)00139-7
Bertrand L, Toborek M (2015) Dysregulation of endoplasmic reticulum stress and autophagic responses by the antiretroviral drug Efavirenz. Mol Pharmacol 88:304–315. https://doi.org/10.1124/mol.115.098590
Bertrand L, Velichkovska M, Toborek M (2021) Cerebral vascular toxicity of antiretroviral therapy. J Neuroimmune Pharmacol 16:74–89. https://doi.org/10.1007/s11481-019-09858-x
Bingham R, Ahmed N, Rangi P et al (2011) HIV encephalitis despite suppressed viraemia: a case of compartmentalized viral escape. Int J STD AIDS 22:608–609. https://doi.org/10.1258/ijsa.2011.010507
Bocedi A, Notaril S, Narciso P et al (2004) Binding of anti-HIV drugs to human serum albumin. IUBMB Life 56:609–614. https://doi.org/10.1080/15216540400016286
Boddiger D (2005) Metamphetamine use linked to rising HIV transmission. Lancet 365:1217–1218
Bonavia R, Bajetto A, Barbero S et al (2001) HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. Biochem Biophys Res Commun 288:301–308. https://doi.org/10.1006/bbrc.2001.5743
Bozzelli PL, Yin T, Avdoshina V et al (2019) HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling. Glia 67:1719–1729. https://doi.org/10.1002/glia.23642
Brew BJ, Barnes SL (2019) The impact of HIV central nervous system persistence on pathogenesis. AIDS 33(Suppl 2):S113–S121. https://doi.org/10.1097/QAD.0000000000002251
Brown KR, Jurisica I (2007) Unequal evolutionary conservation of human protein interactions in interologous networks. Genome Biol 8:R95. https://doi.org/10.1186/gb-2007-8-5-r95
Burkhard K, Shapiro P (2010) Use of inhibitors in the study of MAP kinases. Methods Mol Biolc 661:107–122. https://doi.org/10.1007/978-1-60761-795-2_6
Butters N, Grant I, Haxby J et al (1990) Assessment of AIDS-related cognitive changes: recommendations of the NIMH Workshop on neuropsychological assessment approaches. J Clin Exp Neuropsychol 12:963–978. https://doi.org/10.1080/01688639008401035
Catela C, Shin MM, Dasen JS (2015) Assembly and function of spinal circuits for motor control. Annu Rev Cell Dev Biol 31:669–698. https://doi.org/10.1146/annurev-cellbio-100814-125155
CDC (2021) About HIV/AIDS | HIV Basics | HIV/AIDS | CDC. In: CDC. https://www.cdc.gov/hiv/basics/whatishiv.html. Accessed 26 May 2021
Chang L, Wang G-J, Volkow ND et al (2008) Decreased brain dopamine transporters are related to cognitive deficits in HIV patients with or without cocaine abuse. Neuroimage 42:869–878. https://doi.org/10.1016/j.neuroimage.2008.05.011
Chen L, Liu J, Xu C et al (2011a) HIV-1gp120 induces neuronal apoptosis through enhancement of 4-aminopyridine-senstive outward K+ currents. PLoS ONE 6:e25994. https://doi.org/10.1371/journal.pone.0025994
Chen X, Kirby LG, Palma J et al (2011b) The effect of gp120 on morphine’s antinociceptive and neurophysiological actions. Brain Behav Immun 25:1434–1443. https://doi.org/10.1016/j.bbi.2011.04.014
Cheney L, Guzik H, Macaluso FP et al (2020) HIV Nef and antiretroviral therapy have an inhibitory effect on autophagy in human astrocytes that may contribute to HIV-associated neurocognitive disorders. Cells. https://doi.org/10.3390/cells9061426
Cheung R, Ravyn V, Wang L et al (2008) Signaling mechanism of HIV-1 gp120 and virion-induced IL-1beta release in primary human macrophages. J Immunol 180:6675–6684. https://doi.org/10.4049/jimmunol.180.10.6675
Choe W, Volsky DJ, Potash MJ (2001) Induction of rapid and extensive beta-chemokine synthesis in macrophages by human immunodeficiency virus type 1 and gp120, independently of their coreceptor phenotype. J Virol 75:10738–10745. https://doi.org/10.1128/JVI.75.22.10738-10745.2001
Cirino TJ, Harden SW, McLaughlin JP, Frazier CJ (2020) Region-specific effects of HIV-1 Tat on intrinsic electrophysiological properties of pyramidal neurons in mouse prefrontal cortex and hippocampus. J Neurophysiol 123:1332–1341. https://doi.org/10.1152/jn.00029.2020
Clark RE, Broadbent NJ, Squire LR (2007) The hippocampus and spatial memory: findings with a novel modification of the water maze. J Neurosci 27:6647–6654. https://doi.org/10.1523/JNEUROSCI.0913-07.2007
Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13:976–986. https://doi.org/10.1016/S1473-3099(13)70269-X
Cohen EA, Terwilliger EF, Jalinoos Y et al (1990) Identification of HIV-1 vpr product and function. J Acquir Immune Defic Syndr 3:11–18
Cohen RA, Harezlak J, Schifitto G et al (2010) Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era. J Neurovirol 16:25–32. https://doi.org/10.3109/13550280903552420
Collins MA, Neafsey EJ, Zou JY (2000) HIV-I gpI20 neurotoxicity in brain cultures is prevented by moderate ethanol pretreatment. NeuroReport 11:1219–1222. https://doi.org/10.1097/00001756-200004270-00015
Crowe SM, McGrath MS, Elbeik T et al (1989) Comparative assessment of antiretrovirals in human monocyte-macrophages and lymphoid cell lines acutely and chronically infected with the human immunodeficiency virus. J Med Virol 29:176–180. https://doi.org/10.1002/jmv.1890290306
Cysique LAJ, Maruff P, Brew BJ (2004) Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch Neurol 61:1699–1704. https://doi.org/10.1001/archneur.61.11.1699
Czub S, Koutsilieri E, Sopper S et al (2001) Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs. Acta Neuropathol 101:85–91. https://doi.org/10.1007/s004010000313
Daugherty MD, Liu B, Frankel AD (2010) Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat Struct Mol Biol 17:1337–1342. https://doi.org/10.1038/nsmb.1902
De Marco A, Dans PD, Knezevich A et al (2010) Subcellular localization of the interaction between the human immunodeficiency virus transactivator Tat and the nucleosome assembly protein 1. Amino Acids 38:1583–1593. https://doi.org/10.1007/s00726-009-0378-9
del Palacio M, Alvarez S, Muñoz-Fernández MÁ (2012) HIV-1 infection and neurocognitive impairment in the current era. Rev Med Virol 22:33–45. https://doi.org/10.1002/rmv.711
Del Puerto A, Wandosell F, Garrido JJ (2013) Neuronal and glial purinergic receptors functions in neuron development and brain disease. Front Cell Neurosci 7:197. https://doi.org/10.3389/fncel.2013.00197
Dheen ST, Kaur C, Ling E-A (2007) Microglial activation and its implications in the brain diseases. Curr Med Chem 14:1189–1197. https://doi.org/10.2174/092986707780597961
Di Marzio P, Choe S, Ebright M et al (1995) Mutational analysis of cell cycle arrest, nuclear localization and virion packaging of human immunodeficiency virus type 1 Vpr. J Virol 69:7909–7916. https://doi.org/10.1128/JVI.69.12.7909-7916.1995
Dore GJ, McDonald A, Li Y et al (2003) Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 17:1539–1545. https://doi.org/10.1097/00002030-200307040-00015
Dreos R, Ambrosini G, Périer RC, Bucher P (2015) The eukaryotic promoter database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res 43:D92–D96. https://doi.org/10.1093/nar/gku1111
Dreos R, Ambrosini G, Bucher P (2016) Influence of rotational nucleosome positioning on transcription start site selection in animal promoters. PLoS Comput Biol 12:e1005144. https://doi.org/10.1371/journal.pcbi.1005144
Dreos R, Ambrosini G, Groux R et al (2017) The eukaryotic promoter database in its 30th year: focus on non-vertebrate organisms. Nucleic Acids Res 45:D51–D55. https://doi.org/10.1093/nar/gkw1069
Egger M, May M, Chêne G et al (2002) Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 360:119–129. https://doi.org/10.1016/s0140-6736(02)09411-4
El-Baba RM, Schury MP (2020) Neuroanatomy, frontal cortex. StatPearls Publishing, Treasure Island
Elbirt D, Mahlab-Guri K, Bezalel-Rosenberg S et al (2015) HIV-associated neurocognitive disorders (HAND). IMAJ 17:54–59
El-Hage N, Podhaizer EM, Sturgill J, Hauser KF (2011) Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 Tat, gp120, and morphine. Immunol Invest 40:498–522. https://doi.org/10.3109/08820139.2011.561904
Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44. https://doi.org/10.1038/nrn2040
Ellis RJ, Rosario D, Clifford DB et al (2010) Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the Charter Study. Arch Neurol 67:552–558. https://doi.org/10.1001/archneurol.2010.76
Ellis RJ, Badiee J, Vaida F et al (2011) CD4 nadir is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS 25:1747–1751. https://doi.org/10.1097/QAD.0b013e32834a40cd
Emerman M (1996) HIV-1, Vpr and the cell cycle. Curr Biol 6:1096–1103. https://doi.org/10.1016/s0960-9822(02)00676-0
Eugenin EA, King JE, Nath A et al (2007) HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci USA 104:3438–3443. https://doi.org/10.1073/pnas.0611699104
Eugenin EA, King JE, Hazleton JE et al (2011) Differences in NMDA receptor expression during human development determine the response of neurons to HIV-tat-mediated neurotoxicity. Neurotox Res 19:138–148. https://doi.org/10.1007/s12640-010-9150-x
Everall IP, Hansen LA, Masliah E (2005) The shifting patterns of HIV encephalitis neuropathology. Neurotox Res 8:51–61. https://doi.org/10.1007/BF03033819
Feng Y, Wang Q, Wang T (2017) Drug target protein-protein interaction networks: a systematic perspective. Biomed Res Int 2017:1289259. https://doi.org/10.1155/2017/1289259
Fitting S, Booze RM, Mactutus CF (2008) Neonatal intrahippocampal injection of the HIV-1 proteins gp120 and Tat: differential effects on behavior and the relationship to stereological hippocampal measures. Brain Res 1232:139–154. https://doi.org/10.1016/j.brainres.2008.07.032
Fitting S, Booze RM, Hasselrot U, Mactutus CF (2010) Dose-dependent long-term effects of Tat in the rat hippocampal formation: a design-based stereological study. Hippocampus 20:469–480. https://doi.org/10.1002/hipo.20648
Fitting S, Ignatowska-Jankowska BM, Bull C et al (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiat 73:443–453. https://doi.org/10.1016/j.biopsych.2012.09.026
Fitting S, Booze RM, Mactutus CF (2015) HIV-1 proteins, Tat and gp120, target the developing dopamine system. Curr HIV Res 13:21–42. https://doi.org/10.2174/1570162x13666150121110731
Fornes O, Castro-Mondragon JA, Khan A et al (2020) JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 48:D87–D92. https://doi.org/10.1093/nar/gkz1001
Franke H, Sauer C, Rudolph C et al (2009) P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo. Glia 57:1031–1045. https://doi.org/10.1002/glia.20827
Freed EO (2001) HIV-1 replication. Somat Cell Mol Genet 26:13–33. https://doi.org/10.1023/A:1021070512287
Galicia O, Sánchez-Alavez M, Méndez Díaz M et al (2002) HIV glycoprotein 120: possible etiological agent of AIDS-associated dementia. Revista de Investigacion Clinica; Organo del Hospital de Enfermedades de la Nutricion 54:437–452
Gallo R, Wong-Staal F, Montagnier L et al (1988) HIV/HTLV gene nomenclature. Nature 333:504
Gibbons JM, Marno KM, Pike R et al (2020) HIV-1 accessory protein Vpr interacts with REAF/RPRD2 to mitigate its antiviral activity. J Virol. https://doi.org/10.1128/JVI.01591-19
Giuliani E, Vassena L, Galardi S et al (2018) Dual regulation of L-selectin (CD62L) by HIV-1: enhanced expression by Vpr in contrast with cell-surface down-modulation by Nef and Vpu. Virology 523:121–128. https://doi.org/10.1016/j.virol.2018.07.031
Godai K, Takahashi K, Kashiwagi Y et al (2019) Ryanodine receptor to mitochondrial reactive oxygen species pathway plays an important role in chronic human immunodeficiency virus gp120MN-induced neuropathic pain in rats. Anesth Analg 129:276–286. https://doi.org/10.1213/ANE.0000000000003916
Guha D, Nagilla P, Redinger C et al (2012) Neuronal apoptosis by HIV-1 Vpr: contribution of proinflammatory molecular networks from infected target cells. J Neuroinflammation 9:138. https://doi.org/10.1186/1742-2094-9-138
Guo L, Xing Y, Pan R et al (2013) Curcumin protects microglia and primary rat cortical neurons against HIV-1 gp120-mediated inflammation and apoptosis. PLoS ONE 8:e70565. https://doi.org/10.1371/journal.pone.0070565
Gurwell JA, Nath A, Sun Q et al (2001) Synergistic neurotoxicity of opioids and human immunodeficiency virus-1 Tat protein in striatal neurons in vitro. Neuroscience 102:555–563. https://doi.org/10.1016/s0306-4522(00)00461-9
Hahn YK, Vo P, Fitting S et al (2010) Beta-chemokine production by neural and glial progenitor cells is enhanced by HIV-1 Tat: effects on microglial migration. J Neurochem 114:97–109. https://doi.org/10.1111/j.1471-4159.2010.06744.x
Hallenberger S, Bosch V, Angliker H et al (1992) Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature 360:358–361. https://doi.org/10.1038/360358a0
Hanna Z, Kay DG, Rebai N et al (1998) Nef harbors a major determinant of pathogenicity for an AIDS-like disease induced by HIV-1 in transgenic mice. Cell 95:163–175. https://doi.org/10.1016/s0092-8674(00)81748-1
Harricharan R, Thaver V, Russell VA, Daniels WMU (2015) Tat-induced histopathological alterations mediate hippocampus-associated behavioural impairments in rats. Behav Brain Funct 11:3. https://doi.org/10.1186/s12993-014-0047-3
Harris GJ, Codori AM, Lewis RF et al (1999) Reduced basal ganglia blood flow and volume in pre-symptomatic, gene-tested persons at-risk for Huntington’s disease. Brain 122:1667–1678. https://doi.org/10.1093/brain/122.9.1667
He N, Liu M, Hsu J et al (2010) HIV-1 Tat and host AFF4 recruit two transcription elongation factors into a bifunctional complex for coordinated activation of HIV-1 transcription. Mol Cell 38:428–438. https://doi.org/10.1016/j.molcel.2010.04.013
He X, Yang W, Zeng Z et al (2020) NLRP3-dependent pyroptosis is required for HIV-1 gp120-induced neuropathology. Cell Mol Immunol 17:283–299. https://doi.org/10.1038/s41423-019-0260-y
Heaton RK, Clifford DB, Franklin DRJ et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: Charter Study. Neurology 75:2087–2096. https://doi.org/10.1212/WNL.0b013e318200d727
Herbein G, Gras G, Khan KA, Abbas W (2010) Macrophage signaling in HIV-1 infection. Retrovirology 7:34. https://doi.org/10.1186/1742-4690-7-34
Herzberg U, Sagen J (2001) Peripheral nerve exposure to HIV viral envelope protein gp120 induces neuropathic pain and spinal gliosis. J Neuroimmunol 116:29–39. https://doi.org/10.1016/s0165-5728(01)00288-0
Honeycutt JB, Wahl A, Baker C et al (2016) Macrophages sustain HIV replication in vivo independently of T cells. J Clin Investig 126:1353–1366. https://doi.org/10.1172/JCI84456
Imp BM, Rubin LH, Tien PC et al (2017) Monocyte activation is associated with worse cognitive performance in HIV-infected women with virologic suppression. J Infect Dis 215:114–121. https://doi.org/10.1093/infdis/jiw506
Israel SM, Hassanzadeh-Behbahani S, Turkeltaub PE et al (2019) Different roles of frontal versus striatal atrophy in HIV-associated neurocognitive disorders. Hum Brain Mapp 40:3010–3026. https://doi.org/10.1002/hbm.24577
Janssen RS (1992) Epidemiology of human immunodeficiency virus infection and the neurologic complications of the infection. Semin Neurol 12:10–17. https://doi.org/10.1055/s-2008-1041152
Jones KA (1993) Tat and the HIV-1 promoter. Curr Opin Cell Biol 5:461–468. https://doi.org/10.1016/0955-0674(93)90012-f
Joska JA, Gouse H, Paul RH et al (2010) Does highly active antiretroviral therapy improve neurocognitive function? A systematic review. J Neurovirol 16:101–114. https://doi.org/10.3109/13550281003682513
Kanmogne GD, Kennedy RC, Grammas P (2002) HIV-1 gp120 proteins and gp160 peptides are toxic to brain endothelial cells and neurons: possible pathway for HIV entry into the brain and HIV-associated dementia. J Neuropathol Exp Neurol 61:992–1000. https://doi.org/10.1093/jnen/61.11.992
Kaplan DR, Miller FD (2003) Axon growth inhibition: signals from the p75 neurotrophin receptor. Nat Neurosci 6:435–436
Karimi A, Shojaei A, Tehrani P (2017) Mechanical properties of the human spinal cord under the compressive loading. J Chem Neuroanat 86:15–18. https://doi.org/10.1016/j.jchemneu.2017.07.004
Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA 96:8212–8216. https://doi.org/10.1073/pnas.96.14.8212
Kaul M, Ma Q, Medders KE et al (2007) HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection. Cell Death Differ 14:296–305. https://doi.org/10.1038/sj.cdd.4402006
Kesby JP, Markou A, Semenova S (2016) The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice. Neuropharmacology 109:205–215. https://doi.org/10.1016/j.neuropharm.2016.06.011
Kestler HW 3rd, Ringler DJ, Mori K et al (1991) Importance of the nef gene for maintenance of high virus loads and for development of AIDS. Cell 65:651–662. https://doi.org/10.1016/0092-8674(91)90097-i
Khan MB, Lang MJ, Huang M-B et al (2016) Nef exosomes isolated from the plasma of individuals with HIV-associated dementia (HAD) can induce Aβ(1–42) secretion in SH-SY5Y neural cells. J Neurovirol 22:179–190. https://doi.org/10.1007/s13365-015-0383-6
Langford TD, Letendre SL, Marcotte TD et al (2002) Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16:1019–1029. https://doi.org/10.1097/00002030-200205030-00008
Le LT, Spudich SS (2016) HIV-associated neurologic disorders and central nervous system opportunistic infections in HIV. Semin Neurol 36:373–381. https://doi.org/10.1055/s-0036-1585454
Ledergerber B, Furrer H, Rickenbach M et al (2007) Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis 45:111–119. https://doi.org/10.1086/518619
Levin SN, Lyons JL (2018) HIV and spinal cord disease. Handb Clin Neurol 152:213–227. https://doi.org/10.1016/B978-0-444-63849-6.00017-7
Liner KJ 2nd, Ro MJ, Robertson KR (2010) HIV, antiretroviral therapies, and the brain. Curr HIV/AIDS Rep 7:85–91. https://doi.org/10.1007/s11904-010-0042-8
Liu X, Shah A, Gangwani MR et al (2014) HIV-1 Nef induces CCL5 production in astrocytes through p38-MAPK and PI3K/Akt pathway and utilizes NF-kB, CEBP and AP-1 transcription factors. Sci Rep 4:4450. https://doi.org/10.1038/srep04450
Liu Z, Zang Y, Qiao L et al (2016) ASPP2 involvement in p53-mediated HIV-1 envelope glycoprotein gp120 neurotoxicity in mice cerebrocortical neurons. Sci Rep 6:33378. https://doi.org/10.1038/srep33378
Liu S, Lam MA, Sial A et al (2018) Fluid outflow in the rat spinal cord: the role of perivascular and paravascular pathways. Fluids Barriers CNS 15:13. https://doi.org/10.1186/s12987-018-0098-1
Liu J, Xu C, Chen L et al (2012) Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity. Cell Death Dis 3:e254. https://doi.org/10.1038/cddis.2011.140
Lu YL, Spearman P, Ratner L (1993) Human immunodeficiency virus type 1 viral protein R localization in infected cells and virions. J Virol 67:6542–6550. https://doi.org/10.1128/JVI.67.11.6542-6550.1993
Lu H, Zhou Q, He J et al (2020) Recent advances in the development of protein-protein interactions modulators: mechanisms and clinical trials. Signal Transduct Target Ther 5:213. https://doi.org/10.1038/s41392-020-00315-3
Malim MH, Hauber J, Le SY et al (1989) The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA. Nature 338:254–257. https://doi.org/10.1038/338254a0
Mamik MK, Hui E, Branton WG et al (2017) HIV-1 viral protein R activates NLRP3 Inflammasome in microglia: implications for HIV-1 associated neuroinflammation. J Neuroimmune Pharmacol 12:233–248. https://doi.org/10.1007/s11481-016-9708-3
Maragos WF, Tillman P, Jones M et al (2003) Neuronal injury in hippocampus with human immunodeficiency virus transactivating protein, Tat. Neuroscience 117:43–53. https://doi.org/10.1016/s0306-4522(02)00713-3
Marino J, Maubert ME, Mele AR et al (2020) Functional impact of HIV-1 Tat on cells of the CNS and its role in HAND. Cell Mol Life Sci 77:5079–5099. https://doi.org/10.1007/s00018-020-03561-4
McArthur JC, Hoover DR, Bacellar H et al (1993) Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 43:2245–2252. https://doi.org/10.1212/wnl.43.11.2245
McArthur JC, Brew BJ, Nath A (2005) Neurological complications of HIV infection. Lancet Neurol 4:543–555. https://doi.org/10.1016/S1474-4422(05)70165-4
Medders KE, Sejbuk NE, Maung R et al (2010) Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. J Immunol 185:4883–4895. https://doi.org/10.4049/jimmunol.0902535
Mirza A, Rathore MH (2012) Human immunodeficiency virus and the central nervous system. Semin Pediatr Neurol 19:119–123. https://doi.org/10.1016/j.spen.2012.02.007
Mocroft A, Ledergerber B, Katlama C et al (2003) Decline in the AIDS and death rates in the EuroSIDA Study: an observational study. Lancet 362:22–29. https://doi.org/10.1016/s0140-6736(03)13802-0
Moran LM, Booze RM, Mactutus CF (2014) Modeling deficits in attention, inhibition, and flexibility in HAND. J Neuroimmune Pharmacol 9:508–521. https://doi.org/10.1007/s11481-014-9539-z
Muesing MA, Smith DH, Cabradilla CD et al (1985) Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus. Nature 313:450–458. https://doi.org/10.1038/313450a0
Na H, Acharjee S, Jones G et al (2011) Interactions between human immunodeficiency virus (HIV)-1 Vpr expression and innate immunity influence neurovirulence. Retrovirology 8:44. https://doi.org/10.1186/1742-4690-8-44
Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl):S193–S198. https://doi.org/10.1086/344528
Nath A, Berger J (2004) HIV dementia. Curr Treat Options Neurol 6:139–151. https://doi.org/10.1007/s11940-004-0023-6
Nzwalo H, Añón RP, Àguas MJ (2012) Acute encephalitis as initial presentation of primary HIV infection. BMJ Case Rep. https://doi.org/10.1136/bcr.03.2012.5970
Ortiz G, Koch S, Romano JG et al (2007) Mechanisms of ischemic stroke in HIV-infected patients. Neurology 68:1257–1261. https://doi.org/10.1212/01.wnl.0000259515.45579.1e
Peluso MJ, Meyerhoff DJ, Price RW et al (2013) Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis 207:1703–1712. https://doi.org/10.1093/infdis/jit088
Petito CK, Navia BA, Cho ES et al (1985) Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 312:874–879. https://doi.org/10.1056/NEJM198504043121402
Pikov V, McCreery DB (2004) Mapping of spinal cord circuits controlling the bladder and external urethral sphincter functions in the rabbit. Neurourol Urodyn 23:172–179. https://doi.org/10.1002/nau.20008
Price RW, Spudich S (2008) Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197(Suppl):S294-306. https://doi.org/10.1086/533419
Purohit V, Rapaka R, Shurtleff D (2011) Drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. Mol Neurobiol 44:102–110. https://doi.org/10.1007/s12035-011-8195-z
Rabbani G, Baig MH, Ahmad K, Choi I (2018) Protein-protein Interactions and their role in various diseases and their prediction techniques. Curr Protein Pept Sci 19:948–957. https://doi.org/10.2174/1389203718666170828122927
Rackstraw S, Meadway J, Bingham J et al (2006) An emerging severe leukoencephalopathy: is it due to HIV disease or highly active antiretroviral therapy? Int J STD AIDS 17:205–207. https://doi.org/10.1258/095646206775809222
Rahimian P, He JJ (2016) HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflamm 13:247. https://doi.org/10.1186/s12974-016-0716-2
Rao VS, Srinivas K, Sujini GN, Kumar GNS (2014) Protein-protein interaction detection: methods and analysis. Int J Proteomics 2014:147648. https://doi.org/10.1155/2014/147648
Regina K (2018) Central nervous system complications in HIV: overview, pathophysiology, CNS manifestations. In: Mediscape. https://emedicine.medscape.com/article/1167008-overview. Accessed 8 Sep 2021
Resnick L, Berger JR, Shapshak P, Tourtellotte WW (1988) Early penetration of the blood-brain-barrier by HIV. Neurology 38:9–14. https://doi.org/10.1212/wnl.38.1.9
Rezaie A, Parmar R, Rendon C, Zell SC (2020) HIV-associated vacuolar myelopathy: a rare initial presentation of HIV. SAGE Open Med Case Rep. https://doi.org/10.1177/2050313X20945562
Robichaud GA, Poulin L (2000) HIV type 1 nef gene inhibits tumor necrosis factor alpha-induced apoptosis and promotes cell proliferation through the action of MAPK and JNK in human glial cells. AIDS Res Hum Retrovir 16:1959–1965. https://doi.org/10.1089/088922200750054684
Roca-Bayerri C, Robertson F, Pyle A et al (2020) Mitochondrial DNA damage and brain ageing in HIV. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa984
Rom I, Deshmane SL, Mukerjee R et al (2009) HIV-1 Vpr deregulates calcium secretion in neural cells. Brain Res 1275:81–86. https://doi.org/10.1016/j.brainres.2009.03.024
Ru W, Tang S-J (2016) HIV-1 gp120Bal down-regulates phosphorylated NMDA receptor subunit 1 in cortical neurons via activation of glutamate and chemokine receptors. J Neuroimmune Pharmacol 11:182–191. https://doi.org/10.1007/s11481-015-9644-7
Ru W, Tang S-J (2017) HIV-associated synaptic degeneration. Mol Brain 10:40. https://doi.org/10.1186/s13041-017-0321-z
Rubenstein JLR (2011) Annual research review: development of the cerebral cortex: implications for neurodevelopmental disorders. J Child Psychol Psychiatry 52:339–355. https://doi.org/10.1111/j.1469-7610.2010.02307.x
Sacktor N (2002) The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 8(Suppl 2):115–121. https://doi.org/10.1080/13550280290101094
Sacktor N, Lyles RH, Skolasky R et al (2001) HIV-associated neurologic disease incidence changes: multicenter AIDS Cohort Study, 1990–1998. Neurology 56:257–260. https://doi.org/10.1212/wnl.56.2.257
Sacktor N, McDermott MP, Marder K et al (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neurovirol 8:136–142. https://doi.org/10.1080/13550280290049615
Samikkannu T, Rao KVK, Salam AAA et al (2015) HIV subtypes B and C gp120 and methamphetamine interaction: dopaminergic system implicates differential neuronal toxicity. Sci Rep 5:11130. https://doi.org/10.1038/srep11130
Sanchez AB, Varano GP, de Rozieres CM et al (2016) Antiretrovirals, methamphetamine, and HIV-1 envelope protein gp120 compromise neuronal energy homeostasis in association with various degrees of synaptic and neuritic damage. Antimicrob Agents Chemother 60:168–179. https://doi.org/10.1128/AAC.01632-15
Saylor D, Dickens AM, Sacktor N et al (2016) HIV-associated neurocognitive disorder–pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248. https://doi.org/10.1038/nrneurol.2016.27
Schrier RD, Hong S, Crescini M et al (2015) Cerebrospinal fluid (CSF) CD8+ T-cells that express interferon-gamma contribute to HIV associated neurocognitive disorders (HAND). PLoS ONE 10:e0116526. https://doi.org/10.1371/journal.pone.0116526
Shah A, Kumar A (2016) HIV-1 gp120-mediated mitochondrial dysfunction and HIV-associated neurological disorders. Neurotox Res 30:135–137. https://doi.org/10.1007/s12640-016-9619-3
Shin AH, Thayer SA (2013) Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures. Mol Cell Neurosci 54:22–29. https://doi.org/10.1016/j.mcn.2012.12.005
Sidtis JJ, Gatsonis C, Price RW et al (1993) Zidovudine treatment of the AIDS dementia complex: results of a placebo-controlled trial. AIDS Clinical Trials Group. Ann Neurol 33:343–349. https://doi.org/10.1002/ana.410330403
Smith PD, Crocker SJ, Jackson-Lewis V et al (2003) Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci USA 100:13650–13655. https://doi.org/10.1073/pnas.2232515100
Soontornniyomkij V, Umlauf A, Soontornniyomkij B et al (2018) Association of antiretroviral therapy with brain aging changes among HIV-infected adults. AIDS 32:2005–2015. https://doi.org/10.1097/QAD.0000000000001927
Sorrell ME, Hauser KF (2014) Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. J Neuroimmune Pharmacol 9:233–244. https://doi.org/10.1007/s11481-013-9507-z
Suh J, Sinclair E, Peterson J et al (2014) Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection. J Neuroinflammation 11:199. https://doi.org/10.1186/s12974-014-0199-y
Sutherland RJ, Weisend MP, Mumby D et al (2001) Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks. Hippocampus 11:27–42
Szabò I, Zoratti M, Gulbins E (2010) Contribution of voltage-gated potassium channels to the regulation of apoptosis. FEBS Lett 584:2049–2056. https://doi.org/10.1016/j.febslet.2010.01.038
Szklarczyk D, Franceschini A, Wyder S et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43:D447–D452. https://doi.org/10.1093/nar/gku1003
Szklarczyk D, Morris JH, Cook H et al (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45:D362–D368. https://doi.org/10.1093/nar/gkw937
Szklarczyk D, Gable AL, Lyon D et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–D613. https://doi.org/10.1093/nar/gky1131
Takakusaki K (2013) Neurophysiology of gait: from the spinal cord to the frontal lobe. Mov Disord 28:1483–1491. https://doi.org/10.1002/mds.25669
Teng HK, Teng KK, Lee R et al (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 25:5455–5463. https://doi.org/10.1523/JNEUROSCI.5123-04.2005
Thaney VE, O’Neill AM, Hoefer MM et al (2017) IFNβ protects neurons from damage in a murine model of HIV-1 associated brain injury. Sci Rep 7:46514. https://doi.org/10.1038/srep46514
The Human Memory (2020) Corpus Striatum | Functions, Location, Structure, Disease & Summary. In: The Human Memory. https://human-memory.net/corpus-striatum/#:~:text=Corpus Striatum%2C also called striatum%2C is an important,of basal ganglia%2C it controls many important functions. Accessed 3 Jul 2021
Thompson PM, Dutton RA, Hayashi KM et al (2005) Thinning of the cerebral cortex visualized in HIV/AIDS reflects CD4+ T lymphocyte decline. Proc Natl Acad Sci USA 102:15647–15652. https://doi.org/10.1073/pnas.0502548102
Torres L, Noel RJJ (2014) Astrocytic expression of HIV-1 viral protein R in the hippocampus causes chromatolysis, synaptic loss and memory impairment. J Neuroinflammation 11:53. https://doi.org/10.1186/1742-2094-11-53
UNAIDS (2021) Global HIV & AIDS statistics—fact sheet | UNAIDS. In: UNAIDS. https://www.unaids.org/en/resources/fact-sheet. Accessed 8 Sep 2021
Valcour V, Chalermchai T, Sailasuta N et al (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275–282. https://doi.org/10.1093/infdis/jis326
van Dijkman SC, de Jager NCB, Rauwé WM et al (2018) Effect of age-related factors on the pharmacokinetics of lamotrigine and potential implications for maintenance dose optimisation in future clinical trials. Clin Pharmacokinet 57:1039–1053. https://doi.org/10.1007/s40262-017-0614-5
Verduzco-Mendoza A, Carrillo-Mora P, Avila-Luna A et al (2021) Role of the dopaminergic system in the striatum and its association with functional recovery or rehabilitation after brain injury. Front Neurosci 15:693404. https://doi.org/10.3389/fnins.2021.693404
Verma S, Estanislao L, Simpson D (2005) HIV-associated neuropathic pain: epidemiology, pathophysiology and management. CNS Drugs 19:325–334. https://doi.org/10.2165/00023210-200519040-00005
Volk T, Hensel M, Schuster H, Kox WJ (2000) Secretion of MCP-1 and IL-6 by cytokine stimulated production of reactive oxygen species in endothelial cells. Mol Cell Biochem 206:105–112. https://doi.org/10.1023/a:1007059616914
von Mering C, Jensen LJ, Snel B et al (2005) String: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res 33:D433–D437. https://doi.org/10.1093/nar/gki005
Wang H, Cao J, Yu J, Gao D (2007) Role of PI3-K/Akt pathway and its effect on glial cell line-derived neurotrophic factor in midbrain dopamine cells. Acta Pharmacol Sin 28:166–172. https://doi.org/10.1111/j.1745-7254.2007.00494.x
Wang Q-Y, Lu J, Liao S-M et al (2013) Unconventional interaction forces in protein and protein-ligand systems and their impacts to drug design. Curr Top Med Chem 13:1141–1151. https://doi.org/10.2174/15680266113139990002
Wang Y, Liu M, Lu Q et al (2020) Global prevalence and burden of HIV-associated neurocognitive disorder: a meta-analysis. Neurology 95:e2610–e2621. https://doi.org/10.1212/WNL.0000000000010752
Wang J, Zhang Y, Xu Q et al (2017) Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells. Oncotarget 8:18082–18094. https://doi.org/10.18632/oncotarget.14993
Wei J, Hou J, Su B et al (2020) The prevalence of frascati-criteria-based hiv-associated neurocognitive disorder (HAND) in HIV-infected adults: a systematic review and meta-analysis. Front Neurol 11:581346
WHO (2020) HIV/AIDS. In: WHO. https://www.who.int/news-room/fact-sheets/detail/hiv-aids. Accessed 26 May 2021
WHO (2021) Why the HIV epidemic is not over. https://www.who.int/news-room/spotlight/why-the-hiv-epidemic-is-not-over. Accessed 26 Jun 2021
Wible CG (2013) Hippocampal physiology, structure and function and the neuroscience of schizophrenia: a unified account of declarative memory deficits, working memory deficits and schizophrenic symptoms. Behav Sci 3:298–315. https://doi.org/10.3390/bs3020298
Wuchty S, Barabási A-L, Ferdig MT (2006) Stable evolutionary signal in a yeast protein interaction network. BMC Evol Biol 6:8. https://doi.org/10.1186/1471-2148-6-8
Wuliji N, Mandell MJ, Lunt JM, Merando A (2019) HIV-associated vacuolar myelopathy and HIV-associated dementia as the initial manifestation of HIV/AIDS. Case Rep Infect Dis 2019:3842425
Xu Y, Kulkosky J, Acheampong E et al (2004) HIV-1-mediated apoptosis of neuronal cells: proximal molecular mechanisms of HIV-1-induced encephalopathy. Proc Natl Acad Sci USA 101:7070–7075. https://doi.org/10.1073/pnas.0304859101
Yang J, Hu D, Xia J et al (2013) Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology. J Neuroimmune Pharmacol 8:921–933. https://doi.org/10.1007/s11481-013-9468-2
Yarandi SS, Duggan MR, Sariyer IK (2020) Emerging role of Nef in the development of HIV associated neurological disorders. J Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-020-09964-1
Yilmaz A, Svennerholm B, Hagberg L, Gisslén M (2006) Cerebrospinal fluid viral loads reach less than 2 copies/ml in HIV-1-infected patients with effective antiretroviral therapy. Antivir Ther 11:833–837
Zeng X-F, Li Q, Li J et al (2018) HIV-1 Tat and methamphetamine co-induced oxidative cellular injury is mitigated by N-acetylcysteine amide (NACA) through rectifying mTOR signaling. Toxicol Lett 299:159–171. https://doi.org/10.1016/j.toxlet.2018.09.009
Zhou BY, Liu Y, Kim B et al (2004) Astrocyte activation and dysfunction and neuron death by HIV-1 Tat expression in astrocytes. Mol Cell Neurosci 27:296–305. https://doi.org/10.1016/j.mcn.2004.07.003
Zhou Y, Liu J, Xiong H (2017) HIV-1 glycoprotein 120 enhancement of N-methyl-D-aspartate NMDA receptor-mediated excitatory postsynaptic currents: implications for HIV-1-associated neural injury. J Neuroimmune Pharmacol 12:314–326. https://doi.org/10.1007/s11481-016-9719-0
Zhou F, Liu X, Gao L et al (2019) HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways. J Neuroinflammation 16:71. https://doi.org/10.1186/s12974-019-1466-8
Zou S, Fitting S, Hahn Y-K et al (2011) Morphine potentiates neurodegenerative effects of HIV-1 Tat through actions at μ-opioid receptor-expressing glia. Brain 134:3616–3631. https://doi.org/10.1093/brain/awr281
Zulu SS, Simola N, Mabandla MV, Daniels WMU (2018) Effect of long-term administration of antiretroviral drugs (Tenofovir and Nevirapine) on neuroinflammation and neuroplasticity in mouse hippocampi. J Chem Neuroanat 94:86–92. https://doi.org/10.1016/j.jchemneu.2018.10.003
Zuo C, Liang S, Wang Z et al (2009) Enriching protein-protein and functional interaction networks in human embryonic stem cells. Int J Mol Med 23:811–819. https://doi.org/10.3892/ijmm_00000197
Acknowledgements
Not applicable
Funding
This work was supported by the National Natural Science Foundation of China [NSFC8187108], the Key Research and Development Program of Hunan Province [2018SK2090] and the Natural Science Foundation of Hunan—Youth Foundation Project [2020JJ5701].
Author information
Authors and Affiliations
Contributions
AS conceived the idea and drafted the manuscript. ZG and PAK reviewed articles, provided an extended insight on molecular immunology and neuroscience along with writing and critically revision of the entire manuscript. PAK provided bioinformatics insights and simulation. PP, DFHM, AL, RZ, ZH, LL, MZ, LS, SL, ML, DeC, and DaC revised the final manuscript. HJ and HY contributed to the designing, implementation and finalization of the manuscript for submission. All authors have read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that there is no competing interest in the publication of this review.
Ethical Approval
Not applicable.
Informed Consent
Not applicable.
Consent for Publication
All authors have agreed for publication of this work.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Saro, A., Gao, Z., Kambey, P.A. et al. HIV-Proteins-Associated CNS Neurotoxicity, Their Mediators, and Alternative Treatments. Cell Mol Neurobiol 42, 2553–2569 (2022). https://doi.org/10.1007/s10571-021-01151-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-021-01151-x