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24-05-2023 | Human Immunodeficiency Virus

Microglia proliferation underlies synaptic dysfunction in the prefrontal cortex: implications for the pathogenesis of HIV-1-associated neurocognitive and affective alterations

Authors: Hailong Li, Kristen A. McLaurin, Charles F. Mactutus, Rosemarie M. Booze

Published in: Journal of NeuroVirology | Issue 4/2023

Abstract

Microglia, which are productively infected by HIV-1, are critical for brain development and maturation, as well as synaptic plasticity. The pathophysiology of HIV-infected microglia and their role in the pathogenesis of HIV-1-associated neurocognitive and affective alterations, however, remains understudied. Three complementary aims were undertaken to critically address this knowledge gap. First, the expression of HIV-1 mRNA in the dorsolateral prefrontal cortex of postmortem HIV-1 seropositive individuals with HAND was investigated. Utilization of immunostaining and/or RNAscope multiplex fluorescent assays revealed prominent HIV-1 mRNA in microglia of postmortem HIV-1 seropositive individuals with HAND. Second, measures of microglia proliferation and neuronal damage were evaluated in chimeric HIV (EcoHIV) rats. Eight weeks after EcoHIV inoculation, enhanced microglial proliferation was observed in the medial prefrontal cortex (mPFC) of EcoHIV rats, evidenced by an increased number of cells co-localized with both Iba1 + and Ki67 + relative to control animals. Neuronal damage in EcoHIV infected rats was evidenced by pronounced decreases in both synaptophysin and postsynaptic density protein 95 (PSD-95), markers of presynaptic and postsynaptic damage, respectively. Third, regression analyses were conducted to evaluate whether microglia proliferation mechanistically underlies neuronal damage in EcoHIV and control animals. Indeed, microglia proliferation accounted for 42–68.6% of the variance in synaptic dysfunction. Collectively, microglia proliferation induced by chronic HIV-1 viral protein exposure may underlie the profound synaptodendritic alterations in HIV-1. Understanding how microglia are involved in the pathogenesis of HAND and HIV-1-associated affective disorders affords a key target for the development of novel therapeutics.

Akiyama H, Nishimura T, Kondo H, Ikeda K, Hayashi Y, McGeer PL (1994) Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer’s disease and amyotrophic lateral sclerosis. Brain Res 639:171–174. https://doi.org/10.1016/0006-8993(94)91779-5CrossRefPubMed

Akiyoshi R, Wake H, Kato D, Horiuchi H, Ono R, Ikegami A, Haruwaka K, Omori T, Tachibana Y, Moorhouse AJ, Nabekura J (2018) Microglia enhance synapse activity to promote local network synchronization. eNeuro. 5:ENEURO.0088–18.2018. https://doi.org/10.1523/ENEURO.0088-18.2018.

Antonucci F, Turola E, Riganti L, Caleo M, Gabrielli M, Perrotta C, Novellino L, Clementi E, Giussani P, Viani P, Matteoli M, Verderio C (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31:1231–1240. https://doi.org/10.1038/emboj.2011.489CrossRefPubMedPubMedCentral

Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debré P, Leibowitch J (1997) Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277:112–116. https://doi.org/10.1126/science.277.5322.112CrossRefPubMed

Becker BW, Thames AD, Woo E, Castellon SA, Hinkin CH (2011) Longitudinal change in cognitive function and medication adherence in HIV-infected adults. AIDS Behav 15:1888–1894. https://doi.org/10.1007/s10461-011-9924-zCrossRefPubMedPubMedCentral

Berezovskaya O, Maysinger D, Fedoroff S (1995) The hematopoietic cytokine, colony-stimulating factor 1, is also a growth factor in the CNS: A congenital absence of CSF-1 in mice results in abnormal microglial response and increased neuron vulnerability to injury. Int J Dev Neurosci 13:285–299. https://doi.org/10.1016/0736-5748(95)00013-7CrossRefPubMed

Bergamini A, Perno CF, Dini L, Capozzi M, Pesce CD, Ventura L, Cappannoli L, Falasca L, Milanese G, Caliò R, Rocchi G (1994) Macrophage colony-stimulating factor enhances the susceptibility of macrophages to infection by human immunodeficiency virus and reduces the activity of compounds that inhibit virus binding. Blood 84:3405–3412CrossRefPubMed

Brodmann K (1909) Vergleichende Lokalisationslehre der Grosshirnrinde in Inren Prinzipien Dargestellt auf Grund des Zellenbaues. Barth, Germany, Leipzig

Campos LN, Guimarães MDC, Remien RH (2010) Anxiety and depression symptoms as risk factors for non-adherence to antiretroviral therapy in Brazil. AIDS Behav 14:289–299. https://doi.org/10.1007/s10461-008-9435-8CrossRefPubMed

Carr DB, Sesack SR (1996) Hippocampal afferents to the rat prefrontal cortex: Synaptic targets and relation to dopamine terminals. J Comp Neurol 369:1–15. https://doi.org/10.1002/(SICI)1096-9861(19960520)369:1%3c1::AID-CNE1%3e3.0.CO;2-7CrossRefPubMed

Chen X, Nelson CD, Li X, Winters CA, Azzam R, Sousa AA, Leapman RD, Gainer H, Sheng M, Reese TS (2011) PSD-95 is required to sustain the molecular organization of the postsynaptic density. J Neurosci 31:6329–6338. https://doi.org/10.1523/JNEUROSCI.5968-10.2011CrossRefPubMedPubMedCentral

Choudhury ME, Miyanishi K, Takeda H, Islam A, Matsuoka N, Kubo M, Matsumoto S, Kunieda T, Nomoto M, Yano H, Tanaka J (2020) Phagocytic elimination of synapses by microglia during sleep. Glia 68:44–59. https://doi.org/10.1002/glia.23698CrossRefPubMed

Cysique LA, Brew BJ (2019) Comorbid depression and apathy in HIV-associated neurocognitive disorders in the era of chronic HIV infection. Handb Clin Neurol 165:71–82. https://doi.org/10.1016/B978-0-444-64012-3.00006-XCrossRefPubMed

Denton AR, Samaranayake SA, Kirchner KN, Roscoe RF, Berger SN, Harrod SB, Mactutus CF, Hashemi P, Booze RM (2019) Selective monoaminergic and histaminergic circuit dysregulation following long-term HIV-1 protein exposure. J Neurovirol 25:540–550. https://doi.org/10.1007/s13365-019-00754-xCrossRefPubMedPubMedCentral

Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423. https://doi.org/10.1212/WNL.0b013e31828c2e9eCrossRefPubMedPubMedCentral

Edara VV, Ghorpade A, Borgmann K (2020) Insights into the gene expression profiles of active and restricted red/green-HIV+ human astrocytes: Implications for shock or lock therapies in the brain. J Virol 94:e01563-e1619. https://doi.org/10.1128/JVI.01563-19CrossRefPubMedPubMedCentral

Festa LK, Irollo E, Platt BJ, Tian Y, Floresco S, Meucci O (2020) CXCL12-induced rescue of cortical dendritic spines and cognitive flexibility. Elife. 9:e49717. https://doi.org/10.7554/eLife.49717.

Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, Fox MA, Su J, Medina AE, Krahe TE, Knapp PE, Guido W, Hauser KF (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443–453. https://doi.org/10.1016/j.biopsych.2012.09.026CrossRefPubMed

Garvey LJ, Pavese N, Politis M, Ramlackhansingh A, Brooks DJ, Taylor-Robinson SD, Winston A (2014) Increased microglia activation in neurologically asymptomatic HIV-infected patients receiving effective ART. AIDS 28:67–72. https://doi.org/10.1097/01.aids.0000432467.54003.f7CrossRefPubMed

Gelman BB, Nguyen TP (2010) Synaptic proteins linked to HIV-1 infection and immunoproteasome induction: Proteomic analysis of human synaptosomes. J Neuroimmune Pharmacol 5:92–102. https://doi.org/10.1007/s11481-009-9168-0CrossRefPubMed

Gisslén M, Heslegrave A, Veleva E, Yilmaz A, Andersson LM, Hagberg L, Spudich S, Fuchs D, Price RW, Zetterberg H (2018) CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection. Neurol Neuroimmunol Neuroinflamm. 6: e512. https://doi.org/10.1212/NXI.0000000000000512.

Giulian D, Ingeman JE (1988) Colony-stimulating factors as promoters of ameboid microglia. J Neurosci 8:4707–4717. https://doi.org/10.1523/JNEUROSCI.08-12-04707.1988CrossRefPubMedPubMedCentral

Goldman-Rakic PS, Leranth C, Williams SM, Mons N, Geffard M (1989) Dopamine synaptic complex with pyramidal neurons in primate cerebral cortex. Proc Natl Acad Sci USA 86:9015–9019. https://doi.org/10.1073/pnas.86.22.9015CrossRefPubMedPubMedCentral

Gómez-Nicola D, Fransen NL, Suzzi S, Perry VH (2013) Regulation of microglial proliferation during chronic neurodegeneration. J Neurosci 33:2481–2493. https://doi.org/10.1523/JNEUROSCI.4440-12.2013CrossRefPubMedPubMedCentral

Hauser KF, Hahn YK, Adjan VV, Zou S, Buch SK, Nath A, Bruce-Keller AJ, Knapp PE (2009) HIV-1 Tat and morphine have interactive effects on oligodendrocyte survival and morphology. Glia 57:194–206. https://doi.org/10.1002/glia.20746CrossRefPubMedPubMedCentral

Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, CHARTER Groups, HNRC Group (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: Differences in rates, nature, and predictors. J Neurovirol 17:3–16. https://doi.org/10.1007/s13365-010-0006-1CrossRef

Helm MS, Dankovich TM, Mandad S, Rammner B, Jähne S, Salimi V, Koerbs C, Leibrandt R, Urlaub H, Schikorski T, Rizzoli SO (2021) A large-scale nanoscopy and biochemistry analysis of postsynaptic dendritic spines. Nat Neurosci 24:1151–1162. https://doi.org/10.1038/s41593-021-00874-wCrossRefPubMed

Irons DL, Meinhardt T, Allers C, Kuroda MJ, Kim WK (2019) Overexpression and activation of colony-stimulating factor 1 receptor in the SIV/macaque model of HIV infection and neuroHIV. Brain Pathol 29:826–836. https://doi.org/10.1111/bpa.12731CrossRefPubMedPubMedCentral

Jahn R, Schiebler W, Ouimet C, Greengard P (1985) A 38,000-dalton membrane protein (p38) present in synaptic vesicles. Proc Natl Acad Sci USA 82:4137–4141. https://doi.org/10.1073/pnas.82.12.4137CrossRefPubMedPubMedCentral

Jang M, Gould E, Xu J, Kim EJ, Kim JH (2019) Oligodendrocytes regulate presynaptic properties and neurotransmission through BDNF signaling in the mouse brainstem. Elife. 8: e42156. doi: https://doi.org/10.7554/eLife.42156.

Ji K, Akgul G, Wollmuth LP, Tsirka SE (2013) Microglia actively regulate the number of functional synapses. PLoS One. 8:e56293. https://doi.org/10.1371/journal.pone.0056293.

Kalter DC, Nakamura M, Turpin JA, Baca LM, Hoover DL, Dieffenbach C, Ralph P, Gendelman HE, Meltzer MS (1991) Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. J Immunol 146:298–306CrossRefPubMed

Kamat R, Morgan E, Marcotte TD, Badiee J, Maich I, Cherner M, de Almeida S, de Pereira AP, Ribeiro CE, Barbosa F, Atkinson JH, Ellis R, HNRP Group (2013) Implications of apathy and depression for everyday functioning in HIV/AIDS in Brazil. J Affect Disord 150:1069–1075. https://doi.org/10.1016/j.jad.2012.11.040CrossRef

Kamat R, Woods SP, Marcotte TD, Ellis RJ, Grant I, HIV Neurobehavioral Research Program (HNRP) Group (2012) Implications of apathy for everyday functioning outcomes in persons living with HIV infection. Arch Clin Neuropsychol 27:520–531. https://doi.org/10.1093/arclin/acs055CrossRef

Kesner RP, Churchwell JC (2011) An analysis of rat prefrontal cortex in mediated executive function. Neurobiol Learn Mem 96:417–431. https://doi.org/10.1016/j.nlm.2011.07.002CrossRefPubMed

Knight AC, Brill SA, Queen SE, Tarwater PM, Mankowski JL (2018) Increased microglial CSF1R expression in the SIV/Macaque model of HIV CNS disease. J Neuropathol Exp Neurol 77:199–206. https://doi.org/10.1093/jnen/nlx115CrossRefPubMedPubMedCentral

Ko A, Kang G, Hattler JB, Galadima HI, Zhang J, Li Q, Kim WK (2019) Macrophages but not astrocytes harbor HIV DNA in the brains of HIV-1-infected aviremic individuals on suppressive antiretroviral therapy. J Neuroimmune Pharmacol 14:110–119. https://doi.org/10.1007/s11481-018-9809-2CrossRefPubMed

Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233:1089–1093. https://doi.org/10.1126/science.3016903CrossRefPubMed

Kumar AM, Fernandez JB, Singer EJ, Commins D, Waldrop-Valverde D, Ownby RL, Kumar M (2009) Human immunodeficiency virus type 1 in the central nervous system leads to decreased dopamine in different regions of postmortem human brains. J Neurovirol 15:257–274. https://doi.org/10.1080/13550280902973952CrossRefPubMedPubMedCentral

Lentz MR, Degaonkar M, Mohamed MA, Kim H, Conant K, Halpern EF, Sacktor N, Barker PB, Pomper MG (2010) Exploring the relationship of macrophage colony-stimulating factor levels on neuroaxonal metabolism and cognition during chronic human immunodeficiency virus infection. J Neurovirol 16:368–376. https://doi.org/10.3109/13550284.2010.513029CrossRefPubMedPubMedCentral

Levine AJ, Soontornniyomkij V, Achim CL, Masliah E, Gelman BB, Sinsheimer JS, Singer EJ, Moore DJ (2016) Multilevel analysis of neuropathogenesis of neurocognitive impairment in HIV. J Neurovirol 22:431–441. https://doi.org/10.1007/s13365-015-0410-7CrossRefPubMed

Li H, Illenberger JM, McLaurin KA, Mactutus CF, Booze RM (2018) Identification of dopamine D1-alpha receptor within rodent nucleus accumbens by an innovative RNA in situ detection technology. J vis Exp 133:57444. https://doi.org/10.3791/57444CrossRef

Li H, McLaurin KA, Illenberger JM, Mactutus CF, Booze RM (2021a) Microglial HIV-1 expression: Role in HIV-1 associated neurocognitive disorders. Viruses 13:924. https://doi.org/10.3390/v13050924CrossRefPubMedPubMedCentral

Li H, McLaurin KA, Mactutus CF, Booze RM (2020) Ballistic labeling of pyramidal neurons in brain slices and in primary cell culture. J Vis Exp. 158. https://doi.org/10.3791/60989

Li H, McLaurin KA, Mactutus, CF, Booze RM (2021c) A rat model of EcoHIV brain infection. J Vis Exp. 167. https://doi.org/10.3791/62137

Lim TK, Ruthazer ES (2021) Microglial trogocytosis and the complement system regulate axonal pruning in vivo. Elife. 10:e62167. https://doi.org/10.7554/eLife.62167

McLaurin KA, Li H, Booze RM, Mactutus CF (2019) Disruption of timing: NeuroHIV progression in the post-cART era. Sci Rep 9:827. https://doi.org/10.1038/s41598-018-36822-1CrossRefPubMedPubMedCentral

McLaurin KA, Li H, Mactutus CF, Harrod SB, Booze RM (2022) Disrupted decision-making: EcoHIV inoculation in cocaine dependent rats. Int J Mol Sci 23:9100. https://doi.org/10.3390/ijms23169100CrossRefPubMedPubMedCentral

Miyamoto A, Wake H, Ishikawa AW, Eto K, Shibata K, Murakoshi H, Koizumi S, Moorhouse AJ, Yoshimura Y, Nabekura J (2016) Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun 7:12540. https://doi.org/10.1038/ncomms12540CrossRefPubMedPubMedCentral

Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I, HNRC Group (2006) Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20:879–887. https://doi.org/10.1097/01.aids.0000218552.69834.00CrossRef

Murthy VN, De Camili P (2003) Cell biology of the presynaptic terminal. Annu Rev Neurosci 26:701–728. https://doi.org/10.1146/annurev.neuro.26.041002.131445CrossRefPubMed

Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318. https://doi.org/10.1126/science.1110647CrossRefPubMed

Panos SE, Del Re AC, Thames AD, Arentsen TJ, Patel SM, Castellon SA, Singer EJ, Hinkin CH (2014) The impact of neurobehavioral features on medication adherence in HIV: Evidence from longitudinal models. AIDS Care 26:79–86. https://doi.org/10.1080/09540121.2013.802275CrossRefPubMed

Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458. https://doi.org/10.1126/science.1202529CrossRefPubMed

Papouin T, Dunphy J, Tolman M, Foley JC, Haydon PG (2017) Astrocytic control of synaptic function. Philos Trans R Soc Lond B Biol Sci 372:20160154. https://doi.org/10.1098/rstb.2016.0154CrossRefPubMedPubMedCentral

Polazzi E, Monti B (2010) Microglia and neuroprotection: From in vitro studies to therapeutic applications. Prog Neurobiol 92:293–315. https://doi.org/10.1016/j.pneurobio.2010.06.009CrossRefPubMed

Raghuraman R, Karthikeyan A, Wei WL, Dheen ST, Sajikumar S (2019) Activation of microglia in acute hippocampal slices affects activity-dependent long-term potentiation and synaptic tagging and capture in area CA1. Neurobiol Learn Mem. 163:107039. https://doi.org/10.1016/j.nlm.2019.107039.

Raivich G, Moreno-Flores MT, Möller JC, Kreutzberg GW (1994) Inhibition of posttraumatic microglial proliferation in a genetic model of macrophage colony-stimulating factor deficiency in the mouse. Eur J Neurosci 6:1615–1618. https://doi.org/10.1111/j.1460-9568.1994.tb00552.xCrossRefPubMed

Roscoe RF, Mactutus CF, Booze RM (2014) HIV-1 transgenic female rat: Synaptodendritic alterations of medium spiny neurons in the nucleus accumbens. J Neuroimmune Pharmacol 9:642–653. https://doi.org/10.1007/s11481-014-9555-zCrossRefPubMedPubMedCentral

Rose JE, Woolsey CN (1949) Organization of the mammalian thalamus and its relationships to the cerebral cortex. Electroencephalogr Clin Neurophysiol 1:391–403CrossRefPubMed

Rubin LH, Sacktor N, Creighton J, Du Y, Endres CJ, Pomper MG, Coughlin JM (2018) Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy. AIDS 32:1661–1667. https://doi.org/10.1097/QAD.0000000000001858CrossRefPubMed

Schaeffer DJ, Hori Y, Gilbert KM, Gati JS, Menon RS, Everling S (2020) Divergence of rodent and primate medial frontal cortex functional connectivity. Proc Natl Acad Sci USA 117:21681–21689. https://doi.org/10.1073/pnas.2003181117CrossRefPubMedPubMedCentral

Speidell A, Asuni GP, Wakulski R, Mocchetti I (2020) Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum. Brain Behav Immun 89:371–379. https://doi.org/10.1016/j.bbi.2020.07.023CrossRefPubMedPubMedCentral

Squarzoni P, Oller G, Hoeffel G, Pont-Lexica L, Rostaing P, Low D, Bessis A, Ginhoux F, Garel S (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–1279. https://doi.org/10.1016/j.celrep.2014.07.042CrossRefPubMed

Stanley ER, Heard PM (1977) Factors regulating macrophage production and growth. Purification and some properties of the colony stimulating factor from medium conditioned by mouse L cells. J Biol Chem 252:4305–4312CrossRefPubMed

Torres L, Danver J, Ji K, Miyauchi JT, Chen D, Anderson ME, West BL, Robinson JK, Tsirka SE (2016) Dynamic microglial modulation of spatial learning and social behavior. Brain Behav Immun 55:6–16. https://doi.org/10.1016/j.bbi.2015.09.001CrossRefPubMed

Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:31000527. https://doi.org/10.1371/journal.pbio.1000527CrossRef

Tremblay ME, Zettel ML, Ison JR, Allen PD, Majewska AK (2012) Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60:541–558. https://doi.org/10.1002/glia.22287CrossRefPubMedPubMedCentral

Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17. https://doi.org/10.1016/j.bbr.2003.09.028CrossRefPubMed

Vance DE, Wadley VG, Crowe MG, Raper JL, Ball KK (2011) Cognitive and everyday functioning in older and younger adults with and without HIV. Clin Gerontol 34:413–426. https://doi.org/10.1080/07317115.2011.588545CrossRefPubMedPubMedCentral

Veenstra M, León-Rivera R, Li M, Gama L, Clements JE, Berman JW (2017) Mechanisms of CNS viral seeding by HIV+ CD14+ CD16+ monocytes Establishment and reseeding of viral reservoirs contributing to HIV-associated neurocognitive disorders. mBio 8:e01280–17. https://doi.org/10.1128/mBio.01280-17.

Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980. https://doi.org/10.1523/JNEUROSCI.4363-08.2009CrossRefPubMedPubMedCentral

Walker DG, Tang TM, Lue LF (2017) Studies on colony stimulating factor receptor-1 and ligands colony stimulating factor-1 and interleukin-34 in Alzheimer’s disease brains and human microglia. Front Aging Neurosci 9:244. https://doi.org/10.3389/fnagi.2017.00244CrossRefPubMedPubMedCentral

Wallet C, De Rovere M, Van Assche J, Daouad F, De Wit S, Gautier V, Mallon PWG, Marcello A, Van Lint C, Rohr O, Schwartz C (2019) Microglial cells: The main HIV-1 reservoir in the brain. Front Cell Infect Microbiol 9:362. https://doi.org/10.3389/fcimb.2019.00362CrossRefPubMedPubMedCentral

Wang F, Flanagan J, Su N, Wang LC, Bui S, Nielson A, Wu X, Vo HT, Ma XJ, Luo Y (2012) RNAscope: A novel in situ RNA analysis platform for formalin-fixed paraffin-embedded tissues. J Mol Diagn 14(1):22–29. PMID: 22166544. https://doi.org/10.1016/j.jmoldx.2011.08.002

Wang Y, Liu M, Lu Q, Farrell M, Lappin JM, Shi J, Lu L, Bao Y (2020) Global prevalence and burden of HIV-associated neurocognitive disorder: A meta-analysis. Neurology 95:e2610–e2621. https://doi.org/10.1212/WNL.0000000000010752CrossRefPubMed

Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, Exiga M, Vadisiute A, Raggioli A, Schertel A, Schwab Y, Gross CT (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 9:1228. https://doi.org/10.1038/s41467-018-03566-5CrossRefPubMedPubMedCentral

Weiss JJ, Calvi R, Naganawa M, Toyonaga T, Farhadian SF, Chintanaphol M, Chiarella J, Zheng MQ, Ropchan J, Huang Y, Pietrzak RH, Carson RE, Spudich S (2021) Preliminary in vivo evidence of reduced synaptic density in human immunodeficiency virus (HIV) despite antiretroviral therapy. Clin Infect Dis 73:1404–1411. https://doi.org/10.1093/cid/ciab484CrossRefPubMedPubMedCentral

Whitney JB, Hill AL, Sanisetty S, Penaloza-MacMaster P, Liu J, Shetty M, Parenteau L, Cabral C, Shields J, Blackmore S, Smith JY, Brinkman AL, Peter LE, Mathew SI, Smith KM, Borducchi EN, Rosenbloom DIS, Lewis MG, Hattersley J, Li B, Hesselgesser J, Beleziunas R, Robb ML, Kim JH, Michael NL, Barouch DH (2014) Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512:74–77. https://doi.org/10.1038/nature13594CrossRefPubMedPubMedCentral

Wiedenmann B, Franke WW (1985) Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 41:1017–1028. https://doi.org/10.1016/s0092-8674(85)80082-9CrossRefPubMed

Zenebe Y, Necho M, Yimam W, Akele B (2022) Worldwide occurrence of HIV-associated neurocognitive disorders and its associated factors: A systematic review and meta-analysis. Front Psych 13: 814362. https://doi.org/10.3389/fpsyt.2022.814362.

Zou S, Fuss B, Fitting S, Hahn YK, Hauser KF, Knapp PE (2015) Oligodendrocytes are targets of HIV-1 Tat: NMDA and AMPA receptor-mediated effects on survival and development. J Neurosci 35:11384–11398. https://doi.org/10.1523/JNEUROSCI.4740-14.2015CrossRefPubMedPubMedCentral

Title: Microglia proliferation underlies synaptic dysfunction in the prefrontal cortex: implications for the pathogenesis of HIV-1-associated neurocognitive and affective alterations
Authors: Hailong Li
Kristen A. McLaurin
Charles F. Mactutus
Rosemarie M. Booze
Publication date: 24-05-2023
Publisher: Springer International Publishing
Keyword: Human Immunodeficiency Virus
Published in: Journal of NeuroVirology / Issue 4/2023
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-023-01147-x

At a glance: The STEP trials

Springer Medicine

Microglia proliferation underlies synaptic dysfunction in the prefrontal cortex: implications for the pathogenesis of HIV-1-associated neurocognitive and affective alterations

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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