Abstract
Microglia and macrophages are the main non-neuronal subsets of myeloid origin in the brain, and are critical regulators in neurodegenerative disorders, where inflammation is a key factor. Since HIV infection results in neurological perturbations that are similar to those in aging, we examined microglial and infiltrating myeloid subsets in the search for changes that might resemble the ones in aging. For that, we used the SIV infection in rhesus macaques to model neuroAIDS. We found that Sirt-1, a molecule that impacts survival and health in many models, was decreased in cell preparations containing a majority of microglia and myeloid cells from the brain of infected macaques. The role of Sirt-1 in neuroAIDS is unknown. We hypothesized that Sirt-1 silencing functions are affected by SIV. Mapping of Sirt-1 binding patterns to chromatin revealed that the number of Sirt-1-bound genes was 29.6% increased in myeloid cells from infected animals with mild or no detectable neuropathology, but 51% was decreased in severe neuropathology, compared to controls. Importantly, Sirt-1-bound genes in controls largely participate in neuroinflammation. Promoters of type I IFN pathway genes IRF7, IRF1, IFIT1, and AIF1, showed Sirt-1 binding in controls, which was consistently lost after infection, together with higher transcription. Loss of Sirt-1 binding was also found in brains from old uninfected animals, suggesting a common regulation. The role of Sirt-1 in regulating these inflammatory markers was confirmed in two different in vitro models, where Sirt-1 blockage modulated IRF7, IRF1 and AIF1 levels both in human macrophage cell lines and in human blood-derived monocytes from various normal donors, stimulated with a TLR9 agonist. Our data suggests that Sirt-1-inflammatory gene silencing is disturbed by SIV infection, resembling aging in brains. These findings may impact our knowledge on the contribution of myeloid subsets to the neurological consequences of HIV infection, aggravated and overlapping with the aging process.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baruch K et al (2014) Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346:89–93. https://doi.org/10.1126/science.1252945
Blander G, Olejnik J, Krzymanska-Olejnik E, McDonagh T, Haigis M, Yaffe MB, Guarente L (2005) SIRT1 shows no substrate specificity in vitro. J Biol Chem 280:9780–9785. https://doi.org/10.1074/jbc.M414080200
Boily G et al (2008) SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS One 3:e1759. https://doi.org/10.1371/journal.pone.0001759
Boily G, He XH, Pearce B, Jardine K, McBurney MW (2009) SirT1-null mice develop tumors at normal rates but are poorly protected by resveratrol. Oncogene 28:2882–2893. https://doi.org/10.1038/onc.2009.147
Bortell N, Morsey B, Basova L, Fox HS, Marcondes MC (2015) Phenotypic changes in the brain of SIV-infected macaques exposed to methamphetamine parallel macrophage activation patterns induced by the common gamma-chain cytokine system. Front Microbiol 6:900. https://doi.org/10.3389/fmicb.2015.00900
Bosch-Presegue L, Vaquero A (2011) The dual role of sirtuins in cancer. Genes Cancer 2:648–662. https://doi.org/10.1177/1947601911417862
Bosch-Presegue L, Vaquero A (2013) Sirtuins in stress response: guardians of the genome. Oncogene. https://doi.org/10.1038/onc.2013.344
Burudi EM, Marcondes MC, Watry DD, Zandonatti M, Taffe MA, Fox HS (2002) Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains. J Virol 76:12233–12241
Calvano SE et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437:1032–1037. https://doi.org/10.1038/nature03985
Carvallo L, Lopez L, Fajardo JE, Jaureguiberry-Bravo M, Fiser A, Berman JW (2017) HIV-tat regulates macrophage gene expression in the context of neuroAIDS. PLoS One 12:e0179882. https://doi.org/10.1371/journal.pone.0179882
Castro V et al (2016) Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. FASEB Journal : official publication of the Federation of American Societies for Experimental Biology 30:1234–1246. https://doi.org/10.1096/fj.15-277673
Cerami EG, Bader GD, Gross BE, Sander C (2006) cPath: open source software for collecting, storing, and querying biological pathways. BMC Bioinf 7:497. https://doi.org/10.1186/1471-2105-7-497
Cerami EG et al (2011) Pathway commons, a web resource for biological pathway data. Nucleic Acids Res 39:D685–D690. https://doi.org/10.1093/nar/gkq1039
Chaudhuri AD, Yelamanchili SV, Marcondes MC, Fox HS (2013) Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27:3720–3729. https://doi.org/10.1096/fj.13-232678
Chen J et al (2005) SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 280:40364–40374. https://doi.org/10.1074/jbc.M509329200
Cho SH et al (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta. J Neurosci Official J Soc Neurosci 35:807–818. https://doi.org/10.1523/JNEUROSCI.2939-14.2015
Circu ML, Aw TY (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radic Biol Med 48:749–762. https://doi.org/10.1016/j.freeradbiomed.2009.12.022
Cline MS et al (2007) Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2:2366–2382. https://doi.org/10.1038/nprot.2007.324
Cosgrove MS, Bever K, Avalos JL, Muhammad S, Zhang X, Wolberger C (2006) The structural basis of sirtuin substrate affinity. Biochemistry 45:7511–7521. https://doi.org/10.1021/bi0526332
Dang W et al (2009) Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459:802–807. https://doi.org/10.1038/nature08085
Danish HH, Goyal S, Taunk NK, Wu H, Moran MS, Haffty BG (2013) Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) as a prognostic marker for local control in T1-2 N0 breast cancer treated with breast-conserving surgery and radiation therapy (BCS + RT). Breast J 19:231–239. https://doi.org/10.1111/tbj.12097
Fleige S, Pfaffl MW (2006) RNA integrity and the effect on the real-time qRT-PCR performance. Mol Asp Med 27:126–139. https://doi.org/10.1016/j.mam.2005.12.003
Fleige S, Walf V, Huch S, Prgomet C, Sehm J, Pfaffl MW (2006) Comparison of relative mRNA quantification models and the impact of RNA integrity in quantitative real-time RT-PCR. Biotechnol Lett 28:1601–1613. https://doi.org/10.1007/s10529-006-9127-2
Fraga MF et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400. https://doi.org/10.1038/ng1531
Franceschi C (2007) Inflammaging as a major characteristic of old people: can it be prevented or cured? Nutr Rev 65:S173–S176
Franceschi C et al (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105. https://doi.org/10.1016/j.mad.2006.11.016
Frankel S, Rogina B (2006) Sir2, caloric restriction and aging. Pathol Biol 54:55–57. https://doi.org/10.1016/j.patbio.2005.04.003
Gabay O et al (2013) Sirt1-deficient mice exhibit an altered cartilage phenotype. Joint Bone Spine 80:613–620. https://doi.org/10.1016/j.jbspin.2013.01.001
Gagarina V, Gabay O, Dvir-Ginzberg M, Lee EJ, Brady JK, Quon MJ, Hall DJ (2010) SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin-like growth factor receptor pathway. Arthritis Rheum 62:1383–1392. https://doi.org/10.1002/art.27369
Garske AL, Denu JM (2006) SIRT1 top 40 hits: use of one-bead, one-compound acetyl-peptide libraries and quantum dots to probe deacetylase specificity. Biochemistry 45:94–101. https://doi.org/10.1021/bi052015l
Gersten M, Alirezaei M, Marcondes MC, Flynn C, Ravasi T, Ideker T, Fox HS (2009) An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction. J Neurosc Official J Soc Neurosci 29:12467–12476. https://doi.org/10.1523/JNEUROSCI.3180-09.2009
Ginhoux F et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. https://doi.org/10.1126/science.1194637
Greter M, Merad M (2013) Regulation of microglia development and homeostasis. Glia 61:121–127. https://doi.org/10.1002/glia.22408
Greter M, Lelios I, Croxford AL (2015) Microglia versus myeloid cell nomenclature during brain inflammation. Front Immunol 6:249. https://doi.org/10.3389/fimmu.2015.00249
Haigis MC, Guarente LP (2006) Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. Genes Dev 20:2913–2921. https://doi.org/10.1101/gad.1467506
Herranz D, Serrano M (2010a) Impact of Sirt1 on mammalian aging. Aging 2:315–316
Herranz D, Serrano M (2010b) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10:819–823. https://doi.org/10.1038/nrc2962
Honda K et al (2005a) Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction. Nature 434:1035–1040. https://doi.org/10.1038/nature03547
Honda K et al (2005b) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434:772–777. https://doi.org/10.1038/nature03464
Honda K, Yanai H, Takaoka A, Taniguchi T (2005c) Regulation of the type I IFN induction: a current view. Int Immunol 17:1367–1378. https://doi.org/10.1093/intimm/dxh318
Huang DW et al (2007) DAVID bioinformatics resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 35:W169–W175. https://doi.org/10.1093/nar/gkm415
Huang d W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57. https://doi.org/10.1038/nprot.2008.211
Hui DJ, Bhasker CR, Merrick WC, Sen GC (2003) Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi. J Biol Chem 278:39477–39482. https://doi.org/10.1074/jbc.M305038200
Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000a) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403:795–800. https://doi.org/10.1038/35001622
Imai S, Johnson FB, Marciniak RA, McVey M, Park PU, Guarente L (2000b) Sir2: an NAD-dependent histone deacetylase that connects chromatin silencing, metabolism, and aging. Cold Spring Harb Symp Quant Biol 65:297–302
Jamonnak N, Hirsch BM, Pang Y, Zheng W (2010) Substrate specificity of SIRT1-catalyzed lysine Nepsilon-deacetylation reaction probed with the side chain modified Nepsilon-acetyl-lysine analogs. Bioorg Chem 38:17–25. https://doi.org/10.1016/j.bioorg.2009.10.001
Kaeberlein M, McVey M, Guarente L (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces Cerevisiae by two different mechanisms. Genes Dev 13:2570–2580
Khorooshi R, Owens T (2010) Injury-induced type I IFN signaling regulates inflammatory responses in the central nervous system. J Immunol 185:1258–1264. https://doi.org/10.4049/jimmunol.0901753
Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci 7:44. https://doi.org/10.3389/fncel.2013.00044
Kierdorf K et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280. https://doi.org/10.1038/nn.3318
Kim N, Kukkonen S, Martinez-Viedma Mdel P, Gupta S, Aldovini A (2013) Tat engagement of p38 MAP kinase and IRF7 pathways leads to activation of interferon-stimulated genes in antigen-presenting cells. Blood 121:4090–4100. https://doi.org/10.1182/blood-2012-10-461566
Kolthur-Seetharam U, Teerds K, de Rooij DG, Wendling O, McBurney M, Sassone-Corsi P, Davidson I (2009) The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic-pituitary gonadotropin signaling. Biol Reprod 80:384–391. https://doi.org/10.1095/biolreprod.108.070193
Kong S, Kim SJ, Sandal B, Lee SM, Gao B, Zhang DD, Fang D (2011) The type III histone deacetylase Sirt1 protein suppresses p300-mediated histone H3 lysine 56 acetylation at Bclaf1 promoter to inhibit T cell activation. J Biol Chem 286:16967–16975. https://doi.org/10.1074/jbc.M111.218206
Krishnan S et al (2014) Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis 209:931–939. https://doi.org/10.1093/infdis/jit581
Kumar A et al (2013) Age-associated changes in gene expression in human brain and isolated neurons. Neurobiol Aging 34:1199–1209. https://doi.org/10.1016/j.neurobiolaging.2012.10.021
Lane TE, Buchmeier MJ, Watry DD, Jakubowski DB, Fox HS (1995) Serial passage of microglial SIV results in selection of homogeneous env quasispecies in the brain. Virology 212:458–465. https://doi.org/10.1006/viro.1995.1503
Lemieux ME et al (2005) The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals. Mech Ageing Dev 126:1097–1105. https://doi.org/10.1016/j.mad.2005.04.006
London A, Cohen M, Schwartz M (2013) Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci 7:34. https://doi.org/10.3389/fncel.2013.00034
Marcondes MC et al (2001) Highly activated CD8(+) T cells in the brain correlate with early central nervous system dysfunction in simian immunodeficiency virus infection. J Immunol 167:5429–5438
Marcondes MC, Phillipson CA, Fox HS (2003) Distinct clonal repertoire of brain CD8+ cells in simian immunodeficiency virus infection. AIDS 17:1605–1611. https://doi.org/10.1097/01.aids.0000072648.21517.c9
Marcondes MC, Penedo MC, Lanigan C, Hall D, Watry DD, Zandonatti M, Fox HS (2006) Simian immunodeficiency virus-induced CD4+ T cell deficits in cytokine secretion profile are dependent on monkey origin. Viral Immunol 19:679–689
Marcondes MC, Sopper S, Sauermann U, Burdo TH, Watry D, Zandonatti M, Fox HS (2008) CD4 deficits and disease course acceleration can be driven by a collapse of the CD8 response in rhesus macaques infected with simian immunodeficiency virus. AIDS 22:1441–1452
Marcondes MC, Flynn C, Watry DD, Zandonatti M, Fox HS (2010) Methamphetamine increases brain viral load and activates natural killer cells in simian immunodeficiency virus-infected monkeys. Am J Pathol 177:355–361. https://doi.org/10.2353/ajpath.2010.090953
Marcondes MC, Spina C, Bustamante E, Fox H (2013) Increased toll-like receptor signaling pathways characterize CD8+ cells in rapidly progressive SIV infection. Biomed Res Int 2013:796014. https://doi.org/10.1155/2013/796014
Marcondes MC, Morsey B, Emanuel K, Lamberty BG, Flynn CT, Fox HS (2015) CD8+ T cells maintain suppression of simian immunodeficiency virus in the central nervous system. J Infect Dis 211:40–44. https://doi.org/10.1093/infdis/jiu401
McDermott JE, Vartanian KB, Mitchell H, Stevens SL, Sanfilippo A, Stenzel-Poore MP (2012) Identification and validation of Ifit1 as an important innate immune bottleneck. PLoS One 7:e36465. https://doi.org/10.1371/journal.pone.0036465
Ning S, Pagano JS, Barber GN (2011) IRF7: activation, regulation, modification and function. Genes Immun 12:399–414. https://doi.org/10.1038/gene.2011.21
Oberdoerffer P et al (2008) SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907–918. https://doi.org/10.1016/j.cell.2008.10.025
Palacios JA, Herranz D, De Bonis ML, Velasco S, Serrano M, Blasco MA (2010) SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol 191:1299–1313. https://doi.org/10.1083/jcb.201005160
Pichlmair A et al (2011) IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA. Nat Immunol 12:624–630. https://doi.org/10.1038/ni.2048
Postler E, Rimner A, Beschorner R, Schluesener HJ, Meyermann R (2000) Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions. J Neuroimmunol 104:85–91
Prinz M (2014) Microglia and monocytes: molecularly defined. Acta Neuropathol 128:317–318. https://doi.org/10.1007/s00401-014-1331-x
Prinz M, Tay TL, Wolf Y, Jung S (2014) Microglia: unique and common features with other tissue macrophages. Acta Neuropathol 128:319–331. https://doi.org/10.1007/s00401-014-1267-1
Rauh D et al (2013) An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms. Nat Commun 4:2327. https://doi.org/10.1038/ncomms3327
Roberts ES, Zandonatti MA, Watry DD, Madden LJ, Henriksen SJ, Taffe MA, Fox HS (2003) Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am J Pathol 162:2041–2057. https://doi.org/10.1016/S0002-9440(10)64336-2
Roberts ES et al (2004a) Acute SIV infection of the brain leads to upregulation of IL6 and interferon-regulated genes: expression patterns throughout disease progression and impact on neuroAIDS. J Neuroimmunol 157:81–92. https://doi.org/10.1016/j.jneuroim.2004.08.030
Roberts ES, Masliah E, Fox HS (2004b) CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE). J Neuropathol Exp Neurol 63:1255–1264
Rogina B, Helfand SL (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A 101:15998–16003. https://doi.org/10.1073/pnas.0404184101
Sanders BD, Jackson B, Marmorstein R (2010) Structural basis for sirtuin function: what we know and what we don't. Biochim Biophys Acta 1804:1604–1616. https://doi.org/10.1016/j.bbapap.2009.09.009
Schwab JM, Frei E, Klusman I, Schnell L, Schwab ME, Schluesener HJ (2001) AIF-1 expression defines a proliferating and alert microglial/macrophage phenotype following spinal cord injury in rats. J Neuroimmunol 119:214–222
Seth RB, Sun L, Chen ZJ (2006) Antiviral innate immunity pathways. Cell Res 16:141–147. https://doi.org/10.1038/sj.cr.7310019
Shannon P et al (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303
Sirois M, Robitaille L, Allary R, Shah M, Woelk CH, Estaquier J, Corbeil J (2011) TRAF6 and IRF7 control HIV replication in macrophages. PLoS One 6:e28125. https://doi.org/10.1371/journal.pone.0028125
Smith BC, Settles B, Hallows WC, Craven MW, Denu JM (2011) SIRT3 substrate specificity determined by peptide arrays and machine learning. ACS Chem Biol 6:146–157. https://doi.org/10.1021/cb100218d
Song NY, Surh YJ (2012) Janus-faced role of SIRT1 in tumorigenesis. Ann N Y Acad Sci 1271:10–19. https://doi.org/10.1111/j.1749-6632.2012.06762.x
Tissenbaum HA, Guarente L (2001) Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis Elegans. Nature 410:227–230. https://doi.org/10.1038/35065638
Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16:93–105. https://doi.org/10.1016/j.molcel.2004.08.031
Vempati RK, Haldar D (2012) DNA damage in the presence of chemical genotoxic agents induce acetylation of H3K56 and H4K16 but not H3K9 in mammalian cells. Mol Biol Rep 39:303–308. https://doi.org/10.1007/s11033-011-0739-9
Vempati RK, Jayani RS, Notani D, Sengupta A, Galande S, Haldar D (2010) p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J Biol Chem 285:28553–28564. doi:https://doi.org/10.1074/jbc.M110.149393
Wang C et al (2006) Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol 8:1025–1031. https://doi.org/10.1038/ncb1468
Wang RH et al (2008) Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14:312–323. https://doi.org/10.1016/j.ccr.2008.09.001
Watry D, Lane TE, Streb M, Fox HS (1995) Transfer of neuropathogenic simian immunodeficiency virus with naturally infected microglia. Am J Pathol 146:914–923
Weichselbaum RR et al (2008) An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci U S A 105:18490–18495. https://doi.org/10.1073/pnas.0809242105
Wiley CA et al (2000) Damage and repair of DNA in HIV encephalitis. J Neuropathol Exp Neurol 59:955–965
Yan N, Chen ZJ (2012) Intrinsic antiviral immunity. Nat Immunol 13:214–222. https://doi.org/10.1038/ni.2229
Zhang T, Kraus WL (2010) SIRT1-dependent regulation of chromatin and transcription: linking NAD(+) metabolism and signaling to the control of cellular functions. Biochim Biophys Acta 1804:1666–1675. https://doi.org/10.1016/j.bbapap.2009.10.022
Zhang J et al (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119:3048–3058. https://doi.org/10.1172/JCI38902
Acknowledgements
The authors would like to thank Steven A. Totusek (University of Nebraska Medical Center, Omaha, NE) for the help on depositing the ChIP data into the Gene Expression Omnibus (GEO) system. We thank Dr. Douglas Galasko (Department of Neurosciences, University of California, San Diego - UCSD, and Director of the UCSD Shiley-Marcos Alzheimer's Disease Research Center (ADRC), for important discussions and critical guidance throughout the study. We want to deeply thank the NIH National Institute of Aging Non Human Primate Tissue Repository, at the Wisconsin National Primate Center, for the amazing resource it provides. We also want to thank Dr. Lindsay Whitton for the use of his microscope. This work has been funded by NIH/NIDA grant R01DA036164 and by NIH/NIA grant R21AG054240 to MCGM.
Author information
Authors and Affiliations
Contributions
NB prepared cells for ChIP procedures, analyzed the data, performed most PCRs, and helped write the manuscript.
LB performed all the in vitro assays, the PCRs related to those experiments, and helped write the methods session of the manuscript.
JAN performed cell fixations and participated in discussions.
BM provided paraffin sections from SIV-infected macaques and controls.
HSF was present in all the necropsies, provided samples from macaques, participated in all discussions, and proofread the manuscript.
MCGM designed the study, was present in necropsies, performed cell and tissue isolation, analyzed data, performed systems analysis, performed PCRs, obtained funding and wrote the manuscript.
Corresponding author
Ethics declarations
Competing Interest
The authors declare that there are no competing financial interests.
Rights and permissions
About this article
Cite this article
Bortell, N., Basova, L., Najera, J.A. et al. Sirtuin 1-Chromatin-Binding Dynamics Points to a Common Mechanism Regulating Inflammatory Targets in SIV Infection and in the Aging Brain. J Neuroimmune Pharmacol 13, 163–178 (2018). https://doi.org/10.1007/s11481-017-9772-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-017-9772-3