دورية أكاديمية
Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir.
| العنوان: | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir. |
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| المؤلفون: | Avalos CR; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Abreu CM; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Queen SE; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Li M; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Price S; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Shirk EN; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Engle EL; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Forsyth E; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Bullock BT; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Mac Gabhann F; Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Wietgrefe SW; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA., Haase AT; Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA., Zink MC; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Mankowski JL; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Clements JE; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA., Gama L; Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA lucio@jhmi.edu. |
| المصدر: | MBio [mBio] 2017 Aug 15; Vol. 8 (4). Date of Electronic Publication: 2017 Aug 15. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Society for Microbiology |
| مواضيع طبية MeSH: | Virus Latency*, Brain/*virology , Macrophages/*virology , Simian Acquired Immunodeficiency Syndrome/*virology , Simian Immunodeficiency Virus/*physiology, Animals ; Anti-Retroviral Agents/administration & dosage ; Anti-Retroviral Agents/therapeutic use ; Brain/immunology ; Macaca mulatta ; Polymerase Chain Reaction ; RNA, Viral/genetics ; Simian Acquired Immunodeficiency Syndrome/drug therapy ; Simian Acquired Immunodeficiency Syndrome/immunology ; Simian Immunodeficiency Virus/genetics ; Simian Immunodeficiency Virus/immunology ; Viral Load ; Virus Activation ; Virus Replication |
| مستخلص: | A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. IMPORTANCE Resting CD4 + T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4 + T cells and underscore the importance of macrophages in developing strategies to eradicate HIV. (Copyright © 2017 Avalos et al.) |
| References: | PLoS One. 2012;7(2):e30881. (PMID: 22363505) J Virol. 2003 Jan;77(1):208-16. (PMID: 12477826) PLoS Pathog. 2013;9(5):e1003398. (PMID: 23737751) Arch Neurol. 2008 Jan;65(1):65-70. (PMID: 18195140) Nat Med. 2003 Jun;9(6):727-8. (PMID: 12754504) J Exp Med. 2001 Apr 16;193(8):905-15. (PMID: 11304551) Immunity. 2013 Jan 24;38(1):79-91. (PMID: 23273845) EBioMedicine. 2015 Jun 27;2(8):874-83. (PMID: 26425694) Sci Rep. 2016 Mar 04;6:22555. (PMID: 26939770) Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16725-30. (PMID: 18936487) J Virol. 2000 Nov;74(21):10074-80. (PMID: 11024136) Clin Infect Dis. 2010 Mar 1;50(5):773-8. (PMID: 20100092) J Leukoc Biol. 2012 May;91(5):803-16. (PMID: 22368280) Nat Med. 1999 May;5(5):512-7. (PMID: 10229227) J Neuropathol Exp Neurol. 1994 Jan;53(1):43-50. (PMID: 8301319) J Am Heart Assoc. 2014 Apr 02;3(2):e000874. (PMID: 24695652) AIDS. 2007 Sep 12;21(14):1915-21. (PMID: 17721099) J Clin Invest. 2005 Sep;115(9):2534-45. (PMID: 16110325) Retrovirology. 2013 Apr 15;10:41. (PMID: 23587031) Science. 2009 Mar 6;323(5919):1304-7. (PMID: 19265012) AIDS Res Ther. 2014 May 19;11:13. (PMID: 24894206) Proc Natl Acad Sci U S A. 2016 Mar 22;113(12):E1738-46. (PMID: 26884166) J Neurovirol. 2011 Feb;17(1):120-30. (PMID: 21165785) J Neurovirol. 2008 Aug;14(4):309-17. (PMID: 18780232) Am J Pathol. 2016 Aug;186(8):2068-87. (PMID: 27322772) Cell. 2013 Oct 24;155(3):540-51. (PMID: 24243014) Science. 1985 Jan 11;227(4683):177-82. (PMID: 2981429) J Immunol. 2012 Apr 15;188(8):3876-85. (PMID: 22407919) J Immunol. 2011 Apr 1;186(7):4008-18. (PMID: 21368232) J Virol. 2003 Apr;77(8):4938-49. (PMID: 12663799) J Virol. 2005 Jul;79(14):9217-27. (PMID: 15994816) J Virol. 2009 Sep;83(18):9247-57. (PMID: 19570871) Ann Intern Med. 2014 Sep 2;161(5):319-27. (PMID: 25047577) Ann Neurol. 1986 Jun;19(6):517-24. (PMID: 3729308) J Neuroimmunol. 2004 Dec;157(1-2):66-70. (PMID: 15579282) J Neurovirol. 1998 Jun;4(3):249-59. (PMID: 9639068) J Pathol. 2008 Jan;214(2):231-41. (PMID: 18161758) AIDS. 2010 Jun 1;24(9):1243-50. (PMID: 19996937) J Int AIDS Soc. 2011 Jan 24;14:4. (PMID: 21255462) AIDS Res Hum Retroviruses. 2008 Jul;24(7):957-67. (PMID: 18671478) Cell Host Microbe. 2017 Apr 12;21(4):494-506.e4. (PMID: 28407485) AIDS. 2006 Jan 9;20(2):197-205. (PMID: 16511412) PLoS One. 2009 Dec 17;4(12):e8129. (PMID: 20019816) AIDS. 2017 Jan 2;31(1):5-14. (PMID: 27898590) Curr Opin HIV AIDS. 2016 Jul;11(4):417-23. (PMID: 27078619) PLoS Pathog. 2015 Jul 30;11(7):e1005063. (PMID: 26225566) Blood. 2001 Nov 15;98(10):3006-15. (PMID: 11698284) Am J Pathol. 1997 Sep;151(3):793-803. (PMID: 9284828) Science. 1997 Nov 14;278(5341):1295-300. (PMID: 9360927) J Virol. 2016 May 27;90(12 ):5643-56. (PMID: 27030272) J Neurovirol. 2015 Jun;21(3):276-89. (PMID: 25236812) Science. 1986 Sep 5;233(4768):1089-93. (PMID: 3016903) J Infect Dis. 2010 Dec 15;202(12):1819-25. (PMID: 21050119) Neurology. 2010 Dec 7;75(23):2087-96. (PMID: 21135382) J Neurovirol. 2015 Jun;21(3):235-41. (PMID: 25933548) PLoS One. 2014 May 14;9(5):e97257. (PMID: 24827152) Nature. 1997 May 8;387(6629):188-91. (PMID: 9144290) J Neurovirol. 2002 Dec;8 Suppl 2:42-8. (PMID: 12491150) Open Forum Infect Dis. 2015 Aug 26;2(4):ofv123. (PMID: 26478893) J Neurovirol. 2011 Feb;17(1):3-16. (PMID: 21174240) J Exp Med. 1998 Jul 6;188(1):83-91. (PMID: 9653086) J Infect Dis. 2010 Jul 1;202(1):161-70. (PMID: 20497048) J Virol. 1999 Dec;73(12):10480-8. (PMID: 10559366) PLoS Pathog. 2011 Oct;7(10):e1002286. (PMID: 22007152) J Infect Dis. 2006 Oct 1;194(7):931-8. (PMID: 16960781) Virology. 2001 Sep 1;287(2):371-81. (PMID: 11531414) PLoS One. 2012;7(8):e42801. (PMID: 22952612) AIDS Res Hum Retroviruses. 2009 Feb;25(2):207-12. (PMID: 19239360) PLoS Pathog. 2013 Feb;9(2):e1003174. (PMID: 23459007) BMC Biol. 2013 Sep 03;11:96. (PMID: 24020860) J Infect Dis. 2002 Oct 1;186(7):905-13. (PMID: 12232830) Curr HIV/AIDS Rep. 2015 Mar;12(1):16-24. (PMID: 25604237) |
| معلومات مُعتمدة: | P30 AI094189 United States AI NIAID NIH HHS; R01 NS077869 United States NS NINDS NIH HHS; T32 GM008752 United States GM NIGMS NIH HHS; U42 OD013117 United States OD NIH HHS |
| فهرسة مساهمة: | Keywords: brain; human immunodeficiency virus; latency; macrophages; simian immunodeficiency virus |
| المشرفين على المادة: | 0 (Anti-Retroviral Agents) 0 (RNA, Viral) |
| تواريخ الأحداث: | Date Created: 20170817 Date Completed: 20180405 Latest Revision: 20191227 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5559639 |
| DOI: | 10.1128/mBio.01186-17 |
| PMID: | 28811349 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2150-7511 |
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| DOI: | 10.1128/mBio.01186-17 |