Neuroinvasion of fluorescein-positive monocytes in acute simian immunodeficiency virus infection.
Monocytes and macrophages play a central role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia. They represent prominent targets for HIV infection and are thought to facilitate viral neuroinvasion and neuroinflammatory processes. However, many aspects regarding monocyte brain recruitment in HIV infection remain undefined. The nonhuman primate model of AIDS is uniquely suited for examination of the role of monocytes in the pathogenesis of AIDS-associated encephalitis. Nevertheless, an approach to monitor cell migration from peripheral blood into the central nervous system (CNS) in primates had been lacking. Here, upon autologous transfer of fluorescein dye-labeled leukocytes, we demonstrate the trafficking of dye-positive monocytes into the choroid plexus stromata and perivascular spaces in the cerebra of rhesus macaques acutely infected with simian immunodeficiency virus between days 12 and 14 postinfection (p.i.). Dye-positive cells that had migrated expressed the monocyte activation marker CD16 and the macrophage marker CD68. Monocyte neuroinvasion coincided with the presence of the virus in brain tissue and cerebrospinal fluid and with the induction of the proinflammatory mediators CXCL9/MIG and CCL2/MCP-1 in the CNS. Prior to neuroinfiltration, plasma viral load levels peaked on day 11 p.i. Furthermore, the numbers of peripheral blood monocytes rapidly increased between days 4 and 8 p.i., and circulating monocytes exhibited increased functional capacity to produce CCL2/MCP-1. Our findings demonstrate acute monocyte brain infiltration in an animal model of AIDS. Such studies facilitate future examinations of the migratory profile of CNS-homing monocytes, the role of monocytes in virus import into the brain, and the disruption of blood-cerebrospinal fluid and blood-brain barrier functions in primates.
Clay
Candice C
CC
Department of Pathology and Laboratory Medicine, Research III Building, Room 3400A, University of California-Davis Medical Center, 4645 2nd Avenue, Sacramento, CA 95817, USA.
Rodrigues
Denise S
DS
Ho
Yan S
YS
Fallert
Beth A
BA
Janatpour
Kim
K
Reinhart
Todd A
TA
Esser
Ursula
U
D000818:Animals; D001921:Brain / Q000821:virology*; D001927:Brain Diseases / Q000821:virology*; D018925:Chemokines / Q000378:metabolism; D005434:Flow Cytometry; D019793:Fluorescein / Q000494:pharmacology*; D017403:In Situ Hybridization; D007249:Inflammation; D007963:Leukocytes, Mononuclear / Q000821:virology; D008253:Macaca mulatta; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000821:virology; D012367:RNA, Viral / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications*; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*
D018925:Chemokines; D012367:RNA, Viral; D019793:Fluorescein
J Leukoc Biol. 2003 Nov;74(5):650-6
12960230
J Neurosci. 2006 Apr 26;26(17):4577-85
16641237
J Leukoc Biol. 2003 Nov;74(5):719-25
12960239
J Leukoc Biol. 2003 Nov;74(5):631-4
12960251
J Leukoc Biol. 2003 Nov;74(5):691-701
14595004
Am J Pathol. 2004 Sep;165(3):707-18
15331396
Neuropathol Appl Neurobiol. 1990 Oct;16(5):377-92
2263314
J Neurovirol. 1999 Dec;5(6):579-90
10602399
J Neurovirol. 1999 Dec;5(6):670-7
10602407
Science. 2000 Jan 28;287(5453):602-4
10691542
J Leukoc Biol. 2000 Sep;68(3):413-22
10985259
Microbes Infect. 2000 Nov;2(13):1609-18
11113380
AIDS Res Hum Retroviruses. 2001 Feb 10;17(3):243-51
11177407
J Neurovirol. 2000 Dec;6(6):498-506
11175322
Nature. 2001 Apr 19;410(6831):988-94
11309629
J Virol. 2001 Aug;75(15):7067-77
11435587
Genome Res. 2001 Sep;11(9):1473-83
11544191
J Infect Dis. 2001 Oct 15;184(8):1015-21
11574916
J Immunol. 2001 Nov 1;167(9):5429-38
11673562
J Virol Methods. 2002 Jan;99(1-2):23-32
11684300
J Neurovirol. 2002 Apr;8(2):69-75
11935459
Blood. 2002 May 1;99(9):3119-28
11964273
Annu Rev Neurosci. 2002;25:537-62
12052920
Am J Pathol. 2002 Sep;161(3):813-22
12213709
Am J Pathol. 2006 May;168(5):1553-69
16651622
J Immunol. 2006 May 15;176(10):5760-71
16670281
J Neuroimmunol. 2006 Aug;177(1-2):85-98
16797085
J Leukoc Biol. 2006 Nov;80(5):1156-64
17056766
J Neuropathol Exp Neurol. 2006 Dec;65(12):1170-80
17146291
J Infect Dis. 2002 Dec 1;186 Suppl 2:S199-208
12424698
J Neurovirol. 2002 Dec;8(6):585-98
12476352
Semin Immunol. 2003 Feb;15(1):23-32
12495638
Methods. 2003 Apr;29(4):351-61
12725802
Nat Rev Immunol. 2003 Jul;3(7):569-81
12876559
Am J Pathol. 1991 Sep;139(3):609-21
1716047
Am J Pathol. 1991 Dec;139(6):1273-80
1750503
Neurology. 1992 Sep;42(9):1736-9
1513462
AIDS Res Hum Retroviruses. 1993 Mar;9(3):277-86
8471319
Eur J Immunol. 1995 Dec;25(12):3418-24
8566032
Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):700-4
8570619
Am J Pathol. 1996 Nov;149(5):1459-67
8909235
J Neurovirol. 1996 Dec;2(6):423-32
8972425
J Neurovirol. 1997 Feb;3(1):1-9
9147816
Lancet. 1997 Mar 8;349(9053):692-5
9078201
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3117-21
9501225
AIDS. 1998 Jun 18;12(9):1021-6
9662198
AIDS Res Hum Retroviruses. 1998 Sep 1;14(13):1181-6
9737589
J Immunol. 1998 Dec 15;161(12):6896-903
9862722
J Immunol Methods. 2004 Oct;293(1-2):23-42
15541274
J Neuroimmunol. 2004 Dec;157(1-2):66-70
15579282
J Neuroimmunol. 2004 Dec;157(1-2):71-80
15579283
J Neuroimmunol. 2004 Dec;157(1-2):81-92
15579284
J Clin Invest. 2005 Sep;115(9):2534-45
16110325
J Neuroimmunol. 2005 Nov;168(1-2):154-63
16091292
J Virol. 2005 Nov;79(21):13759-68
16227295
Expert Rev Mol Med. 2005 Dec 2;7(27):1-26
16321172
Trends Pharmacol Sci. 2006 Jan;27(1):48-55
16310865
J Neurosci. 2006 Jan 25;26(4):1098-106
16436595
Nat Immunol. 2006 Mar;7(3):311-7
16462739
AJNR Am J Neuroradiol. 2006 Mar;27(3):589-92
16551998
J Neurovirol. 2006 Feb;12(1):25-33
16595371
J Leukoc Biol. 2003 Nov;74(5):635-41
12960232