Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells.
Interferon regulatory factor 3 (IRF-3) is essential for innate intracellular immune defenses that limit virus replication, but these defenses fail to suppress human immunodeficiency virus (HIV) infection, which can ultimately associate with opportunistic coinfections and the progression to AIDS. Here, we examined antiviral defenses in CD4+ cells during virus infection and coinfection, revealing that HIV type 1 (HIV-1) directs a global disruption of innate immune signaling and supports a coinfection model through suppression of IRF-3. T cells responded to paramyxovirus infection to activate IRF-3 and interferon-stimulated gene expression, but they failed to mount a response against HIV-1. The lack of response associated with a marked depletion of IRF-3 but not IRF-7 in HIV-1-infected cells, which supported robust viral replication, whereas ectopic expression of active IRF-3 suppressed HIV-1 infection. IRF-3 depletion was dependent on a productive HIV-1 replication cycle and caused the specific disruption of Toll-like receptor and RIG-I-like receptor innate immune signaling that rendered cells permissive to secondary virus infection. IRF-3 levels were reduced in vivo within CD4+ T cells from patients with acute HIV-1 infection but not from long-term nonprogressors. Our results indicate that viral suppression of IRF-3 promotes HIV-1 infection by disrupting IRF-3-dependent signaling pathways and innate antiviral defenses of the host cell. IRF-3 may direct an innate antiviral response that regulates HIV-1 replication and viral set point while governing susceptibility to opportunistic virus coinfections.
Doehle
Brian P
BP
University of Washington School of Medicine, Department of Immunology, Seattle, WA 98195, USA.
Hladik
Florian
F
McNevin
John P
JP
McElrath
M Juliana
MJ
Gale
Michael
M
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
Nat Rev Immunol. 2008 Jul;8(7):559-68
18575461
Science. 2008 May 30;320(5880):1220-4
18436744
Virology. 2008 Mar 30;373(1):85-97
18082865
EMBO J. 1995 Apr 3;14(7):1552-60
7729429
Nature. 2008 Jul 24;454(7203):523-7
18548002
J Infect Dis. 2005 Jul 15;192(2):303-10
15962225
Mol Cell Biol. 1999 Apr;19(4):2465-74
10082512
J Virol. 2002 Jun;76(11):5532-9
11991981
J Immunol Methods. 2007 Apr 30;322(1-2):57-69
17382342
J Virol. 1999 Jul;73(7):5833-42
10364335
J Immunol. 1999 Aug 15;163(4):2306-13
10438976
Ann Intern Med. 1996 Aug 15;125(4):257-64
8678387
J Virol. 2008 Jan;82(1):335-45
17942531
J Virol. 2006 Feb;80(3):1067-76
16414984
Curr Opin Immunol. 2007 Feb;19(1):17-23
17118636
Nat Rev Immunol. 2007 Mar;7(3):179-90
17318230
Postgrad Med. 1997 Oct;102(4):143-6, 149-51
9336602
Nat Med. 2008 Oct;14(10):1077-87
18806803
Immunity. 2006 Jan;24(1):93-103
16413926
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9837-42
9707562
AIDS Res Hum Retroviruses. 2004 Nov;20(11):1210-22
15588343
J Clin Invest. 2005 Nov;115(11):3265-75
16224540
J Exp Med. 2008 Jul 7;205(7):1601-10
18591409
Clin Immunol. 2003 Sep;108(3):167-74
14499239
Science. 2003 May 16;300(5622):1145-8
12702807
Nat Rev Immunol. 2007 May;7(5):353-64
17457343
Science. 2004 Mar 5;303(5663):1526-9
14976262
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1440-5
16434471
Nat Med. 2003 Jul;9(7):853-60
12835705
Cell Host Microbe. 2008 Oct 16;4(4):374-86
18854241
Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2986-91
15710892
J Infect Dis. 2001 May 15;183(10):1466-75
11319682
J Virol. 2006 Dec;80(23):11723-32
16971436
Blood. 2001 Aug 15;98(4):906-12
11493432
Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11657-61
8524823
J Virol. 2007 Aug;81(15):8180-91
17507480
J Gen Virol. 2005 Aug;86(Pt 8):2221-2229
16033969
Mol Cell Biol. 1998 May;18(5):2986-96
9566918
Nat Rev Immunol. 2008 Jun;8(6):447-57
18469831
J Virol. 1994 Jul;68(7):4650-5
8207839
Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4114-9
15741273
Nat Rev Immunol. 2008 Nov;8(11):849-60
18836477
J Virol. 2007 May;81(9):4473-81
17301153
Curr Top Microbiol Immunol. 2007;316:295-313
17969453
J Virol. 1997 Jul;71(7):5495-504
9188623