title: Cellular and molecular mechanisms involved in the establishment of HIV-1 latency.
abstract: Latently infected cells represent the major barrier to either a sterilizing or a functional HIV-1 cure. Multiple approaches to reactivation and depletion of the latent reservoir have been attempted clinically, but full depletion of this compartment remains a long-term goal. Compared to the mechanisms involved in the maintenance of HIV-1 latency and the pathways leading to viral reactivation, less is known about the establishment of latent infection. This review focuses on how HIV-1 latency is established at the cellular and molecular levels. We first discuss how latent infection can be established following infection of an activated CD4 T-cell that undergoes a transition to a resting memory state and also how direct infection of a resting CD4 T-cell can lead to latency. Various animal, primary cell, and cell line models also provide insights into this process and are discussed with respect to the routes of infection that result in latency. A number of molecular mechanisms that are active at both transcriptional and post-transcriptional levels have been associated with HIV-1 latency. Many, but not all of these, help to drive the establishment of latent infection, and we review the evidence in favor of or against each mechanism specifically with regard to the establishment of latency. We also discuss the role of immediate silent integration of viral DNA versus silencing of initially active infections. Finally, we discuss potential approaches aimed at limiting the establishment of latent infection.
authors: McGill University AIDS Centre, Lady Davis Institute, Jewish General Hospital, Montreal, Québec, Canada. mark.wainberg@mail.mcgill.ca.
authors: Daniel A
authors: DA
authors: Donahue
authors: Mark A
authors: MA
authors: Wainberg
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D044127:Epigenesis, Genetic; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008954:Models, Biological; D014158:Transcription, Genetic; D017735:Virus Latency
references: Cell. 2002 Aug 23;110(4):521-9
references: 12202041
references: Proc Natl Acad Sci U S A. 1990 Aug;87(16):6058-62
references: 2385584
references: Virology. 2011 Mar 15;411(2):344-54
references: 21284992
references: EMBO J. 2007 Dec 12;26(24):4985-95
references: 18007589
references: Nature. 2005 Apr 28;434(7037):1148-52
references: 15793562
references: Retrovirology. 2011 Sep 16;8:73
references: 21923919
references: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73
references: 9671771
references: Trends Genet. 2005 Jun;21(6):339-45
references: 15922833
references: Curr HIV Res. 2011 Dec 1;9(8):568-78
references: 22211661
references: J Virol. 2011 Jun;85(11):5384-93
references: 21430059
references: AIDS. 2005 Nov 4;19(16):1739-50
references: 16227781
references: EMBO J. 2007 Jan 24;26(2):412-23
references: 17245431
references: AIDS Res Hum Retroviruses. 2003 Oct;19(10):847-56
references: 14585216
references: Curr Opin HIV AIDS. 2011 Jan;6(1):30-6
references: 21242891
references: J Virol. 2009 Apr;83(7):3078-93
references: 19144703
references: AIDS Res Hum Retroviruses. 1998 May 1;14(7):607-17
references: 9591715
references: J Virol. 2005 Nov;79(22):14179-88
references: 16254353
references: J Virol. 2010 Jun;84(12):5958-74
references: 20357084
references: Immunity. 2012 Mar 23;36(3):491-501
references: 22406268
references: Cell. 1990 Apr 20;61(2):213-22
references: 2331748
references: PLoS Biol. 2011 Nov;9(11):e1001206
references: 22140357
references: Virology. 1996 Nov 1;225(1):196-212
references: 8918547
references: Science. 2001 Aug 10;293(5532):1074-80
references: 11498575
references: Curr HIV/AIDS Rep. 2010 Feb;7(1):37-43
references: 20425056
references: J Virol. 2011 Sep;85(17):9078-89
references: 21715480
references: Science. 2010 Jul 9;329(5988):174-80
references: 20616270
references: Genome Res. 2007 Aug;17(8):1186-94
references: 17545577
references: Cytokine Growth Factor Rev. 2012 Aug-Oct;23(4-5):143-9
references: 22743037
references: Immunity. 2012 Sep 21;37(3):377-88
references: 22999944
references: PLoS One. 2012;7(3):e33948
references: 22479485
references: J Virol. 2010 Jul;84(13):6425-37
references: 20410271
references: AIDS. 2012 Jun 19;26(10):1261-8
references: 22472858
references: Cell Host Microbe. 2008 Aug 14;4(2):123-33
references: 18692772
references: PLoS Pathog. 2009 Jun;5(6):e1000495
references: 19557157
references: Antivir Ther. 2011;16(4):535-45
references: 21685541
references: Cell. 2005 Jul 29;122(2):169-82
references: 16051143
references: Curr Opin Immunol. 2009 Apr;21(2):167-72
references: 19282163
references: Mol Cell. 2010 May 14;38(3):428-38
references: 20471948
references: Retrovirology. 2009 Mar 09;6:26
references: 19272132
references: J Virol. 2012 Jan;86(1):630-4
references: 22013053
references: Retrovirology. 2012 May 28;9:45
references: 22640593
references: J Virol. 2004 Jun;78(12):6122-33
references: 15163705
references: J Infect Dis. 2010 Dec 1;202(11):1738-48
references: 20979453
references: Annu Rev Med. 2008;59:487-501
references: 17845138
references: EMBO J. 2003 Apr 15;22(8):1868-77
references: 12682019
references: Retrovirology. 2009 Jun 01;6:51
references: 19486514
references: J Virol. 2009 May;83(9):4528-37
references: 19211752
references: Retrovirology. 2010 Apr 09;7:32
references: 20380694
references: Nat Med. 2007 Oct;13(10):1241-7
references: 17906637
references: Curr HIV Res. 2011 Dec 1;9(8):554-67
references: 22211660
references: J Immunol. 2008 Dec 1;181(11):7713-20
references: 19017960
references: Nat Med. 2001 Apr;7(4):459-64
references: 11283673
references: J Virol. 2007 Jul;81(14):7424-34
references: 17475639
references: J Virol. 1994 Jan;68(1):535-40
references: 8254768
references: AIDS Res Hum Retroviruses. 1996 Jun 10;12(9):759-67
references: 8738427
references: J Infect Dis. 2012 Mar 15;205(6):1014-8
references: 22275402
references: AIDS. 2009 Jul 31;23(12):1461-71
references: 19550285
references: Cold Spring Harb Perspect Med. 2011 Sep;1(1):a007096
references: 22229121
references: J Virol. 2012 Sep;86(17):9337-50
references: 22718820
references: J Biol Chem. 2012 Oct 12;287(42):35455-35469
references: 22879601
references: EMBO J. 1990 May;9(5):1551-60
references: 2184033
references: Cytokine Growth Factor Rev. 2012 Aug-Oct;23(4-5):151-7
references: 22749173
references: Antimicrob Agents Chemother. 2005 Dec;49(12):5185-8
references: 16304201
references: Immunity. 2001 Oct;15(4):671-82
references: 11672548
references: Nat Med. 2009 Aug;15(8):893-900
references: 19543283
references: Retrovirology. 2012 Oct 23;9:87
references: 23092122
references: J Infect Dis. 2007 Jun 15;195(12):1762-4
references: 17492591
references: Curr HIV Res. 2011 Dec 1;9(8):579-87
references: 22211662
references: J Clin Invest. 2005 Nov;115(11):3250-5
references: 16276421
references: Blood. 2007 Nov 1;110(9):3143-9
references: 17693583
references: PLoS Pathog. 2007 Apr;3(4):e46
references: 17411338
references: Nature. 1997 May 8;387(6629):183-8
references: 9144289
references: J Leukoc Biol. 2010 Apr;87(4):575-88
references: 19801499
references: J Virol. 2004 Feb;78(3):1160-8
references: 14722271
references: J Virol. 2009 Jun;83(12):6222-33
references: 19369341
references: FEMS Microbiol Rev. 2012 May;36(3):706-16
references: 22372374
references: J Exp Med. 1999 Jun 7;189(11):1735-46
references: 10359577
references: PLoS Pathog. 2012;8(7):e1002818
references: 22911005
references: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9
references: 20837531
references: J Infect Dis. 2005 May 1;191(9):1410-8
references: 15809898
references: Blood. 2009 Jan 1;113(1):58-65
references: 18849485
references: J Virol. 1999 Aug;73(8):6430-5
references: 10400736
references: J Virol. 2012 Jan;86(1):114-20
references: 22013038
references: Retrovirology. 2008 Apr 25;5:37
references: 18439275
references: Nature. 2003 Dec 18;426(6968):853-7
references: 14685242
references: J Infect Dis. 2012 Jul 1;206(1):28-34
references: 22536001
references: Blood. 2007 Dec 15;110(13):4161-4
references: 17881634
references: J Clin Invest. 2000 Oct;106(7):839-45
references: 11018071
references: Nat Genet. 2008 Apr;40(4):466-70
references: 18344999
references: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16725-30
references: 18936487
references: Science. 1996 Mar 15;271(5255):1582-6
references: 8599114
references: Nat Med. 2012 Nov;18(11):1682-7
references: 22972397
references: Curr Opin HIV AIDS. 2011 Jan;6(1):62-7
references: 21242895
references: Nat Rev Microbiol. 2009 Nov;7(11):798-812
references: 19834480
references: J Virol. 2013 Feb;87(4):2264-77
references: 23236059
references: PLoS Pathog. 2009 Jan;5(1):e1000260
references: 19132086
references: J Cell Sci. 2007 Aug 15;120(Pt 16):2755-61
references: 17690303
references: J Virol. 2013 Jan;87(2):1211-20
references: 23152527
references: Retrovirology. 2011 Oct 12;8:80
references: 21992606
references: J Exp Med. 2007 Jan 22;204(1):79-91
references: 17190839
references: PLoS Comput Biol. 2009 Oct;5(10):e1000533
references: 19834532
references: J Virol. 2000 Sep;74(17):7824-33
references: 10933689
references: Retrovirology. 2008 Nov 26;5:107
references: 19036147
references: Viruses. 2012 Sep;4(9):1390-409
references: 23170164
references: J Virol. 2012 Mar;86(6):3253-63
references: 22238306
references: PLoS One. 2012;7(1):e30176
references: 22291913
references: J Immunol. 2005 Nov 15;175(10):6489-97
references: 16272303
references: Blood. 1997 Mar 1;89(5):1635-41
references: 9057646
references: Curr Opin HIV AIDS. 2011 Jan;6(1):43-8
references: 21242893
references: J Virol. 2012 Jan;86(1):339-47
references: 22072769
references: J Virol. 2011 Apr;85(7):3187-202
references: 21270164
references: J Exp Med. 2004 Sep 20;200(6):725-35
references: 15381728
references: Immunol Res. 2010 Dec;48(1-3):110-21
references: 20725862
references: Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1925-30
references: 9050881
references: Curr Opin HIV AIDS. 2011 Jan;6(1):80-5
references: 21242898
references: EMBO J. 2006 Aug 9;25(15):3596-604
references: 16874302
references: Nat Immunol. 2010 Aug;11(8):674-80
references: 20644573
references: J Clin Invest. 2009 Nov;119(11):3473-86
references: 19805909
references: Mol Cell. 2010 May 14;38(3):439-51
references: 20471949
references: Annu Rev Immunol. 2004;22:745-63
references: 15032595
references: EMBO J. 2007 Jan 24;26(2):424-35
references: 17245432
references: Virology. 2009 Apr 25;387(1):98-108
references: 19268337
references: PLoS Pathog. 2006 Jul;2(7):e68
references: 16839202
references: Curr Opin HIV AIDS. 2011 Jan;6(1):57-61
references: 21242894
references: J Virol. 2005 Jun;79(11):6610-9
references: 15890899
references: Microbiol Mol Biol Rev. 2006 Sep;70(3):646-59
references: 16959964
references: Cell Host Microbe. 2008 Aug 14;4(2):134-46
references: 18692773
references: Nat Med. 2010 Apr;16(4):446-51
references: 20208541
references: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9523-8
references: 22645358
references: Virology. 2006 Nov 25;355(2):127-37
references: 16919704
references: J Virol. 2008 Dec;82(24):12291-303
references: 18829756
references: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3879-84
references: 18332425