title: Dendritic cell-induced activation of latent HIV-1 provirus in actively proliferating primary T lymphocytes.
abstract: HIV-1 latency remains a formidable barrier towards virus eradication as therapeutic attempts to purge these reservoirs are so far unsuccessful. The pool of transcriptionally silent proviruses is established early in infection and persists for a lifetime, even when viral loads are suppressed below detection levels using anti-retroviral therapy. Upon therapy interruption the reservoir can re-establish systemic infection. Different cellular reservoirs that harbor latent provirus have been described. In this study we demonstrate that HIV-1 can also establish a silent integration in actively proliferating primary T lymphocytes. Co-culturing of these proliferating T lymphocytes with dendritic cells (DCs) activated the provirus from latency. Activation did not involve DC-mediated C-type lectin DC-SIGN signaling or TCR-stimulation but was mediated by DC-secreted component(s) and cell-cell interaction between DC and T lymphocyte that could be inhibited by blocking ICAM-1 dependent adhesion. These results imply that circulating DCs could purge HIV-1 from latency and re-initiate virus replication. Moreover, our data show that viral latency can be established early after infection and supports the idea that actively proliferating T lymphocytes with an effector phenotype contribute to the latent viral reservoir. Unraveling this physiologically relevant purging mechanism could provide useful information for the development of new therapeutic strategies that aim at the eradication of HIV-1 reservoirs.
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Centre for Infection and Immunity Amsterdam, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Renée M
authors.initials: RM
authors.lastname: van der Sluis
authors.forename: Thijs
authors.initials: T
authors.lastname: van Montfort
authors.forename: Georgios
authors.initials: G
authors.lastname: Pollakis
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: Dave
authors.initials: D
authors.lastname: Speijer
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.forename: Rienk E
authors.initials: RE
authors.lastname: Jeeninga
mesh_terms: D049109:Cell Proliferation; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D057809:HEK293 Cells; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D054884:Host-Pathogen Interactions; D006801:Humans; D011533:Proviruses / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014775:Virus Activation / Q000276:immunology*; D017735:Virus Latency
references.citation: J Virol Methods. 2013 Jan;187(1):94-102
references.pmid: 23059551
references.citation: J Immunol. 2007 Mar 1;178(5):3177-85
references.pmid: 17312166
references.citation: J Virol. 2010 Jul;84(13):6425-37
references.pmid: 20410271
references.citation: Curr Opin HIV AIDS. 2011 Jan;6(1):62-7
references.pmid: 21242895
references.citation: Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974-8
references.pmid: 2762307
references.citation: Nat Med. 1999 May;5(5):512-7
references.pmid: 10229227
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12955-60
references.pmid: 14569007
references.citation: Retrovirology. 2011 Sep 16;8:73
references.pmid: 21923919
references.citation: J Immunol. 1989 Jan 15;142(2):431-8
references.pmid: 2463307
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8869-73
references.pmid: 9671771
references.citation: J Virol. 1999 Jan;73(1):81-91
references.pmid: 9847310
references.citation: J Virol. 2009 Apr;83(7):3078-93
references.pmid: 19144703
references.citation: Science. 1997 Nov 14;278(5341):1291-5
references.pmid: 9360926
references.citation: Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193-7
references.pmid: 9371822
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: J Virol. 2007 Jun;81(11):6043-56
references.pmid: 17376917
references.citation: Science. 1989 May 5;244(4904):575-7
references.pmid: 2470148
references.citation: EMBO J. 2003 Apr 15;22(8):1868-77
references.pmid: 12682019
references.citation: Retrovirology. 2009 Jun 01;6:51
references.pmid: 19486514
references.citation: Immunol Rev. 2000 Oct;177:134-40
references.pmid: 11138771
references.citation: J Virol. 2002 Aug;76(15):7812-21
references.pmid: 12097593
references.citation: Science. 1999 Nov 12;286(5443):1353-7
references.pmid: 10558989
references.citation: J Virol. 2006 Jul;80(13):6441-57
references.pmid: 16775332
references.citation: J Immunol. 2008 Dec 1;181(11):7713-20
references.pmid: 19017960
references.citation: Nat Immunol. 2010 May;11(5):419-26
references.pmid: 20364151
references.citation: Nature. 2012 Jul 25;487(7408):439-40
references.pmid: 22836995
references.citation: J Virol. 2006 Feb;80(3):1599-603
references.pmid: 16415036
references.citation: Nat Med. 2003 Jun;9(6):727-8
references.pmid: 12754504
references.citation: J Virol. 2002 Jan;76(2):707-16
references.pmid: 11752161
references.citation: J Allergy Clin Immunol. 2008 Jul;122(1):22-8
references.pmid: 18602567
references.citation: Cell. 2000 Mar 3;100(5):587-97
references.pmid: 10721995
references.citation: AIDS. 2011 Jan 14;25(2):159-64
references.pmid: 21124203
references.citation: Nature. 1997 May 8;387(6629):183-8
references.pmid: 9144289
references.citation: J Exp Med. 1999 Jun 7;189(11):1735-46
references.pmid: 10359577
references.citation: J Virol. 2002 Nov;76(21):11091-103
references.pmid: 12368351
references.citation: Nat Med. 2000 Jul;6(7):757-61
references.pmid: 10888923
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9
references.pmid: 20837531
references.citation: Proc Natl Acad Sci U S A. 1989 Apr;86(7):2365-8
references.pmid: 2784570
references.citation: Blood. 2009 Jan 1;113(1):58-65
references.pmid: 18849485
references.citation: Annu Rev Immunol. 2000;18:665-708
references.pmid: 10837072
references.citation: Retrovirology. 2008 Apr 25;5:37
references.pmid: 18439275
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16725-30
references.pmid: 18936487
references.citation: J Virol. 2009 May;83(9):4195-204
references.pmid: 19211748
references.citation: Blood. 2007 Dec 15;110(13):4161-4
references.pmid: 17881634
references.citation: Nature. 1991 Apr 11;350(6318):508-11
references.pmid: 2014052
references.citation: Nature. 2012 Jul 25;487(7408):482-5
references.pmid: 22837004
references.citation: Retrovirology. 2011 Oct 12;8:80
references.pmid: 21992606
references.citation: EMBO J. 2006 Jan 11;25(1):139-49
references.pmid: 16319923
references.citation: J Biol Chem. 2004 Oct 1;279(40):42008-17
references.pmid: 15284245
references.citation: J Virol. 2012 Apr;86(8):4548-58
references.pmid: 22345467
references.citation: J Virol. 1991 Sep;65(9):4645-53
references.pmid: 1678437
references.citation: PLoS One. 2012;7(1):e30176
references.pmid: 22291913
references.citation: Retrovirology. 2006 Nov 01;3:75
references.pmid: 17078873
references.citation: Nat Rev Immunol. 2011 Sep 09;11(10):672-84
references.pmid: 21904389
references.citation: Nature. 1999 Oct 28;401(6756):874-5
references.pmid: 10553903
references.citation: PLoS One. 2010 Oct 12;5(10):e13310
references.pmid: 20967271
references.citation: Virology. 2008 Jan 5;370(1):63-76
references.pmid: 17900651
references.citation: J Virol. 2007 Apr;81(7):3574-82
references.pmid: 17229711
references.citation: Nature. 1989 Oct 19;341(6243):619-24
references.pmid: 2477710
references.citation: Methods. 2009 Apr;47(4):254-60
references.pmid: 19195495
references.citation: Annu Rev Med. 2002;53:557-93
references.pmid: 11818490
references.citation: J Virol. 2008 Aug;82(16):7886-96
references.pmid: 18524826
references.citation: J Virol. 2005 Feb;79(4):2199-210
references.pmid: 15681422
references.citation: J Virol. 2009 Sep;83(18):9247-57
references.pmid: 19570871
references.citation: Nature. 1989 Dec 14;342(6251):811-3
references.pmid: 2574829