title: Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs.
abstract: Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure. We look at new approaches to unravelling the complex virus-host interactions that lead to persistent infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV.
authors.affiliation: Department of Infectious Diseases, Pierre and Marie Curie University, Pitié-Salpêtriere Hospital, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Katlama
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.forename: Javier
authors.initials: J
authors.lastname: Martinez-Picado
authors.forename: Jan
authors.initials: J
authors.lastname: van Lunzen
authors.forename: Christine
authors.initials: C
authors.lastname: Rouzioux
authors.forename: Michael
authors.initials: M
authors.lastname: Miller
authors.forename: Stefano
authors.initials: S
authors.lastname: Vella
authors.forename: Joern E
authors.initials: JE
authors.lastname: Schmitz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ahlers
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.forename: Rafick P
authors.initials: RP
authors.lastname: Sekaly
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D004359:Drug Therapy, Combination / Q000379:methods; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D012367:RNA, Viral / Q000187:drug effects / Q000502:physiology; D019713:Receptors, CCR5 / Q000187:drug effects; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D019713:Receptors, CCR5
references.citation: Antivir Ther. 1998;3(4):209-14
references.pmid: 10682140
references.citation: PLoS One. 2012;7(3):e33948
references.pmid: 22479485
references.citation: Nat Rev Immunol. 2011 May;11(5):330-42
references.pmid: 21508983
references.citation: J Virol. 2012 Sep;86(17):8920-36
references.pmid: 22718830
references.citation: EMBO J. 1996 Mar 1;15(5):1112-20
references.pmid: 8605881
references.citation: Immunol Cell Biol. 2012 Jan;90(1):47-54
references.pmid: 22083528
references.citation: Nat Med. 2006 Dec;12(12):1365-71
references.pmid: 17115046
references.citation: J Leukoc Biol. 2012 Dec;92(6):1147-54
references.pmid: 22802445
references.citation: Clin Infect Dis. 2012 Jul;55(2):291-300
references.pmid: 22550117
references.citation: J Mol Biol. 2011 Jul 29;410(5):896-916
references.pmid: 21763495
references.citation: Nat Med. 2010 Apr;16(4):452-9
references.pmid: 20208540
references.citation: J Infect Dis. 2011 Feb 15;203(4):473-8
references.pmid: 21233310
references.citation: AIDS. 1997 Jul 15;11(9):1103-10
references.pmid: 9233456
references.citation: HIV Med. 2012 May;13(5):291-6
references.pmid: 22276680
references.citation: Antivir Ther. 2012;17(6):1001-9
references.pmid: 22865544
references.citation: N Engl J Med. 2009 Feb 12;360(7):692-8
references.pmid: 19213682
references.citation: AIDS. 2012 Jul 31;26(12):1473-82
references.pmid: 22555163
references.citation: J Virol. 2005 Nov;79(22):14179-88
references.pmid: 16254353
references.citation: Blood. 2011 Mar 10;117(10):2791-9
references.pmid: 21148083
references.citation: J Clin Invest. 2009 Apr;119(4):997-1007
references.pmid: 19287090
references.citation: Immunity. 2012 Mar 23;36(3):491-501
references.pmid: 22406268
references.citation: Mol Med. 2012 Oct 24;18:1169-82
references.pmid: 22777388
references.citation: PLoS One. 2011 Apr 05;6(4):e18270
references.pmid: 21483687
references.citation: J Infect Dis. 2011 Mar 15;203(6):780-90
references.pmid: 21252259
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14807-12
references.pmid: 16199516
references.citation: Cold Spring Harb Perspect Med. 2012 Feb;2(2):a006916
references.pmid: 22355797
references.citation: PLoS Pathog. 2012;8(8):e1002840
references.pmid: 22916009
references.citation: JAMA. 2012 Jul 25;308(4):353-61
references.pmid: 22820788
references.citation: Arch Intern Med. 2012 Sep 10;172(16):1252-5
references.pmid: 22826124
references.citation: J Virol. 2011 Jun;85(12):6060-4
references.pmid: 21471244
references.citation: Clin Infect Dis. 2012 May;54(10):1495-503
references.pmid: 22441653
references.citation: J Virol. 2011 Sep;85(17):9078-89
references.pmid: 21715480
references.citation: Curr HIV Res. 2010 Sep;8(6):418-29
references.pmid: 20636281
references.citation: Sci Signal. 2012 Jun 26;5(230):ra46
references.pmid: 22740686
references.citation: J Virol. 2011 Sep;85(18):9334-45
references.pmid: 21752903
references.citation: AIDS. 2010 Oct 23;24(16):2451-60
references.pmid: 20827162
references.citation: Antivir Ther. 2012;17(2):355-64
references.pmid: 22290239
references.citation: PLoS One. 2010 Feb 23;5(2):e9390
references.pmid: 20186346
references.citation: Blood. 2011 Dec 22;118(26):6845-8
references.pmid: 22067383
references.citation: J Virol. 2011 Jul;85(13):6557-66
references.pmid: 21490090
references.citation: Mol Ther. 2012 Nov;20(11):2064-75
references.pmid: 22828501
references.citation: J Virol. 2012 Sep;86(17):9055-69
references.pmid: 22696646
references.citation: AIDS. 2011 Jul 17;25(11):1385-94
references.pmid: 21505312
references.citation: J Mol Biol. 2011 Aug 19;411(3):581-96
references.pmid: 21699904
references.citation: Nat Med. 2009 Aug;15(8):893-900
references.pmid: 19543283
references.citation: Antivir Ther. 2012;17(4):669-78
references.pmid: 22297608
references.citation: Trends Immunol. 2010 Mar;31(3):120-30
references.pmid: 20089450
references.citation: J Infect Dis. 2007 Jun 15;195(12):1762-4
references.pmid: 17492591
references.citation: Curr Opin HIV AIDS. 2011 Jan;6(1):74-9
references.pmid: 21242897
references.citation: J Infect Dis. 2002 Nov 15;186(10):1403-11
references.pmid: 12404155
references.citation: Arch Intern Med. 2007 Mar 26;167(6):597-605
references.pmid: 17389292
references.citation: Nat Med. 2006 Oct;12(10):1198-202
references.pmid: 16917489
references.citation: AIDS. 2010 Jun 19;24(10):1598-601
references.pmid: 20549847
references.citation: Science. 2011 Dec 23;334(6063):1614
references.pmid: 22194536
references.citation: FEMS Microbiol Rev. 2012 May;36(3):706-16
references.pmid: 22372374
references.citation: J Virol. 2010 Sep;84(17):8712-20
references.pmid: 20538859
references.citation: Mol Ther. 2007 May;15(5):1024-33
references.pmid: 17356541
references.citation: PLoS Pathog. 2012 Jan;8(1):e1002437
references.pmid: 22241988
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9
references.pmid: 20837531
references.citation: Blood. 2011 Sep 22;118(12):3263-72
references.pmid: 21576701
references.citation: Blood. 2009 Jan 1;113(1):58-65
references.pmid: 18849485
references.citation: J Clin Invest. 2005 Jan;115(1):128-37
references.pmid: 15630452
references.citation: Science. 2004 Jul 9;305(5681):205-8
references.pmid: 15247470
references.citation: J Immunol. 2011 Feb 15;186(4):2106-16
references.pmid: 21257970
references.citation: Virol J. 2011 Aug 12;8:400
references.pmid: 21838863
references.citation: J Acquir Immune Defic Syndr. 2012 Jan 1;59(1):1-9
references.pmid: 21963936
references.citation: PLoS One. 2012;7(3):e34134
references.pmid: 22479542
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 27;108(52):21182-7
references.pmid: 22160724
references.citation: J Infect Dis. 2007 Mar 15;195(6):833-6
references.pmid: 17299713
references.citation: Nat Rev Cancer. 2012 Feb 09;12(3):181-95
references.pmid: 22318237
references.citation: Immunol Rev. 2012 Mar;246(1):286-310
references.pmid: 22435562
references.citation: PLoS Comput Biol. 2009 Oct;5(10):e1000533
references.pmid: 19834532
references.citation: Nature. 2012 Jul 25;487(7408):482-5
references.pmid: 22837004
references.citation: J Clin Invest. 2011 Apr;121(4):1549-60
references.pmid: 21403397
references.citation: Nat Med. 2009 Mar;15(3):285-92
references.pmid: 19219022
references.citation: J Clin Invest. 2011 Jun;121(6):2401-12
references.pmid: 21576818
references.citation: J Virol. 2012 Apr;86(7):3795-808
references.pmid: 22258251
references.citation: Nat Chem. 2012 Sep;4(9):705-10
references.pmid: 22914190
references.citation: PLoS One. 2009 Jun 30;4(6):e6093
references.pmid: 19564922
references.citation: J Virol. 2012 Apr;86(8):4548-58
references.pmid: 22345467
references.citation: Nat Med. 2010 Apr;16(4):460-5
references.pmid: 20228817
references.citation: J Exp Med. 2012 Jun 4;209(6):1201-17
references.pmid: 22641383
references.citation: J Exp Med. 1998 Mar 16;187(6):949-59
references.pmid: 9500797
references.citation: J Virol. 2010 Nov;84(22):12082-6
references.pmid: 20844049
references.citation: J Biol Chem. 2010 May 28;285(22):16538-45
references.pmid: 20335163
references.citation: J Exp Med. 2007 Oct 1;204(10):2473-85
references.pmid: 17893201
references.citation: Retrovirology. 2012 May 03;9:37
references.pmid: 22554282
references.citation: Blood. 2009 Jun 18;113(25):6304-14
references.pmid: 19380868
references.citation: AIDS. 2006 Apr 4;20(6):813-20
references.pmid: 16549964
references.citation: J Infect Dis. 2013 Jan 15;207(2):213-22
references.pmid: 23105144
references.citation: J Infect Dis. 2013 Jun 1;207(11):1694-702
references.pmid: 23460751
references.citation: Nature. 2011 Aug 17;477(7362):95-8
references.pmid: 21849975
references.citation: Retrovirology. 2012 Sep 07;9:72
references.pmid: 22958464
references.citation: PLoS One. 2011;6(11):e27463
references.pmid: 22102898
references.citation: Nat Rev Immunol. 2012 Jul 20;12(8):607-14
references.pmid: 22814509
references.citation: J Infect Dis. 2011 Jul 1;204(1):135-8
references.pmid: 21628667
references.citation: J Immunol. 2011 Aug 15;187(4):1634-42
references.pmid: 21742975
references.citation: PLoS One. 2012;7(5):e35416
references.pmid: 22590502
references.citation: PLoS Pathog. 2011 Aug;7(8):e1002184
references.pmid: 21876670
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9523-8
references.pmid: 22645358
references.citation: J Infect Dis. 2013 Jul;208(1):50-6
references.pmid: 23089590
references.citation: AIDS. 1997 Jun;11(7):849-57
references.pmid: 9189209
references.citation: Nucleic Acids Res. 2011 Nov;39(21):9283-93
references.pmid: 21813459
references.citation: Semin Immunol. 2008 Jun;20(3):196-203
references.pmid: 18757210
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3879-84
references.pmid: 18332425
references.citation: Curr Opin Infect Dis. 2001 Feb;14(1):17-22
references.pmid: 11979110