Finding a cure for HIV: will it ever be achievable?
Combination antiretroviral therapy (cART) has led to a major reduction in HIV-related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life-long treatment, there is now a real urgency to find a cure for HIV.There are currently multiple barriers to curing HIV. The most significant barrier is the establishment of a latent or "silent" infection in resting CD4+ T cells. In latent HIV infection, the virus is able to integrate into the host cell genome, but does not proceed to active replication. As a consequence, antiviral agents, as well as the immune system, are unable to eliminate these long-lived, latently infected cells. Reactivation of latently infected resting CD4+ T cells can then re-establish infection once cART is stopped. Other significant barriers to cure include residual viral replication in patients receiving cART, even when the virus is not detectable by conventional assays. In addition, HIV can be sequestered in anatomical reservoirs, such as the brain, gastrointestinal tract and genitourinary tract.Achieving either a functional cure (long-term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV-infected cells) remains a major challenge. Several studies have now demonstrated that treatment intensification appears to have little impact on latent reservoirs. Some potential and promising approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could potentially reverse latent infection.Agents that reverse latent infection will promote viral production; however, simultaneous administration of cART will prevent subsequent rounds of viral replication. Such drugs as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers, or activating latently infected resting cells with cytokines, such as IL-7 or prostratin, show promising results in reversing latency in vitro when used either alone or in combination. In order to move forward toward clinical trials that target eradication, there needs to be careful consideration of the risks and benefits of these approaches, agreement on the most informative endpoints for eradication studies and greater engagement of the infected community.
Department of Medicine, Monash University, Melbourne, Australia. s.lewin@alfred.org.au
Sharon R
SR
Lewin
Vanessa A
VA
Evans
Julian H
JH
Elliott
Bruno
B
Spire
Nicolas
N
Chomont
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D017735:Virus Latency / Q000187:drug effects
D019380:Anti-HIV Agents
Lancet. 2003 Jul 5;362(9377):22-9
12853195
Cell. 1990 Apr 20;61(2):213-22
2331748
Nat Rev Drug Discov. 2006 Sep;5(9):769-84
16955068
N Engl J Med. 1998 Mar 26;338(13):853-60
9516219
PLoS Med. 2005 Nov;2(11):e298
16231970
Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16934-9
20837531
Clin Infect Dis. 2010 Mar 15;50(6):912-9
20156060
AIDS. 2008 Jul 11;22(11):1313-22
18580611
Science. 2010 Jun 11;328(5984):1359-60
20538936
AIDS. 2003 May 23;17(8):1179-93
12819520
Science. 1997 Nov 14;278(5341):1291-5
9360926
N Engl J Med. 2009 Feb 12;360(7):692-8
19213682
J Biol Chem. 2009 Mar 13;284(11):6782-9
19136668
J Infect Dis. 2008 Jan 1;197(1):126-33
18171295
J Clin Invest. 2009 Apr;119(4):997-1007
19287090
J Neurovirol. 2006 Apr;12(2):146-52
16798676
J Virol. 2010 Jun;84(12):5958-74
20357084
PLoS Pathog. 2007 Aug 31;3(8):e122
17784786
J Neurovirol. 1998 Aug;4(4):377-86
9718129
J Infect Dis. 2010 Dec 1;202(11):1738-48
20979453
J Virol. 2009 Sep;83(17):8470-81
19535437
Science. 1999 Nov 12;286(5443):1353-7
10558989
J Immunol. 2008 Dec 1;181(11):7713-20
19017960
Nat Med. 2001 Apr;7(4):459-64
11283673
J Acquir Immune Defic Syndr. 2006 Jun;42(2):192-202
16688094
AIDS. 2010 Oct 23;24(16):2451-60
20827162
J Acquir Immune Defic Syndr. 2010 Dec 15;55(5):590-6
20847699
Immunity. 2007 Sep;27(3):406-16
17892849
Immunity. 2001 Oct;15(4):671-82
11672548
Ann Neurol. 2009 Aug;66(2):253-8
19743454
N Engl J Med. 2006 Nov 30;355(22):2283-96
17135583
J Infect Dis. 2009 Sep 15;200(6):984-90
19656066
Nat Med. 2009 Aug;15(8):893-900
19543283
Clin Cancer Res. 2009 Jun 15;15(12):3958-69
19509172
J Infect Dis. 2007 Jun 15;195(12):1762-4
17492591
Nat Med. 2003 Jun;9(6):727-8
12754504
J Virol. 2009 Jan;83(1):329-35
18945778
Lancet. 2005 Aug 13-19;366(9485):549-55
16099290
Sci Transl Med. 2010 Jun 16;2(36):36ra43
20555022
Science. 1997 Nov 14;278(5341):1295-300
9360927
PLoS Pathog. 2007 Apr;3(4):e46
17411338
AIDS. 2010 Mar 13;24(5):697-706
20177360
AIDS. 2010 Jun 19;24(10):1598-601
20549847
J Virol. 2010 Jul;84(14):7018-28
20444904
Nature. 1997 May 8;387(6629):183-8
9144289
Nat Biotechnol. 2010 Aug;28(8):839-47
20601939
Blood. 2009 Jan 1;113(1):58-65
18849485
AIDS. 2008 Jun 19;22(10):1125-9
18525257
J Infect Dis. 1999 Aug;180(2):278-84
10395840
JAMA. 2001 Jul 11;286(2):196-207
11448283
BMJ. 2009 Jan 26;338:a3172
19171560
J Infect Dis. 2010 Nov 15;202(10):1553-61
20939732
J Clin Invest. 2005 Jan;115(1):128-37
15630452
Blood. 2007 Dec 15;110(13):4161-4
17881634
J Infect Dis. 2007 Mar 15;195(6):833-6
17299713
J Infect Dis. 2010 Jun 15;201(12):1788-95
20446848
J Virol. 1992 Mar;66(3):1717-25
1371173
AIDS Res Hum Retroviruses. 2009 Feb;25(2):207-12
19239360
N Engl J Med. 2003 Nov 20;349(21):1993-2003
14627784
Ann Intern Med. 2007 Jan 16;146(2):87-95
17227932
PLoS One. 2009 Jun 30;4(6):e6093
19564922
AIDS. 2008 Jun 19;22(10):1131-5
18525258
Nat Med. 2010 Apr;16(4):460-5
20228817
Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6580-4
1631159
Lancet. 2006 Mar 11;367(9513):817-24
16530575
Nat Med. 1999 May;5(5):512-7
10229227
Blood. 2009 Jun 18;113(25):6304-14
19380868
J Immunol. 2004 Feb 15;172(4):2687-96
14764744
AIDS. 2001 Jan 5;15(1):17-22
11192864
J Infect Dis. 2002 Sep 1;186(5):634-43
12195350
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9403-8
19470482
J Virol. 2004 Jan;78(2):968-79
14694128
Science. 2010 Sep 3;329(5996):1168-74
20643915
J Clin Invest. 2009 Nov;119(11):3473-86
19805909
Health Aff (Millwood). 2009 Nov-Dec;28(6):1591-605
19887401
Nat Med. 2010 Apr;16(4):446-51
20208541
J Infect Dis. 2008 Mar 1;197(5):714-20
18260759
PLoS One. 2010 May 13;5(5):e10569
20485526
Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3879-84
18332425