Efficacy of Carraguard-based microbicides in vivo despite variable in vitro activity.
Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard and a new generation Carraguard-based formulation containing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (PC-817). Since dendritic cells (DCs) are believed to be important in HIV transmission, the formulations were tested for the ability to limit DC-driven infection in vitro versus vaginal infection of macaques with RT-SHIV (SIVmac239 bearing HIV reverse transcriptase). Carraguard showed limited activity against cell-free and mature DC-driven RT-SHIV infections and, surprisingly, low doses of Carraguard enhanced infection. However, nanomolar amounts of MIV-150 overcame enhancement and blocked DC-transmitted infection. In contrast, Carraguard impeded infection of immature DCs coincident with DC maturation. Despite this variable activity in vitro, Carraguard and PC-817 prevented vaginal transmission of RT-SHIV when applied 30 min prior to challenge. PC-817 appeared no more effective than Carraguard in vivo, due to the limited activity of a single dose of MIV-150 and the dominant barrier effect of Carraguard. However, 3 doses of MIV-150 in placebo gel at and around challenge limited vaginal infection, demonstrating the potential activity of a topically applied NNRTI. These data demonstrate discordant observations when comparing in vitro and in vivo efficacy of Carraguard-based microbicides, highlighting the difficulties in testing putative anti-viral strategies in vitro to predict in vivo activity. This work also underscores the potential of Carraguard-based formulations for the delivery of anti-viral drugs to prevent vaginal HIV infection.
Turville
Stuart G
SG
Center for Biomedical Research, HIV and AIDS Program, Population Council, New York, New York, United States of America.
Aravantinou
Meropi
M
Miller
Todd
T
Kenney
Jessica
J
Teitelbaum
Aaron
A
Hu
Lieyu
L
Chudolij
Anne
A
Zydowsky
Tom M
TM
Piatak
Michael
M
Bess
Julian W
JW
Lifson
Jeffrey D
JD
Blanchard
James
J
Gettie
Agegnehu
A
Robbiani
Melissa
M
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002351:Carrageenan / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000821:virology; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission; D006801:Humans; D008251:Macaca; D009000:Monocytes / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control / Q000635:transmission; D015302:Simian Immunodeficiency Virus / Q000378:metabolism; D019562:Viral Load
D000890:Anti-Infective Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D018894:Reverse Transcriptase Inhibitors; D002351:Carrageenan
J Virol. 1994 Oct;68(10):6391-400
8083977
Science. 2003 May 23;300(5623):1295-7
12730499
Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5640-5
15064398
J Exp Med. 2004 Apr 19;199(8):1065-75
15078900
Science. 2004 Oct 15;306(5695):485-7
15486300
Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8210-4
7545297
Cell. 1994 Aug 12;78(3):389-98
7914836
Nat Rev Immunol. 2006 Nov;6(11):859-68
17063186
J Biol Chem. 1977 Sep 25;252(18):6438-42
893418
J Virol. 2008 Jun;82(11):5329-39
18367527
Viral Immunol. 1999;12(1):23-33
10333239
J Acquir Immune Defic Syndr. 2003 Sep 1;34(1):7-19
14501788
J Biol Chem. 2008 May 30;283(22):15193-200
18378683
J Acquir Immune Defic Syndr. 2008 Feb 1;47(2):253-7
18025996
J Immunol. 2001 Mar 15;166(6):3780-8
11238620
Sex Transm Dis. 2001 May;28(5):259-65
11354263
J Acquir Immune Defic Syndr. 2008 Aug 1;48(4):398-407
18614931
Antiviral Res. 2003 Apr;58(2):139-47
12742574
J Acquir Immune Defic Syndr. 2007 Dec 15;46(5):538-46
18193495
J Virol. 2006 Feb;80(4):1992-9
16439555
Infect Immun. 1995 Sep;63(9):3520-6
7642286
Clin Diagn Lab Immunol. 1997 Jul;4(4):465-8
9220165
Blood. 1999 Jun 1;93(11):3866-75
10339495
Science. 2008 Apr 4;320(5872):30-1
18388263
Am J Pathol. 1999 Jun;154(6):1923-32
10362819
AIDS Res Hum Retroviruses. 2004 Jul;20(7):772-87
15307924
J Virol. 2007 Oct;81(20):11352-62
17686876
J Virol. 1998 Apr;72(4):2733-7
9525591
Blood. 2004 Mar 15;103(6):2170-9
14630806
J Virol. 2004 Mar;78(6):3140-4
14990733
AIDS Res Hum Retroviruses. 1999 Dec 10;15(18):1691-701
10606092
Nature. 2002 May 2;417(6884):95-8
11986671
J Leukoc Biol. 2006 Nov;80(5):1076-83
16908515
Nat Med. 2003 Jul;9(7):847-52
12835704
Nat Rev Microbiol. 2003 Oct;1(1):25-34
15040177
J Virol. 2000 Feb;74(4):1948-60
10644368
Nat Rev Immunol. 2005 Oct;5(10):783-92
16200081
Antimicrob Agents Chemother. 1994 Dec;38(12):2910-6
7695283
JAMA. 2004 Jul 14;292(2):171-9
15249566
J Virol. 2002 Apr;76(7):3338-49
11884559
Nature. 2005 Nov 3;438(7064):99-102
16258536
J Virol. 2007 Jul;81(13):6858-68
17442711
Cell. 2007 Dec 14;131(6):1059-71
18083097
Science. 1999 Nov 12;286(5443):1353-7
10558989
J Virol. 2005 Nov;79(21):13519-27
16227272
AIDS. 2007 Nov 30;21(18):2369-76
18025873
J Virol. 2009 Jan;83(2):884-95
19004943
Antimicrob Agents Chemother. 2004 Oct;48(10):3834-44
15388443
Science. 2006 Feb 3;311(5761):664-6
16456081
J Exp Med. 2005 Jun 20;201(12):2023-33
15967828
Science. 1999 Feb 5;283(5403):857-60
9933172
Science. 2004 Apr 30;304(5671):714-8
15118157
Nat Methods. 2008 Jan;5(1):75-85
18059278
JAMA. 2002 Mar 6;287(9):1171-2
11879115
AIDS. 1998 Jul 9;12(10):1129-38
9677161
J Biol Chem. 2005 Jun 3;280(22):21353-7
15797855
Sex Transm Dis. 2008 Mar;35(3):226-32
18490865
Antimicrob Agents Chemother. 2007 May;51(5):1770-9
17353237
Nat Med. 2007 Jul;13(7):857-61
17603495
Sex Transm Dis. 2007 Jan;34(1):9-14
16924181
J Virol. 2001 Nov;75(21):10187-99
11581387
AIDS Res Hum Retroviruses. 2003 Mar;19(3):177-86
12689409
J Med Primatol. 2005 Oct;34(5-6):303-12
16128925
J Exp Med. 2003 Nov 17;198(10):1551-62
14623909
J Virol. 2007 Jul;81(14):7559-70
17475656
Sex Transm Dis. 1998 Oct;25(9):494-500
9800263
Nat Rev Immunol. 2006 May;6(5):371-82
16639430
Antimicrob Agents Chemother. 1988 Nov;32(11):1742-5
2472775
Nat Med. 2003 Mar;9(3):343-6
12579198
J Exp Med. 1998 May 18;187(10):1623-31
9584140
J Virol. 2003 Feb;77(4):2762-7
12552019
JAMA. 2000 Sep 20;284(11):1376
11023388
PLoS Pathog. 2006 Jul;2(7):e69
16839203
J Virol. 2002 Mar;76(6):2936-51
11861860
AIDS Res Hum Retroviruses. 2004 Jan;20(1):11-8
15000694
Lancet. 2008 Dec 6;372(9654):1977-87
19059048
J Exp Med. 2000 Nov 20;192(10):1491-500
11085750
J Virol. 2007 Sep;81(17):8933-43
17567699