An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice.
Therapeutic strategies designed to treat HIV infection with combinations of antiviral drugs have proven to be the best approach for slowing the progression to AIDS. Despite this progress, there are problems with viral drug resistance and toxicity, necessitating new approaches to combating HIV-1 infection. We have therefore developed a different combination approach for the treatment of HIV infection in which an RNA aptamer, with high binding affinity to the HIV-1 envelope (gp120) protein and virus neutralization properties, is attached to and delivers a small interfering RNA (siRNA) that triggers sequence-specific degradation of HIV RNAs. We have tested the antiviral activities of these chimeric RNAs in a humanized Rag2(-/-)γc(-/-) (RAG-hu) mouse model with multilineage human hematopoiesis. In this animal model, HIV-1 replication and CD4(+) T cell depletion mimic the situation seen in human HIV-infected patients. Our results show that treatment with either the anti-gp120 aptamer or the aptamer-siRNA chimera suppressed HIV-1 replication by several orders of magnitude and prevented the viral-induced helper CD4(+) T cell decline. In comparison to the aptamer alone, the aptamer-siRNA combination provided more extensive inhibition, resulting in a significantly longer antiviral effect that extended several weeks beyond the last injected dose. The aptamer thus acts as a broad-spectrum HIV-neutralizing agent and an siRNA delivery vehicle. The combined aptamer-siRNA agent provides an attractive, nontoxic therapeutic approach for treatment of HIV infection.
Department of Microbiology, Immunology and Pathology, Colorado State University, 1619 Campus Delivery, Fort Collins, CO 80523, USA.
Charles Preston
CP
Neff
Jiehua
J
Zhou
Leila
L
Remling
Jes
J
Kuruvilla
Jane
J
Zhang
Haitang
H
Li
David D
DD
Smith
Piotr
P
Swiderski
John J
JJ
Rossi
Ramesh
R
Akkina
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009690:Nucleic Acid Conformation; D034741:RNA, Small Interfering / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000821:virology*; D019562:Viral Load
D000998:Antiviral Agents; D052157:Aptamers, Nucleotide; D034741:RNA, Small Interfering
Mol Cell. 2004 Jul 23;15(2):185-97
15260970
Retrovirology. 2009 Aug 12;6:76
19674458
Nat Rev Immunol. 2009 Apr;9(4):235-45
19319142
Nucleic Acids Res. 2009 May;37(9):3094-109
19304999
Virology. 2008 Apr 10;373(2):342-51
18207484
Nat Med. 2002 Jul;8(7):681-6
12042777
Curr Opin Mol Ther. 2007 Apr;9(2):137-44
17458167
Nat Biotechnol. 2005 Jun;23(6):709-17
15908939
Cell. 2005 Nov 18;123(4):607-20
16271386
Mol Ther. 2008 Aug;16(8):1481-9
18461053
Nat Biotechnol. 2006 Aug;24(8):1005-15
16823371
Retrovirology. 2006 Nov 01;3:76
17078891
Cancer Res. 2006 Jun 15;66(12):5989-92
16778167
Cell Host Microbe. 2009 Jul 23;6(1):5-9
19616761
Nat Biotechnol. 2009 Sep;27(9):839-49
19701187
Nature. 2009 Jan 22;457(7228):426-33
19158789
Nucleic Acids Res. 2006 Jun 01;34(10):e73
16740739
Vet Pathol. 2011 Mar;48(2):495-9
20817888
Nat Biotechnol. 2005 Apr;23(4):457-62
15778705
Nature. 2006 Jan 5;439(7072):89-94
16306938
Biotechniques. 2006 Apr;Suppl:25-9
16629384
Science. 1990 Aug 3;249(4968):505-10
2200121
Angew Chem Int Ed Engl. 2009;48(15):2672-89
19319884
Cell. 2008 Aug 22;134(4):577-86
18691745
Curr Opin Mol Ther. 2004 Aug;6(4):373-80
15468596
Genome Res. 2008 May;18(5):763-70
18212088
Nature. 1990 Aug 30;346(6287):818-22
1697402
Nat Med. 2005 Mar;11(3):263-70
15723075
Curr HIV/AIDS Rep. 2009 Feb;6(1):13-9
19149992
Virology. 2010 Feb 5;397(1):100-3
19922970
Nat Biotechnol. 2007 Dec;25(12):1444-54
18066041
Science. 2009 Mar 6;323(5919):1304-7
19265012
Gene Ther. 2007 Jul;14(14):1057-64
17607313