Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody.
Due to the inherent immune evasion properties of the HIV envelope, broadly neutralizing HIV-specific antibodies capable of suppressing HIV infection are rarely produced by infected individuals. We examined the feasibility of utilizing genetic engineering to circumvent the restricted capacity of individuals to endogenously produce broadly neutralizing HIV-specific antibodies. We constructed a single lentiviral vector that encoded the heavy and light chains of 2G12, a broadly neutralizing anti-HIV human antibody, and that efficiently transduced and directed primary human B cells to secrete 2G12. To evaluate the capacity of this approach to provide protection from in vivo HIV infection, we used the humanized NOD/SCID/gamma(c)(null) mouse model, which becomes populated with human B cells, T cells, and macrophages after transplantation with human hematopoietic stem cells (hu-HSC) and develops in vivo infection after inoculation with HIV. The plasma of the irradiated NOD/SCID/gamma(c)(null) mice transplanted with hu-HSC transduced with the 2G12-encoding lentivirus contained 2G12 antibody, likely secreted by progeny human lymphoid and/or myeloid cells. After intraperitoneal inoculation with high-titer HIV-1(JR-CSF), mice engrafted with 2G12-transduced hu-HSC displayed marked inhibition of in vivo HIV infection as manifested by a profound 70-fold reduction in plasma HIV RNA levels and an almost 200-fold reduction in HIV-infected human cell numbers in mouse spleens, compared to control hu-HSC-transplanted NOD/SCID/gamma(c)(null) mice inoculated with equivalent high-titer HIV-1(JR-CSF). These results support the potential efficacy of this new gene therapy approach of using lentiviral vectors encoding a mixture of broadly neutralizing HIV antibodies for the treatment of HIV infection, particularly infection with multiple-drug-resistant isolates.
Joseph
Aviva
A
Departments of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Zheng
Jian Hua
JH
Chen
Ken
K
Dutta
Monica
M
Chen
Cindy
C
Stiegler
Gabriela
G
Kunert
Renate
R
Follenzi
Antonia
A
Goldstein
Harris
H
D000818:Animals; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016086:Lentivirus / Q000235:genetics; D016180:Lentivirus Infections; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000821:virology; D019562:Viral Load
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral
J Virol. 2006 Feb;80(4):1850-62
16439541
Science. 2005 Jun 24;308(5730):1906-8
15860590
Virology. 2009 May 10;387(2):414-26
19298995
Antimicrob Agents Chemother. 2002 Jun;46(6):1896-905
12019106
Science. 1998 Jun 19;280(5371):1884-8
9632381
Mol Biotechnol. 2007 Jul;36(3):184-204
17873406
J Virol. 2003 Jun;77(12):6965-78
12768015
Biochem Biophys Res Commun. 2004 Jun 4;318(3):673-9
15144890
Virology. 2008 Jun 5;375(2):315-20
18367229
J Virol. 2007 Oct;81(20):11016-31
17686878
Blood. 2000 Jan 1;95(1):102-10
10607692
Hum Vaccin. 2005 Mar-Apr;1(2):45-60
17038830
Nat Biotechnol. 2004 May;22(5):589-94
15064769
Nat Immunol. 2004 Mar;5(3):233-6
14985706
J Virol. 2009 Jan;83(1):98-104
18945777
Nat Med. 2005 Jun;11(6):593-4
15937465
J Virol. 1996 Feb;70(2):1100-8
8551569
J Virol. 2008 Mar;82(6):3078-89
18184707
J Virol. 2003 Apr;77(7):4095-103
12634368
J Virol. 2007 Aug;81(16):8793-808
17567707
AIDS. 2000 Dec 22;14(18):2813-22
11153662
Curr HIV Res. 2007 Nov;5(6):642-55
18045119
J Infect Dis. 2002 Nov 15;186(10):1412-21
12404156
AIDS Res Hum Retroviruses. 1998 Sep 1;14(13):1115-28
9737583
AIDS. 2005 Nov 18;19(17):1957-66
16260901
AIDS Res Hum Retroviruses. 2005 Feb;21(2):125-39
15725751
Protein Expr Purif. 1996 Jun;7(4):335-42
8776749
Nat Rev Microbiol. 2008 Feb;6(2):143-55
18197170
J Infect Dis. 1998 Feb;177(2):337-46
9466519
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17372-7
17090675
Blood. 2003 Aug 1;102(3):873-80
12689924
Methods Mol Biol. 2004;246:367-90
14970605
Immunol Lett. 1998 Dec;64(2-3):139-44
9870665
Nat Med. 2009 Aug;15(8):901-6
19448633
Nature. 2003 Mar 20;422(6929):307-12
12646921
AIDS Res Hum Retroviruses. 1994 Apr;10(4):359-69
7520721
Blood. 2007 Jan 1;109(1):212-8
16954502
Nat Genet. 2000 Jun;25(2):217-22
10835641
PLoS Med. 2006 Nov;3(11):e427
17090209
Methods Enzymol. 2002;346:454-65
11883085
Mol Ther. 2009 May;17(5):844-50
19259065