Despite nearly three decades of research, a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) has yet to be achieved. More recently, the discovery of highly potent anti-gp160 broadly neutralizing antibodies (bNAbs) has garnered renewed interest in using antibody-based prophylactic and therapeutic approaches. Here, we encoded bNAbs in first-generation adenoviral (ADV) vectors, which have the distinctive features of a large coding capacity and ease of propagation. A single intramuscular injection of ADV-vectorized bNAbs in humanized mice generated high serum levels of bNAbs that provided protection against multiple repeated challenges with a high dose of HIV-1, prevented depletion of peripheral CD4+ T cells, and reduced plasma viral loads to below detection limits. Our results suggest that ADV vectors may be a viable option for the prophylactic and perhaps therapeutic use of bNAbs in humans.
Get full access to this article
View all access options for this article.
References
1.
FauciAS, JohnstonMI, DieffenbachCW, et al.HIV vaccine research: the way forward. Science, 2008; 321:530–532.
2.
WalkerBD, BurtonDR. Toward an AIDS vaccine. Science, 2008; 320:760–764.
3.
EsteJA, CihlarT. Current status and challenges of antiretroviral research and therapy. Antiviral Res, 2010; 85:25–33.
4.
PiacentiFJ. An update and review of antiretroviral therapy. Pharmacotherapy, 2006; 26:1111–1133.
5.
KleinF, DiskinR, ScheidJF, et al.Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell, 2013; 153:126–138.
YangG, HollTM, LiuY, et al.Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp Med, 2013; 210:241–256.
8.
JohnsonPR, SchneppBC, ZhangJ, et al.Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat Med, 2009; 15:901–906.
9.
BalazsAB, ChenJ, HongCM, et al.Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature, 2012; 481:81–84.
10.
BalazsAB, OuyangY, HongCM, et al.Vectored immunoprophylaxis protects humanized mice from mucosal HIV transmission. Nat Med, 2014; 20:296–300.
11.
HeilbronnR, WegerS. Viral vectors for gene transfer: current status of gene therapeutics. Handb Exp Pharmacol, 2006; 2010:143–170.
Van Der LaanLJ, WangY, TilanusHW, et al.AAV-mediated gene therapy for liver diseases: the prime candidate for clinical application?. Expert Opin Biol Ther, 2011; 11:315–327.
14.
McConnellMJ, ImperialeMJ. Biology of adenovirus and its use as a vector for gene therapy. Hum Gene Ther, 2004; 15:1022–1033.
15.
VolpersC, KochanekS. Adenoviral vectors for gene transfer and therapy. J Gene Med, 2004; 6Suppl 1:S164–S171.
16.
CrystalRG. Adenovirus: the first effective in vivo gene delivery vector. Hum Gene Ther, 2014; 25:3–11.
17.
CrystalRG, HarveyBG, WisniveskyJP, et al.Analysis of risk factors for local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum Gene Ther, 2002; 13:65–100.
18.
HarveyBG, MaroniJ, O'DonoghueKA, et al.Safety of local delivery of low- and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of morbid conditions. Hum Gene Ther, 2002; 13:15–63.
19.
WuX, YangZY, LiY, et al.Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science, 2010; 329:856–861.
20.
WalkerLM, PhogatSK, Chan-HuiPY, et al.Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science, 2009; 326:285–289.
21.
KumarP, BanHS, KimSS, et al.T cell-specific siRNA delivery suppresses HIV-1 infection in humanized mice. Cell, 2008; 134:577–586.
22.
PalmerDJ, NgP. Methods for the production of first generation adenoviral vectors. Methods Mol Biol, 2008; 433:55–78.
23.
BrasierAR, FortinJJ. Nonisotopic assays for reporter gene activity. In: Current Protocols in Molecular Biology.AusubelFM, AlbrightLM, JuJ, eds. John Wiley & Sons, New York. 2001; Chapter 9, Unit 9.7B.
24.
PetersPJ, RichardsK, ClaphamP. Human immunodeficiency viruses: propagation, quantification, and storage. Curr Protoc Microbiol Chapter 2013; 15, Unit 15J.1.
25.
KimSS, KumarP, YeC, et al.Humanized mice for studying human leukocyte integrins in vivo. Methods Mol Biol, 2012; 757:509–521.
26.
PalmerDJ, NgP. Methods for the production of helper-dependent adenoviral vectors. Methods Mol Biol, 2008; 433:33–53.
27.
BurtonDR, PyatiJ, KoduriR, et al.Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science, 1994; 266:1024–1027.
28.
CalareseDA, ScanlanCN, ZwickMB, et al.Antibody domain exchange is an immunological solution to carbohydrate cluster recognition. Science, 2003; 300:2065–2071.
29.
ManriqueA, RusertP, JoosB, et al.In vivo and in vitro escape from neutralizing antibodies 2G12, 2F5, and 4E10. J Virol, 2007; 81:8793–8808.
30.
MascolaJR, LewisMG, StieglerG, et al.Protection of macaques against pathogenic simian/human immunodeficiency virus 89.6PD by passive transfer of neutralizing antibodies. J Virol, 1999; 73:4009–4018.
31.
MehandruS, VcelarB, WrinT, et al.Adjunctive passive immunotherapy in human immunodeficiency virus type 1-infected individuals treated with antiviral therapy during acute and early infection. J Virol, 2007; 81:11016–11031.
32.
PoignardP, SabbeR, PicchioGR, et al.Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity, 1999; 10:431–438.
33.
ChunTW, MurrayD, JustementJS, et al.Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proc Natl Acad Sci U S A, 2014; 111:13151–13156.
34.
Halper-StrombergA, LuCL, KleinF, et al.Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell, 2014; 158:989–999.
35.
TrkolaA, KusterH, RusertP, et al.Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing antibodies. Nat Med, 2005; 11:615–622.
36.
KleinF, Halper-StrombergA, HorwitzJA, et al.HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature, 2012; 492:118–122.
37.
BarouchDH, WhitneyJB, MoldtB, et al.Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature, 2013; 503:224–228.
38.
ShingaiM, NishimuraY, KleinF, et al.Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature, 2013; 503:277–280.
39.
JiangM, ShiW, ZhangQ, et al.Gene therapy using adenovirus-mediated full-length anti-HER-2 antibody for HER-2 overexpression cancers. Clin Cancer Res, 2006; 12:6179–6185.
40.
KasuyaK, BoyerJL, TanY, et al.Passive immunotherapy for anthrax toxin mediated by an adenovirus expressing an anti-protective antigen single-chain antibody. Mol Ther, 2005; 11:237–244.
41.
SkaricicD, TraubeC, DeB, et al.Genetic delivery of an anti-RSV antibody to protect against pulmonary infection with RSV. Virology, 2008; 378:79–85.
42.
ChenW, FengY, PrabakaranP, et al.Exceptionally potent and broadly cross-reactive, bispecific multivalent HIV-1 inhibitors based on single human CD4 and antibody domains. J Virol, 2014; 88:1125–1139.
43.
PaceCS, SongR, OchsenbauerC, et al.Bispecific antibodies directed to CD4 domain 2 and HIV envelope exhibit exceptional breadth and picomolar potency against HIV-1. Proc Natl Acad Sci U S A, 2013; 110:13540–13545.
44.
MarshallE. Gene therapy death prompts review of adenovirus vector. Science, 1999; 286:2244–2245.
45.
KaiserJ. Clinical research: death prompts a review of gene therapy vector. Science, 2007; 317:580.
46.
AntrobusRD, CoughlanL, BerthoudTK, et al.Clinical assessment of a novel recombinant simian adenovirus ChAdOx1 as a vectored vaccine expressing conserved influenza A antigens. Mol Ther, 2014; 22:668–674.
47.
WuH, DmitrievI, KashentsevaE, et al.Construction and characterization of adenovirus serotype 5 packaged by serotype 3 hexon. J Virol, 2002; 76:12775–12782.
48.
Brunetti-PierriN, NgT, IannittiD, et al.Transgene expression up to 7 years in nonhuman primates following hepatic transduction with helper-dependent adenoviral vectors. Hum Gene Ther, 2013; 24:761–765.
49.
McCormackWMJr, SeilerMP, BertinTK, et al.Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model. J Thromb Haemost, 2006; 4:1218–1225.
50.
PastoreL, BelalcazarLM, OkaK, et al.Helper-dependent adenoviral vector-mediated long-term expression of human apolipoprotein A-I reduces atherosclerosis in apo E-deficient mice. Gene, 2004; 327:153–160.
51.
ToiettaG, ManeVP, NoronaWS, et al.Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A, 2005; 102:3930–3935.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
