The key to an effective HIV vaccine is development of an immunogen that elicits persisting antibodies with broad neutralizing activity against field strains of the virus. Unfortunately, very little progress has been made in finding or designing such immunogens. Using the simian immunodeficiency virus (SIV) model, we have taken a markedly different approach: delivery to muscle of an adeno-associated virus gene transfer vector expressing antibodies or antibody-like immunoadhesins having predetermined SIV specificity. With this approach, SIV-specific molecules are endogenously synthesized in myofibers and passively distributed to the circulatory system. Using such an approach in monkeys, we have now generated long-lasting neutralizing activity in serum and have observed complete protection against intravenous challenge with virulent SIV. In essence, this strategy bypasses the adaptive immune system and holds considerable promise as a unique approach to an effective HIV vaccine.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
npj Vaccines Open Access 04 July 2022
Virology Journal Open Access 30 January 2021
Cellular and Molecular Life Sciences Open Access 17 October 2018
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Buchbinder, S.P. et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372, 1881–1893 (2008).
Flynn, N.M. et al. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J. Infect. Dis. 191, 654–665 (2005).
McElrath, M.J. et al. HIV-1 vaccine–induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372, 1894–1905 (2008).
Pitisuttithum, P. et al. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194, 1661–1671 (2006).
Desrosiers, R.C. Prospects for an AIDS vaccine. Nat. Med. 10, 221–223 (2004).
Fauci, A.S. et al. HIV vaccine research: the way forward. Science 321, 530–532 (2008).
Morgan, C. et al. The use of nonhuman primate models in HIV vaccine development. PLoS Med. 5, e173 (2008).
Walker, B.D. & Burton, D.R. Toward an AIDS vaccine. Science 320, 760–764 (2008).
Watkins, D.I. Basic HIV vaccine development. Top. HIV Med. 16, 7–8 (2008).
Binley, J.M. et al. Profiling the specificity of neutralizing antibodies in a large panel of plasmas from patients chronically infected with human immunodeficiency virus type 1 subtypes B and C. J. Virol. 82, 11651–11668 (2008).
Li, Y. et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat. Med. 13, 1032–1034 (2007).
Burton, D.R. et al. Efficient neutralization of primary isolates of HIV-1 by a recombinant human monoclonal antibody. Science 266, 1024–1027 (1994).
Muster, T. et al. A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1. J. Virol. 67, 6642–6647 (1993).
Trkola, A. et al. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1. J. Virol. 70, 1100–1108 (1996).
Zwick, M.B. et al. Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41. J. Virol. 75, 10892–10905 (2001).
Baba, T.W. et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat. Med. 6, 200–206 (2000).
Mascola, J.R. et al. Protection of macaques against vaginal transmission of a pathogenic HIV-1/SIV chimeric virus by passive infusion of neutralizing antibodies. Nat. Med. 6, 207–210 (2000).
Parren, P.W. et al. Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J. Virol. 75, 8340–8347 (2001).
Sanhadji, K. et al. Gene transfer of anti-gp41 antibody and CD4 immunoadhesin strongly reduces the HIV-1 load in humanized severe combined immunodeficient mice. AIDS 14, 2813–2822 (2000).
Lewis, A.D., Chen, R., Montefiori, D.C., Johnson, P.R. & Clark, K.R. Generation of neutralizing activity against human immunodeficiency virus type 1 in serum by antibody gene transfer. J. Virol. 76, 8769–8775 (2002).
Johnson, W.E. et al. Assorted mutations in the envelope gene of simian immunodeficiency virus lead to loss of neutralization resistance against antibodies representing a broad spectrum of specificities. J. Virol. 77, 9993–10003 (2003).
Means, R.E. et al. Ability of the V3 loop of simian immunodeficiency virus to serve as a target for antibody-mediated neutralization: correlation of neutralization sensitivity, growth in macrophages, and decreased dependence on CD4. J. Virol. 75, 3903–3915 (2001).
Mori, K., Ringler, D.J., Kodama, T. & Desrosiers, R. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J. Virol. 66, 2067–2075 (1992).
Allaway, G.P., Ryder, A.M., Beaudry, G.A. & Maddon, P.J. Synergistic inhibition of HIV-1 envelope-mediated cell fusion by CD4-based molecules in combination with antibodies to gp120 or gp41. AIDS Res. Hum. Retroviruses 9, 581–587 (1993).
McCarty, D.M. et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 10, 2112–2118 (2003).
McCarty, D.M. Self-complementary AAV vectors; advances and applications. Mol. Ther. 16, 1648–1656 (2008).
Rabinowitz, J.E. et al. Cross-packaging of a single adeno-associated virus (AAV) type 2 vector genome into multiple AAV serotypes enables transduction with broad specificity. J. Virol. 76, 791–801 (2002).
Herzog, R.W. et al. Long-term correction of canine hemophilia B by gene transfer of blood coagulation factor IX mediated by adeno-associated viral vector. Nat. Med. 5, 56–63 (1999).
Davidoff, A.M. et al. Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol. Ther. 11, 875–888 (2005).
Fang, J. et al. Stable antibody expression at therapeutic levels using the 2A peptide. Nat. Biotechnol. 23, 584–590 (2005).
Honegger, A. Engineering antibodies for stability and efficient folding. Handb. Exp. Pharmacol. 181, 47–68 (2008).
dos Santos Coura, R. & Nardi, N.B. The state of the art of adeno-associated virus–based vectors in gene therapy. Virol. J. 4, 99 (2007).
Daya, S. & Berns, K.I. Gene therapy using adeno-associated virus vectors. Clin. Microbiol. Rev. 21, 583–593 (2008).
Chenuaud, P. et al. Optimal design of a single recombinant adeno-associated virus derived from serotypes 1 and 2 to achieve more tightly regulated transgene expression from nonhuman primate muscle. Mol. Ther. 9, 410–418 (2004).
Penaud-Budloo, M. et al. Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J. Virol. 82, 7875–7885 (2008).
Rivera, V.M. et al. Long-term pharmacologically regulated expression of erythropoietin in primates following AAV-mediated gene transfer. Blood 105, 1424–1430 (2005).
Toromanoff, A. et al. Safety and efficacy of regional intravenous (r.i.) versus intramuscular (i.m.) delivery of rAAV1 and rAAV8 to nonhuman primate skeletal muscle. Mol. Ther. 16, 1291–1299 (2008).
Schnepp, B.C., Clark, K.R., Klemanski, D.L., Pacak, C.A. & Johnson, P.R. Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J. Virol. 77, 3495–3504 (2003).
Schnepp, B.C., Jensen, R.L., Clark, K.R. & Johnson, P.R. Infectious molecular clones of adeno-associated virus isolated directly from human tissues. J. Virol. 83, 1456–1464 (2009).
Fang, J. et al. An antibody delivery system for regulated expression of therapeutic levels of monoclonal antibodies in vivo. Mol. Ther. 15, 1153–1159 (2007).
Frade, R., Rousselet, N. & Jean, D. Intratumoral gene delivery of anti–cathepsin L single-chain variable fragment by lentiviral vector inhibits tumor progression induced by human melanoma cells. Cancer Gene Ther. 15, 591–604 (2008).
He, J. et al. Construction and delivery of gene therapy vector containing soluble TNFα receptor–IgGFc fusion gene for the treatment of allergic rhinitis. Cytokine 36, 296–304 (2006).
Jiang, M. et al. Gene therapy using adenovirus-mediated full-length anti–HER-2 antibody for HER-2 overexpression cancers. Clin. Cancer Res. 12, 6179–6185 (2006).
Kasuya, K. et al. Passive immunotherapy for anthrax toxin mediated by an adenovirus expressing an anti-protective antigen single-chain antibody. Mol. Ther. 11, 237–244 (2005).
Pereboev, A. et al. Genetically delivered antibody protects against West Nile virus. Antiviral Res. 77, 6–13 (2008).
Sandalon, Z. et al. Secretion of a TNFR:Fc fusion protein following pulmonary administration of pseudotyped adeno-associated virus vectors. J. Virol. 78, 12355–12365 (2004).
Skaricic, D. et al. Genetic delivery of an anti-RSV antibody to protect against pulmonary infection with RSV. Virology 378, 79–85 (2008).
Vigna, E. et al. “Active” cancer immunotherapy by anti-Met antibody gene transfer. Cancer Res. 68, 9176–9183 (2008).
Yuvaraj, S. et al. Human scFv SIgA expressed on Lactococcus lactis as a vector for the treatment of mucosal disease. Mol. Nutr. Food Res. 52, 913–920 (2008).
Zuber, C. et al. Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy. J. Gen. Virol. 89, 2055–2061 (2008).
Jones, T.D. et al. The development of a modified human IFN-α2b linked to the Fc portion of human IgG1 as a novel potential therapeutic for the treatment of hepatitis C virus infection. J. Interferon Cytokine Res. 24, 560–572 (2004).
Swann, P.G. et al. Considerations for the development of therapeutic monoclonal antibodies. Curr. Opin. Immunol. 20, 493–499 (2008).
Cadogan, M. & Dalgleish, A.G. HIV immunopathogenesis and strategies for intervention. Lancet Infect. Dis. 8, 675–684 (2008).
Hessell, A.J. et al. Fc receptor but not complement binding is important in antibody protection against HIV. Nature 449, 101–104 (2007).
Schiller, J.T., Castellsague, X., Villa, L.L. & Hildesheim, A. An update of prophylactic human papillomavirus L1 virus–like particle vaccine clinical trial results. Vaccine 26 Suppl 10, K53–K61 (2008).
Barash, S., Wang, W. & Shi, Y. Human secretory signal peptide description by hidden Markov model and generation of a strong artificial signal peptide for secreted protein expression. Biochem. Biophys. Res. Commun. 294, 835–842 (2002).
Ostedgaard, L.S. et al. A shortened adeno-associated virus expression cassette for CFTR gene transfer to cystic fibrosis airway epithelia. Proc. Natl. Acad. Sci. USA 102, 2952–2957 (2005).
Levitt, N., Briggs, D., Gil, A. & Proudfoot, N.J. Definition of an efficient synthetic poly(A) site. Genes Dev. 3, 1019–1025 (1989).
Clark, K.R., Liu, X., McGrath, J.P. & Johnson, P.R. Highly purified recombinant adeno-associated virus vectors are biologically active and free of detectable helper and wild-type viruses. Hum. Gene Ther. 10, 1031–1039 (1999).
Lifson, J.D. et al. Role of CD8+ lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment. J. Virol. 75, 10187–10199 (2001).
We thank A. Hessell and D. Burton (The Scripps Research Institute) for providing the SIV Fab molecular clones, D. McCarty (The Research Institute at Nationwide Children's Hospital) for the self-complementary AAV vector genome, R. Doms (University of Pennsylvania) for purified SIVmac gp120, J. Bixby and E. Mackenzie for technical assistance and M. Piatek and J. Lifson for SIV viral load data. We also thank J. Hoxie and S. Douglas for helpful comments on the manuscript. Funding for this work was provided by grants from the US National Institutes of Health National Institute of Allergy and Infectious Diseases Division of AIDS (P.R.J. and R.C.D.), National Institutes of Health National Center for Research Resources (R.C.D.) and support from The Children's Hospital of Philadelphia.
About this article
Cite this article
Johnson, P., Schnepp, B., Zhang, J. et al. Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Nat Med 15, 901–906 (2009). https://doi.org/10.1038/nm.1967
This article is cited by
Adeno-associated virus mediated expression of monoclonal antibody MR191 protects mice against Marburg virus and provides long-term expression in sheep
Gene Therapy (2022)
npj Vaccines (2022)
Nature Biotechnology (2022)
Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial
Nature Medicine (2022)
Virology Journal (2021)