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Control of Viremia and Prevention of Clinical AIDS in Rhesus Monkeys by Cytokine-Augmented DNA Vaccination
Dan H. Barouch,1*Sampa Santra,1Jörn E. Schmitz,1Marcelo J. Kuroda,1Tong-Ming Fu,2Wendeline Wagner,3Miroslawa Bilska,4Abie Craiu,1Xin Xiao Zheng,1Georgia R. Krivulka,1Kristin Beaudry,1Michelle A. Lifton,1Christine E. Nickerson,1Wendy L. Trigona,2Kara Punt,2Dan C. Freed,2Liming Guan,2Sheri Dubey,2Danilo Casimiro,2Adam Simon,2Mary-Ellen Davies,2Michael Chastain,2Terry B. Strom,1Rebecca S. Gelman,5David C. Montefiori,4Mark G. Lewis,3Emilio A. Emini,2John W. Shiver,2Norman L. Letvin1
With accumulating evidence indicating the importance of
cytotoxic T lymphocytes (CTLs) in containing human immunodeficiencyvirus-1 (HIV-1) replication in infected individuals, strategiesare
being pursued to elicit virus-specific CTLs with prototypeHIV-1
vaccines. Here, we report the protective efficacy of vaccine-elicitedimmune responses against a pathogenic SHIV-89.6P challenge inrhesus
monkeys. Immune responses were elicited by DNA vaccinesexpressing
SIVmac239 Gag and HIV-1 89.6P Env, augmented by theadministration of
the purified fusion protein IL-2/Ig, consistingof interleukin-2 (IL-2)
and the Fc portion of immunoglobulin G(IgG), or a plasmid encoding
IL-2/Ig. After SHIV-89.6P infection,sham-vaccinated monkeys developed
weak CTL responses, rapid lossof CD4+ T cells, no
virus-specific CD4+ T cell responses, high setpoint viral
loads, significant clinicaldisease progression, and death in half of
the animals by day 140after challenge. In contrast, all monkeys that
received the DNAvaccines augmented with IL-2/Ig were infected, but
demonstratedpotent secondary CTL responses, stable CD4+ T
cell counts, preserved virus-specific CD4+ T cell
responses, low to undetectable setpoint viral loads, andno evidence of
clinical disease or mortality by day 140 afterchallenge.
1 Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston,
MA 02215, USA.
2 Merck Research Laboratories, West
Point, PA 19486, USA.
3 Southern Research Institute,
431 Aviation Way, Frederick, MD 21701, USA.
4 Duke
University Medical Center, Durham, NC 27710, USA.
5 Department of Biostatistical Science, Dana-Farber
Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
*
To whom correspondence should be addressed. E-mail:
dan_barouch{at}hotmail.com
The editors suggest the following Related Resources on Science sites:
In Science Magazine
LETTERS
Miles B. Markus, John E. Fincham;, Dan H. Barouch, and Norman L. Letvin (5 January 2001) Science291 (5501), 46.
[DOI: 10.1126/science.10.1126/SCIENCE.291.5501.46] |Full Text »
PERSPECTIVES
Xuefei Shen and Robert F. Siliciano (20 October 2000) Science290 (5491), 463.
[DOI: 10.1126/science.290.5491.463] |Summary »|Full Text »
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High-Potency Human Immunodeficiency Virus Vaccination Leads to Delayed and Reduced CD8+ T-Cell Expansion but Improved Virus Control.
M. P. Davenport, L. Zhang, A. Bagchi, A. Fridman, T.-M. Fu, W. Schleif, J. W. Shiver, R. M. Ribeiro, and A. S. Perelson (2005)
J. Virol.
79, 10059-10062
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A Human T-Cell Leukemia Virus Type 1 Regulatory Element Enhances the Immunogenicity of Human Immunodeficiency Virus Type 1 DNA Vaccines in Mice and Nonhuman Primates.
D. H. Barouch, Z.-y. Yang, W.-p. Kong, B. Korioth-Schmitz, S. M. Sumida, D. M. Truitt, M. G. Kishko, J. C. Arthur, A. Miura, J. R. Mascola, et al. (2005)
J. Virol.
79, 8828-8834
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Effect of CD8+ Lymphocyte Depletion on Virus Containment after Simian Immunodeficiency Virus SIVmac251 Challenge of Live Attenuated SIVmac239{Delta}3-Vaccinated Rhesus Macaques.
J. E. Schmitz, R. P. Johnson, H. M. McClure, K. H. Manson, M. S. Wyand, M. J. Kuroda, M. A. Lifton, R. S. Khunkhun, K. J. McEvers, J. Gillis, et al. (2005)
J. Virol.
79, 8131-8141
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Enhanced Potency of Plasmid DNA Microparticle Human Immunodeficiency Virus Vaccines in Rhesus Macaques by Using a Priming-Boosting Regimen with Recombinant Proteins.
G. R. Otten, M. Schaefer, B. Doe, H. Liu, I. Srivastava, J. zur Megede, J. Kazzaz, Y. Lian, M. Singh, M. Ugozzoli, et al. (2005)
J. Virol.
79, 8189-8200
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DNA Vaccines Expressing Different Forms of Simian Immunodeficiency Virus Antigens Decrease Viremia upon SIVmac251 Challenge.
M. Rosati, A. von Gegerfelt, P. Roth, C. Alicea, A. Valentin, M. Robert-Guroff, D. Venzon, D. C. Montefiori, P. Markham, B. K. Felber, et al. (2005)
J. Virol.
79, 8480-8492
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Novel Protein and Poxvirus-Based Vaccine Combinations for Simultaneous Induction of Humoral and Cell-Mediated Immunity.
C. L. Hutchings, S. C. Gilbert, A. V. S. Hill, and A. C. Moore (2005)
J. Immunol.
175, 599-606
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Immunization of Macaques with Single-Cycle Simian Immunodeficiency Virus (SIV) Stimulates Diverse Virus-Specific Immune Responses and Reduces Viral Loads after Challenge with SIVmac239.
D. T. Evans, J. E. Bricker, H. B. Sanford, S. Lang, A. Carville, B. A. Richardson, M. Piatak Jr., J. D. Lifson, K. G. Mansfield, and R. C. Desrosiers (2005)
J. Virol.
79, 7707-7720
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Induction of T-Cell Immunity to Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1.
I. Stratov, C. J. Dale, S. Chea, J. McCluskey, and S. J. Kent (2005)
J. Virol.
79, 7728-7737
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Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques.
Y. Nishimura, C. R. Brown, J. J. Mattapallil, T. Igarashi, A. Buckler-White, B. A. P. Lafont, V. M. Hirsch, M. Roederer, and M. A. Martin (2005)
PNAS
102, 8000-8005
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Replication-Defective Adenovirus Serotype 5 Vectors Elicit Durable Cellular and Humoral Immune Responses in Nonhuman Primates.
S. Santra, M. S. Seaman, L. Xu, D. H. Barouch, C. I. Lord, M. A. Lifton, D. A. Gorgone, K. R. Beaudry, K. Svehla, B. Welcher, et al. (2005)
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79, 6516-6522
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Rapid Viral Escape at an Immunodominant Simian-Human Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitope Exacts a Dramatic Fitness Cost.
C. S. Fernandez, I. Stratov, R. De Rose, K. Walsh, C. J. Dale, M. Z. Smith, M. B. Agy, S.-l. Hu, K. Krebs, D. I. Watkins, et al. (2005)
J. Virol.
79, 5721-5731
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Novel simian immunodeficiency virus CTL epitopes restricted by MHC class I molecule Mamu-B*01 are highly conserved for long term in DNA/MVA-vaccinated, SHIV-challenged rhesus macaques.
J. Su, M. A. Luscher, Y. Xiong, T. Rustam, R. R. Amara, E. Rakasz, H. L. Robinson, and K. S. MacDonald (2005)
Int. Immunol.
17, 637-648
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Vaccine-Elicited Memory Cytotoxic T Lymphocytes Contribute to Mamu-A*01-Associated Control of Simian/Human Immunodeficiency Virus 89.6P Replication in Rhesus Monkeys.
M. S. Seaman, S. Santra, M. H. Newberg, V. Philippon, K. Manson, L. Xu, R. S. Gelman, D. Panicali, J. R. Mascola, G. J. Nabel, et al. (2005)
J. Virol.
79, 4580-4588
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Human Immunodeficiency Virus (HIV)-Specific Gamma Interferon Secretion Directed against All Expressed HIV Genes: Relationship to Rate of CD4 Decline.
Y. Peretz, G. Alter, M.-P. Boisvert, G. Hatzakis, C. M. Tsoukas, and N. F. Bernard (2005)
J. Virol.
79, 4908-4917
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Signature for Long-Term Vaccine-Mediated Control of a Simian and Human Immunodeficiency Virus 89.6P Challenge: Stable Low-Breadth and Low-Frequency T-Cell Response Capable of Coproducing Gamma Interferon and Interleukin-2.
S. Sadagopal, R. R. Amara, D. C. Montefiori, L. S. Wyatt, S. I. Staprans, N. L. Kozyr, H. M. McClure, B. Moss, and H. L. Robinson (2005)
J. Virol.
79, 3243-3253
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Immunologic Pressure within Class I-Restricted Cognate Human Immunodeficiency Virus Epitopes during Highly Active Antiretroviral Therapy.
J. P. Casazza, M. R. Betts, B. J. Hill, J. M. Brenchley, D. A. Price, D. C. Douek, and R. A. Koup (2005)
J. Virol.
79, 3653-3663
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Enhanced Cellular Immunity in Macaques following a Novel Peptide Immunotherapy.
S. Chea, C. J. Dale, R. De Rose, I. A. Ramshaw, and S. J. Kent (2005)
J. Virol.
79, 3748-3757
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Enhanced immunogenicity using an alphavirus replicon DNA vaccine against human immunodeficiency virus type 1.
E. K. L. Nordstrom, M. N. E. Forsell, C. Barnfield, E. Bonin, T. Hanke, M. Sundstrom, G. B. Karlsson, and P. Liljestrom (2005)
J. Gen. Virol.
86, 349-354
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Vaccination of Rhesus Macaques with Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Env V3 Elicits Neutralizing Antibody-Mediated Protection against Simian-Human Immunodeficiency Virus with a Homologous but Not a Heterologous V3 Motif.
K. Someya, D. Cecilia, Y. Ami, T. Nakasone, K. Matsuo, S. Burda, H. Yamamoto, N. Yoshino, M. Kaizu, S. Ando, et al. (2005)
J. Virol.
79, 1452-1462
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HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro.
K. Muthumani, D. S. Hwang, A. Y. Choo, S. Mayilvahanan, N. S. Dayes, K. P. Thieu, and D. B. Weiner (2005)
Int. Immunol.
17, 103-116
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Unparalleled complexity of the MHC class I region in rhesus macaques.
N. Otting, C. M. C. Heijmans, R. C. Noort, N. G. de Groot, G. G. M. Doxiadis, J. J. van Rood, D. I. Watkins, and R. E. Bontrop (2005)
PNAS
102, 1626-1631
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Analysis of Pigtail Macaque Major Histocompatibility Complex Class I Molecules Presenting Immunodominant Simian Immunodeficiency Virus Epitopes.
M. Z. Smith, C. J. Dale, R. De Rose, I. Stratov, C. S. Fernandez, A. G. Brooks, J. Weinfurter, K. Krebs, C. Riek, D. I. Watkins, et al. (2005)
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79, 684-695
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Neutralizing Antibodies Elicited by Immunization of Monkeys with DNA Plasmids and Recombinant Adenoviral Vectors Expressing Human Immunodeficiency Virus Type 1 Proteins.
J. R. Mascola, A. Sambor, K. Beaudry, S. Santra, B. Welcher, M. K. Louder, T. C. VanCott, Y. Huang, B. K. Chakrabarti, W.-P. Kong, et al. (2005)
J. Virol.
79, 771-779
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Novel Adeno-Associated Virus Vector Vaccine Restricts Replication of Simian Immunodeficiency Virus in Macaques.
P. R. Johnson, B. C. Schnepp, M. J. Connell, D. Rohne, S. Robinson, G. R. Krivulka, C. I. Lord, R. Zinn, D. C. Montefiori, N. L. Letvin, et al. (2005)
J. Virol.
79, 955-965
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Immunogenicity Study of Glycoprotein-Deficient Rabies Virus Expressing Simian/Human Immunodeficiency Virus SHIV89.6P Envelope in a Rhesus Macaque.
P. M. McKenna, P. P. Aye, B. Dietzschold, D. C. Montefiori, L. N. Martin, P. A. Marx, R. J. Pomerantz, A. Lackner, and M. J. Schnell (2004)
J. Virol.
78, 13455-13459
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Efficacy of DNA and Fowlpox Virus Priming/Boosting Vaccines for Simian/Human Immunodeficiency Virus.
C. J. Dale, R. De Rose, I. Stratov, S. Chea, D. C. Montefiori, S. Thomson, I. A. Ramshaw, B. E. H. Coupar, D. B. Boyle, M. Law, et al. (2004)
J. Virol.
78, 13819-13828
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Gene Expression Profiling of Host Response in Models of Acute HIV Infection.
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173, 6858-6863
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Intranasal HIV-1-gp160-DNA/gp41 Peptide Prime-Boost Immunization Regimen in Mice Results in Long-Term HIV-1 Neutralizing Humoral Mucosal and Systemic Immunity.
C. Devito, B. Zuber, U. Schroder, R. Benthin, K. Okuda, K. Broliden, B. Wahren, and J. Hinkula (2004)
J. Immunol.
173, 7078-7089
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Predicting the Impact of a Nonsterilizing Vaccine against Human Immunodeficiency Virus.
M. P. Davenport, R. M. Ribeiro, D. L. Chao, and A. S. Perelson (2004)
J. Virol.
78, 11340-11351
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Repertoire and Immunofocusing of CD8 T Cell Responses Generated by HIV-1 gag-pol and Expression Library Immunization Vaccines.
Novel and Promiscuous CTL Epitopes in Conserved Regions of Gag Targeted by Individuals with Early Subtype C HIV Type 1 Infection from Southern Africa.
A. M. Masemola, T. N. Mashishi, G. Khoury, H. Bredell, M. Paximadis, T. Mathebula, D. Barkhan, A. Puren, E. Vardas, M. Colvin, et al. (2004)
J. Immunol.
173, 4607-4617
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Kinetics of Virus-Specific CD8+ T Cells and the Control of Human Immunodeficiency Virus Infection.
M. P. Davenport, R. M. Ribeiro, and A. S. Perelson (2004)
J. Virol.
78, 10096-10103
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Induction of Cellular Immune Responses to Simian Immunodeficiency Virus Gag by Two Recombinant Negative-Strand RNA Virus Vectors.
Y. Nakaya, T. Nakaya, M.-S. Park, J. Cros, J. Imanishi, P. Palese, and A. Garcia-Sastre (2004)
J. Virol.
78, 9366-9375
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Proliferation and Differentiation of CD8+ T Cells in the Absence of IL-2/15 Receptor {beta}-Chain Expression or STAT5 Activation.
R. M. Teague, R. M. Tempero, S. Thomas, K. Murali-Krishna, and B. H. Nelson (2004)
J. Immunol.
173, 3131-3139
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Essential role for virus-neutralizing antibodies in sterilizing immunity against Friend retrovirus infection.
R. J. Messer, U. Dittmer, K. E. Peterson, and K. J. Hasenkrug (2004)
PNAS
101, 12260-12265
|Abstract »|Full Text »|PDF »
Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses.
Y. Nishimura, T. Igarashi, O. K. Donau, A. Buckler-White, C. Buckler, B. A. P. Lafont, R. M. Goeken, S. Goldstein, V. M. Hirsch, and M. A. Martin (2004)
PNAS
101, 12324-12329
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Recombinant poxvirus boosting of DNA-primed rhesus monkeys augments peak but not memory T lymphocyte responses.
S. Santra, D. H. Barouch, B. Korioth-Schmitz, C. I. Lord, G. R. Krivulka, F. Yu, M. H. Beddall, D. A. Gorgone, M. A. Lifton, A. Miura, et al. (2004)
PNAS
101, 11088-11093
|Abstract »|Full Text »|PDF »
Heterologous Envelope Immunogens Contribute to AIDS Vaccine Protection in Rhesus Monkeys.
N. L. Letvin, Y. Huang, B. K. Chakrabarti, L. Xu, M. S. Seaman, K. Beaudry, B. Korioth-Schmitz, F. Yu, D. Rohne, K. L. Martin, et al. (2004)
J. Virol.
78, 7490-7497
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