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Journal of Virology, December 2005, p. 14822-14833, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14822-14833.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Induction of Human Immunodeficiency Virus Type 1-Specific T Cells by a Bluetongue Virus Tubule-Vectored Vaccine Prime-Recombinant Modified Virus Ankara Boost Regimen

Natasha Larke,¹ Aileen Murphy,² Christoph Wirblich,² Denise Teoh,¹ Marie J. Estcourt,^1, Andrew J. McMichael,¹ Polly Roy,² and Tomá Hanke^1*

MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, University of Oxford, Oxford OX3 9DS,¹ Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom²

Received 24 June 2005/ Accepted 11 September 2005

In the absence of strategies for reliable induction of antibodies broadly neutralizing human immunodeficiency virus type 1 (HIV-1), vaccine efforts have shifted toward the induction of cell-mediated immunity. Here we describe the construction and immunogenicity of novel T-cell vaccine NS1.HIVA, which delivers the HIV-1 clade A consensus-derived immunogen HIVA on the surface of tubular structures spontaneously formed by protein NS1 of bluetongue virus. We demonstrated that NS1 tubules can accommodate a protein as large as 527 amino acids without losing their self-assembly capability. When injected into BALB/c mice by several routes, chimeric NS1.HIVA tubules induced HIV-1-specific major histocompatibility complex class I-restricted T cells. These could be boosted by modified virus Ankara expressing the same immunogen and generate a memory capable of gamma interferon (IFN-) production, proliferation, and lysis of sensitized target cells. Induced memory T cells readily produced IFN- 230 days postimmunization, and upon a surrogate virus challenge, NS1.HIVA vaccine alone decreased the vaccinia virus vv.HIVA load in ovaries by 2 orders of magnitude 280 days after immunization. Thus, because of its T-cell immunogenicity and antigenic simplicity, the NS1 delivery system could serve as a priming agent for heterologous prime-boost vaccination regimens. Its usefulness in primates, including humans, remains to be determined.

Present address: Department of Pathology and Molecular Medicine, Institute for Molecular Medicine and Health, McMaster University, MDCL 4074, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.

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