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Blood, 15 May 2006, Vol. 107, No. 10, pp. 3976-3982.
Prepublished online as a Blood First Edition Paper on January 19, 2006; DOI 10.1182/blood-2005-11-4551.
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IMMUNOBIOLOGY
Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1
Joshua Arnold,
Brenda Yamamoto,
Min Li,
Andrew J. Phipps,
Ihab Younis,
Michael D. Lairmore, and
Patrick L. Green
From the Departments of Veterinary Biosciences and Molecular Virology Immunology, and Medical Genetics, Center for Retrovirus Research, Comprehensive Cancer Center and Solove Research Institute, The Ohio State University, Columbus, OH.
Natural antisense viral transcripts have been recognized in retroviruses, including human T-cell leukemia virus type 1 (HTLV-1), HIV-1, and feline immunodeficiency virus (FIV), and have been postulated to encode proteins important for the infection cycle and/or pathogenesis of the virus. The antisense strand of the HTLV-1 genome encodes HBZ, a novel nuclear basic region leucine zipper (b-ZIP) protein that in overexpression assays down-regulates Tax oncoprotein-induced viral transcription. Herein, we investigated the contribution of HBZ to HTLV-1–mediated immortalization of primary T lymphocytes in vitro and HTLV-1 infection in a rabbit animal model. HTLV-1 HBZ mutant viruses were generated and evaluated for viral gene expression, protein production, and immortalization capacity. Biologic properties of HBZ mutant viruses in vitro were indistinguishable from wild-type HTLV-1, providing the first direct evidence that HBZ is dispensable for viral replication and cellular immortalization. Rabbits inoculated with irradiated cells expressing HTLV-1 HBZ mutant viruses became persistently infected. However, these rabbits displayed a decreased antibody response to viral gene products and reduced proviral copies in peripheral blood mononuclear cells (PBMCs) as compared with wild-type HTLV-1–infected animals. Our findings indicated that HBZ was not required for in vitro cellular immortalization, but enhanced infectivity and persistence in inoculated rabbits. This study demonstrates that retroviruses use negative-strand–encoded proteins in the establishment of chronic viral infections.
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