Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo

doi:10.1128/JVI.74.3.1094-1100.2000

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Journal of Virology, February 2000, p. 1094-1100, Vol. 74, No. 3
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functional Role of pX Open Reading Frame II of Human T-Lymphotropic Virus Type 1 in Maintenance of Viral Loads In Vivo

Joshua T. Bartoe,¹ Björn Albrecht,¹ Nathaniel D. Collins,¹ Michael D. Robek,² Lee Ratner,² Patrick L. Green,¹^,³ and Michael D. Lairmore¹^,³^,^*

Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210-1093¹; Departments of Medicine, Pathology, and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110²; and Comprehensive Cancer Center, The Arthur James Cancer Hospital and Research Institute, The Ohio State University, Columbus, Ohio 43210³

Received 4 August 1999/Accepted 1 November 1999

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma and is associated with a variety of immune-mediateddisorders. The role of four open reading frames (ORFs), locatedbetween env and the 3' long terminal repeat of HTLV-1, in mediatingdisease is not entirely clear. By differential splicing, ORF IIencodes two proteins, p13^II and p30^II, both of which have not been functionally defined. p13^II localizes to mitochondria and may alter the configuration ofthe tubular network of this cellular organelle. p30^II localizes to the nucleolus and shares homology with the transcriptionfactors Oct-1 and -2, Pit-1, and POU-M1. Both p13^II and p30^II are dispensable for infection and immortalization of primaryhuman and rabbit lymphocytes in vitro. To test the role of ORFII gene products in vivo, we inoculated rabbits with lethallyirradiated cell lines expressing the wild-type molecular cloneof HTLV-1 (ACH.1) or a clone containing selected mutations inORF II (ACH.30/13.1). ACH.1-inoculated animals maintained higherHTLV-1-specific antibody titers than animals inoculated with ACH.30/13.1.Viral p19 antigen was transiently detected in ex vivo culturesof peripheral blood mononuclear cells (PBMC) from only two ACH.30/13.1-inoculatedrabbits, while PBMC cultures from all ACH.1-inoculated rabbitsroutinely produced p19 antigen. In only three of six animals exposedto the ACH.p30^II/p13^II clone could provirus be consistently PCR amplified from extractedPBMC DNA and quantitative competitive PCR showed the proviralloads in PBMC from ACH.p30^II/p13^II-infected rabbits to be dramatically lower than the proviral loadsin rabbits exposed to ACH. Our data indicate selected mutationsin pX ORF II diminish the ability of HTLV-1 to maintain high viralloads in vivo and suggest an important function for p13^II and p30^II in viralpathogenesis.

^* Corresponding author. Mailing address: Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Rd., Columbus,OH 43210-1093. Phone: (614) 292-4819. Fax: (614) 292-6473. E-mail:lairmore.1{at}osu.edu.

Journal of Virology, February 2000, p. 1094-1100, Vol. 74, No. 3
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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