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Microbiology and Molecular Biology Reviews, September 2002, p. 396-406, Vol. 66, No. 3
1092-2172/02/$04.00+0     DOI: 10.1128/MMBR.66.3.396-406.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Critical Role of Human T-Lymphotropic Virus Type 1 Accessory Proteins in Viral Replication and Pathogenesis

Björn Albrecht1,2,{dagger} and Michael D. Lairmore1,2,3,4,5*

Center for Retrovirus Research,1 Department of Veterinary Biosciences,2 Comprehensive Cancer Center and Arthur G. James Cancer Hospital,3 Solove Research Center,4 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 432105

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with a diverse range of lymphoproliferative and neurodegenerative diseases, yet pathogenic mechanisms induced by the virus remain obscure. This complex retrovirus contains typical structural and enzymatic genes but also unique regulatory and accessory genes in four open reading frames (ORFs) of the pX region of the viral genome (pX ORFs I to IV). The regulatory proteins encoded by pX ORFs III and IV, Tax and Rex, respectively, have been extensively characterized. In contrast the contribution of the four accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORFs I and II, to viral replication and pathogenesis remained unclear. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. Emerging evidence indicates that the HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation, and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes, suggesting a role for p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I, encoded from pX ORF I, activates NFAT, a key T-cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30II localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related coactivators of transcription. p13II targets mitochondrial proteins, where it alters the organelle morphology and may influence energy metabolism. Collectively, studies of the molecular functions of the HTLV-1 accessory proteins provide insight into strategies used by retroviruses that are associated with lymphoproliferative diseases.

* Corresponding author. Mailing address: The Ohio State University, Center for Retrovirus Research and Department of Veterinary Biosciences, 1925 Coffey Rd., Columbus, OH 43210. Phone: (614) 292-4489. Fax: (614) 292-6473. E-mail: lairmore.1{at}osu.edu.

{dagger} Present address: Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016.

Microbiology and Molecular Biology Reviews, September 2002, p. 396-406, Vol. 66, No. 3
1092-2172/02/$04.00+0     DOI: 10.1128/MMBR.66.3.396-406.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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Copyright © 2002 by the American Society for Microbiology. All rights reserved.