title: Role of accessory proteins of HTLV-1 in viral replication, T cell activation, and cellular gene expression.
abstract: Human T-cell lymphotropic virus type 1 (HTLV-1), causes adult T cell leukemia/lymphoma (ATLL), and initiates a variety of immune mediated disorders. The viral genome encodes common structural and enzymatic proteins characteristic of all retroviruses and utilizes alternative splicing and alternate codon usage to make several regulatory and accessory proteins encoded in the pX region (pX ORF I to IV). Recent studies indicate that the accessory proteins p12I, p27I, p13II, and p30II, encoded by pX ORF I and II, contribute to viral replication and the ability of the virus to maintain typical in vivo expression levels. 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. These 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 the calcineurin-binding protein p12I in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12I 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 co-activators of transcription. The mitochondrial localizing p13II induces morphologic changes in the organelle and may influence energy metabolism infected cells. Future studies of the molecular details HTLV-1 "accessory" proteins interactions will provide important new directions for investigations of HTLV-1 and related viruses associated with lymphoproliferative diseases. Thus, the accessory proteins of HTLV-1, once thought to be dispensable for viral replication, have proven to be directly involved in viral spread in vivo and represent potential targets for therapeutic intervention against HTLV-1 infection and disease.
authors.affiliation: Center for Retrovirus Research and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210-1093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bindhu
authors.forename: Amrithraj
authors.initials: A
authors.lastname: Nair
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lairmore
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002448:Cell Adhesion; D003062:Codon; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015723:Gene Library; D006056:Golgi Apparatus / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D016366:Open Reading Frames; D011817:Rabbits; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication
chemical_list: D003062:Codon; D018076:DNA, Complementary; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D054334:Viral Regulatory and Accessory Proteins; C072343:pX protein, Human T-lymphotropic virus 1