Critical role of human T-lymphotropic virus type 1 accessory proteins in viral replication and pathogenesis

Björn Albrecht, Michael Dale Lairmore

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76 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)396-406
Number of pages11
JournalMicrobiology and Molecular Biology Reviews
Volume66
Issue number3
DOIs
StatePublished - Sep 2002
Externally publishedYes

Fingerprint

Viral Regulatory and Accessory Proteins
Human T-lymphotropic virus 1
Open Reading Frames
T-Lymphocytes
Lymphocyte Activation
Retroviridae
Proteins
TCF Transcription Factors
Calcium Signaling
Mitochondrial Genes
Viral Genome
Mitochondrial Proteins
Virus Diseases
Regulator Genes
Endoplasmic Reticulum
Neurodegenerative Diseases
Organelles
Energy Metabolism
Transcription Factors
Clone Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology
  • Genetics

Cite this

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abstract = "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.",
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