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<p>HTLV-1 type-A rarely causes lung disease in humans, whereas HTLV-1 type-C is more frequently associated with respiratory failure and premature death. We investigated the genetic basis of HTLV-1C morbidity by constructing a chimeric HTLV-1A/C<sub><i>oI-L</i></sub> encompassing the highly divergent type C orf-I. We demonstrate that systemic infectivity of HTLV-1A and HTLV-1A/C<sub><i>oI-L</i></sub> is equivalent in macaques, but viral expression in lungs is significantly higher in HTLV-1A/C<sub><i>oI-L</i></sub> infection. In addition, bronchoalveolar-lavage immune cell dynamics differs greatly with neutrophils and monocytes producing TNF-α in HTLV-1A/C<sub><i>oI-L</i></sub>, but producing IL-10 in HTLV-1A infection. Animals infected with HTLV-1A/C<sub><i>oI-L</i></sub> develops bronchiectasis at 10 months from infection, but at the same timepoint those infected with HTLV-1A do not. HTLV-1A/C<sub><i>oI-L</i></sub> expressed a 16 kDa fusion protein (p16C) via a doubly spliced, Rex-orf-IC, mRNA able to shield T-cells from efferocytosis, a monocyte function that mitigates inflammation via clearance of apoptotic cells. The Rex-orf-IC mRNA is expressed as more frequent in the lung of HTLV-1A/C<sub><i>oI-L</i></sub> than HTLV-1A infected animals. Since defective efferocytosis is associated with lung obstructive pathologies, the data raise the hypothesis that p16C may contribute to the lung morbidity observed in HTLV-1C infection.</p>

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High expression of Rex-orf-I and HBZ mRNAs and bronchiectasis in lung of HTLV-1A/C infected macaques

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月26日

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  • Sarkis Sarkis,
  • Anna Gutowska,
  • Mohammad Arif Rahman,
  • Luca Schifanella,
  • Katherine C. Goldfarbmuren,
  • Massimiliano Bissa,
  • Ramona Moles,
  • Christina Ramirez,
  • Elijah F. Edmondson,
  • Andrew Warner,
  • Melvin Doster,
  • Isabela Silva de Castro,
  • Robyn Washington-Parks,
  • Sophia Brown,
  • Joshua Kramer,
  • Matthew W. Breed,
  • Kristin E. Killoran,
  • Yogita Jethmalani,
  • Leonid Serebryannyy,
  • Damian FJ. Purcell,
  • Cynthia A. Pise-Masison,
  • Genoveffa Franchini

摘要

HTLV-1 type-A rarely causes lung disease in humans, whereas HTLV-1 type-C is more frequently associated with respiratory failure and premature death. We investigated the genetic basis of HTLV-1C morbidity by constructing a chimeric HTLV-1A/CoI-L encompassing the highly divergent type C orf-I. We demonstrate that systemic infectivity of HTLV-1A and HTLV-1A/CoI-L is equivalent in macaques, but viral expression in lungs is significantly higher in HTLV-1A/CoI-L infection. In addition, bronchoalveolar-lavage immune cell dynamics differs greatly with neutrophils and monocytes producing TNF-α in HTLV-1A/CoI-L, but producing IL-10 in HTLV-1A infection. Animals infected with HTLV-1A/CoI-L develops bronchiectasis at 10 months from infection, but at the same timepoint those infected with HTLV-1A do not. HTLV-1A/CoI-L expressed a 16 kDa fusion protein (p16C) via a doubly spliced, Rex-orf-IC, mRNA able to shield T-cells from efferocytosis, a monocyte function that mitigates inflammation via clearance of apoptotic cells. The Rex-orf-IC mRNA is expressed as more frequent in the lung of HTLV-1A/CoI-L than HTLV-1A infected animals. Since defective efferocytosis is associated with lung obstructive pathologies, the data raise the hypothesis that p16C may contribute to the lung morbidity observed in HTLV-1C infection.