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

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 and Genoveffa Franchini ()
Additional contact information
Sarkis Sarkis: National Cancer Institute
Anna Gutowska: National Cancer Institute
Mohammad Arif Rahman: National Cancer Institute
Luca Schifanella: National Cancer Institute
Katherine C. Goldfarbmuren: Frederick National Laboratory for Cancer Research
Massimiliano Bissa: National Cancer Institute
Ramona Moles: National Cancer Institute
Christina Ramirez: Frederick National Laboratory for Cancer Research
Elijah F. Edmondson: Frederick National Laboratory for Cancer Research
Andrew Warner: Frederick National Laboratory for Cancer Research
Melvin Doster: National Cancer Institute
Isabela Silva de Castro: National Cancer Institute
Robyn Washington-Parks: National Cancer Institute
Sophia Brown: National Cancer Institute
Joshua Kramer: Frederick National Laboratory for Cancer Research
Matthew W. Breed: Frederick National Laboratory for Cancer Research
Kristin E. Killoran: Frederick National Laboratory for Cancer Research
Yogita Jethmalani: National Institutes of Health
Leonid Serebryannyy: National Institutes of Health
Damian FJ. Purcell: The University of Melbourne
Cynthia A. Pise-Masison: National Cancer Institute
Genoveffa Franchini: National Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63325-1

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