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
- Genoveffa Franchini
2025-09-26
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 oI-L encompassing the highly divergent type C orf-I. We demonstrate that systemic infectivity of HTLV-1A and HTLV-1A/C oI-L is equivalent in macaques, but viral expression in lungs is significantly higher in HTLV-1A/C oI-L infection. In addition, bronchoalveolar-lavage immune cell dynamics differs greatly with neutrophils and monocytes producing TNF-α in HTLV-1A/C oI-L , but producing IL-10 in HTLV-1A infection. Animals infected with HTLV-1A/C oI-L develops bronchiectasis at 10 months from infection, but at the same timepoint those infected with HTLV-1A do not. HTLV-1A/C oI-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/C oI-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.