High expression of Rex-orf-I and HBZ mRNAs and bronchiectasis in lung of HTLV-1A/C infected macaques
Nature Communications, 2025
Sarkis S., Gutowska A., Rahman M., Schifanella L., Goldfarbmuren K., Bissa M., Moles R., Ramirez C., Edmondson E., Warner A., Doster M., Silva de Castro I., Washington-Parks R., Brown S., Kramer J., Breed M., Killoran K., Jethmalani Y., Serebryannyy L., Purcell D., Pise-Masison C., Franchini G.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Respiratory Diseases Infectious Diseases | Pathophysiology | Monkey Plasma Monkey Balf |  Olink Target 48 |
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/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.