High expression of Rex-orf-I and HBZ mRNAs and bronchiectasis in lung of HTLV-1A/C infected macaques
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>oI-L</sub> encompassing the highly divergent type C orf-I. We demonstrate that systemic infectivity of HTLV-1A and HTLV-1A/C<sub>oI-L</sub> is equivalent in macaques, but viral expression in lungs is significantly higher in HTLV-1A/C<sub>oI-L</sub> infection. In addition, bronchoalveolar-lavage immune cell dynamics differs greatly with neutrophils and monocytes producing TNF-α in HTLV-1A/C<sub>oI-L</sub>, but producing IL-10 in HTLV-1A infection. Animals infected with HTLV-1A/C<sub>oI-L</sub> develops bronchiectasis at 10 months from infection, but at the same timepoint those infected with HTLV-1A do not. HTLV-1A/C<sub>oI-L</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>oI-L</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.
Authors
- Luca Schifanella (ORCID: https://orcid.org/0000-0002-6123-536X)
- Sophia Brown (ORCID: https://orcid.org/0000-0001-5782-8755)
- Cynthia A. Pise-Masison (ORCID: https://orcid.org/0000-0003-2788-235X)
- Matthew W. Breed (ORCID: https://orcid.org/0000-0002-2286-1106)
- Kristin E. Killoran (ORCID: https://orcid.org/0000-0002-5400-1231)
- Andrew Warner (ORCID: https://orcid.org/0000-0001-6023-1423)
- Anna Gutowska (ORCID: https://orcid.org/0000-0002-9873-6432)
- Isabela Silva de Castro (ORCID: https://orcid.org/0000-0003-2186-4556)
- Damian F. J. Purcell (ORCID: https://orcid.org/0000-0002-4485-1726)
- Ramona Moles (ORCID: https://orcid.org/0000-0001-8576-2394)
- Genoveffa Franchini (ORCID: https://orcid.org/0000-0003-2851-6589)
- Massimiliano Bissa (ORCID: https://orcid.org/0000-0003-3455-3992)
- Leonid Serebryannyy (ORCID: https://orcid.org/0000-0003-0213-1779)
- Melvin N. Doster
- Katherine C. Goldfarbmuren (ORCID: https://orcid.org/0000-0001-8774-7454)
- Elijah F. Edmondson (ORCID: https://orcid.org/0000-0002-6106-3705)
- Mohammad Arif Rahman (ORCID: https://orcid.org/0000-0002-6120-8943)
- Robyn Washington‐Parks (ORCID: https://orcid.org/0000-0002-5284-9765)
- Yogita Jethmalani (ORCID: https://orcid.org/0000-0003-3422-8356)
- Christina N. Ramirez
- Joshua Kramer (ORCID: https://orcid.org/0000-0002-4031-275X)
- Sarkis Sarkis (ORCID: https://orcid.org/0000-0002-4355-6338)
Institutions
- National Institutes of Health (US)
- The University of Melbourne (AU)
- University of Mississippi Medical Center (US)
- Office of the Director (US)
- Peter Doherty Institute (AU)
- Frederick National Laboratory for Cancer Research (US)
- National Institute of Allergy and Infectious Diseases (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Clemson University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63325-1
- Citations
- 2
- Primary Topic
- T-cell and Retrovirus Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- U.S. Department of Health and Human Services
- National Institutes of Health
- National Cancer Institute