Journal Article

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

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

2025

Overview

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. HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/2 / 13/21 / 13/31 / 13/51 / 14/34 / 38/47 / 38/88 / 38/90 / 38/91 / 631/250/255/2514 / 631/326/596/2553 / 631/326/596/2557 / 631/80/304 / Animals / Antibodies / Apoptosis / Basic-Leucine Zipper Transcription Factors - genetics / Basic-Leucine Zipper Transcription Factors - metabolism / Bronchiectasis / Bronchiectasis - genetics / Bronchiectasis - virology / Bronchus / Cloning / Disease control / Fusion protein / Gene Expression Regulation, Viral / Genomes / Homeostasis / HTLV-I Infections - virology / Human T-lymphotropic virus 1 - genetics / Human T-lymphotropic virus 1 - pathogenicity / Humanities and Social Sciences / Humans / Hypotheses / Immune clearance / Immune response / Immune system / Infections / Infectivity / Lavage / Leukocytes (neutrophilic) / Lung - metabolism / Lung - pathology / Lung - virology / Lung diseases / Lymphocytes T / Macaca / Macaca mulatta / Male / Monocytes / Monocytes - immunology / Morbidity / mRNA / multidisciplinary / Mutation / Native peoples / Open Reading Frames / Pathogenesis / Proteins / Retroviridae Proteins - genetics / Retroviridae Proteins - metabolism / Retroviridae Proteins, Oncogenic - genetics / Retroviridae Proteins, Oncogenic - metabolism / RNA, Messenger - genetics / RNA, Messenger - metabolism / Science / Science (multidisciplinary) / Tumor necrosis factor-α / Viruses