Document text
Principal Investigator: Genoveffa Franchini
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2024
Award: $249,755
Funding agency: National Cancer Institute
HTLV-1A is the most common form of HTLV-1 worldwide and causes leukemia and inflammatory diseases such as the neurodegenerative HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HTLV-1C, first genetically characterized in Melanesia in the early 1990s, is endemic in indigenous Australian and New Caledonian populations and reaches an extraordinarily high seroprevalence of up to 36% in Aboriginal communities in Australia's Northern Territory. Here, HTLV-1C is coupled with high mortality attributed to lung inflammation, bronchiectasis, and infection by other infectious pathogens, suggesting immune disregulation. HTLV-1C differs from HTLV-1A primarily in the orf-I, which has been the focus of the HTLV-1 research in my lab for the past several years. The HTLV-1A orf-I p8 and p12 proteins, encoded by a singly-spliced mRNA, affect STAT-5 activation, TCR signaling, protect infected cells from recognition by cytotoxic T-cells (CTL) and NK cells, increase viral transmission, and are required for persistent infection of primary monocytes in vitro and of macaques in vivo. Comparison of primary CD4+ T cells infected with HTLV-1A WT or orf-I knockout viruses demonstrates that HTLV-1A orf-I proteins inhibit activation of the inflammasome, a pathway essential for the initiation of innate responses. Knocking out HTLV-1A orf-I expression from an infectious molecular clone (HTLV-1p12KO) resulted in loss of virus infectivity in macaques. However, simultaneous transient depletion of NK cells, CD8+ cells, and monocytes prior to exposure to HTLV-1p12KO is sufficient to completely rescue viral infectivity, confirming the importance of orf-I inhibition of NK cells, CTL, and monocytes in acute viral infection. Interestingly, HTLV-1C lacks the translation initiation codon for orf-I raising the question of how this viral strain counteracts host immunity. To investigate this, we constructed in silico a chimeric HTLV-1A/C by swapping the orf-I of HTLV-1C into the HTLV-1A backbone. The infectivity of HTLV-1A and chimeric HTLV-1A/C in human and macaque cells in vitro, and macaques in vivo was equivalent. Macaques infected by HTLV-1A/C developed higher inflammatory responses in blood and bronchoalveolar-lavage (BAL) than HTLV-1A infected animals and clear signs of lung infiltration by T-cells and B cells, pulmonary hemorrhage, alpha-smooth muscle actin peripheral fibrosis, interstitial pneumonia, alveolitis, and bronchiectasis consistent with the development of lung fibrotic disease. In addition, we found that subtype C orf-I (orf-I C) can be expressed in vitro and in vivo in the lungs of infected macaques by a doubly-spliced mRNA juxtaposed with the first exon of Rex, which provides its ATG in frame with orf-I and encodes a fusion protein of 152 aa, designated as p16C. In vitro, stable expression of p16, but not of p12/p8 conferred apoptotic T-cells with resistance to monocytic engulfment by efferocytosis, suggesting a possible pathogenetic mechanism underlying the increased inflammation and lung disease observed in HTLV-1C infection. Early intervention in HTLV-1C infection may prevent the vicious inflammatory cycle caused by the virus that culminates not only in injuries of the lung, but also in leukemia and other immune-based HTLV-1 manifestations like HAM/TSP.
Terms: <ATLL><Ablation><Aboriginal><Aborigine><Actins><Acute><Adult T-Cell Leukemia><Adult T-Cell Leukemia-Lymphoma Virus I><Adult T-Cell Leukemia/Lymphoma><Adult T-Cell Lymphoma/Leukemia><Affect><Alveolitis><Animals><Apoptotic><Arthritis><Australia><Autoimmune><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bleeding><Blood><Blood Reticuloendothelial System><Blood monocyte><Bronchiectasis><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Chimera Protein><Chimeric Proteins><Collaborations><Communities><Coupled><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Degenerative Neurologic Disorders><Deoxyribonucleic Acid><Dermatitis><Differential Gene Expression><Disease><Disorder><Early Intervention><Equilibrium><Exons><Exposure to><Fibrosis><Fusion Protein><Gene Transcription><Genetic><Genetic Transcription><Genetic mutation><Goals><HTLV-1><HTLV-I><HTLV-I-Associated Myelopathy><HTLV1><Hemorrhage><Human><Human T-Cell Leukemia Virus I><Human T-lymphotropic virus 1><Immune><Immunes><Immunity><Impairment><In Vitro><Indigenous><Individual><Induction of Apoptosis><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Initiation Codon><Initiator Codon><Interstitial Lung Inflammation><Interstitial Pneumonia><Interstitial Pneumonitis><Interstitial Pulmonary Inflammation><Intracellular Communication and Signaling><Involuntary Muscle><Jurkat Cells><K lymphocyte><Knock-out><Knockout><Link><Lung><Lung Diseases><Lung Inflammation><Lung Lavage><Lung Respiratory System><Lung damage><Macaca><Macaque><Marrow monocyte><Measures><Melanesia><Messenger RNA><Modeling><Modern Man><Molecular Cloning><Morbidity><Morbidity - disease rate><Motility><Mucosa><Mucosal Tissue><Mucous Membrane><NK Cells><Natural Killer Cells><Nerve Degeneration><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuron Degeneration><Northern Territory><ORFs><Onset of illness><Open Reading Frames><Pathogenicity><Pathway interactions><Peripheral><Pneumonitis><Population><Preventive><Protein Coding Region><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><RNA Expression><RNA Splicing><RNA vaccine><RNA-based vaccine><Research><Resistance><Retroviridae><Retroviruses><Role><Sequence Alteration><Seroprevalences><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smooth Muscle><Spinal Column><Spinal Cord Diseases><Spinal Cord Disorders><Spine><Splicing><Start Codon><T cell infiltration><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Tissue-Specific Differential Gene Expression><Tissue-Specific Gene Expression><Transcription><Translation Initiation><Translations><Tropical Spastic Paraparesis><Tropical Spastic Paraplegia><Type I Human T-Lymphotropic Virus><Uveitis><Vaccines><Variant><Variation><Vertebral column><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Virus-HTLV-I><Virus-Retrovirus><arthritic><backbone><balance><balance function><biological signal transduction><blood loss><bronchopulmonary lavage therapy><chronic infection><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><disease of the lung><disease onset><disorder of the lung><disorder onset><driving><druggable target><fibrotic lung disease><fibrotic pulmonary disease><genomic alteration><human T cell lymphoma virus I><human T cell lymphoma virus type I><human T cell lymphotropic virus 1><human T cell lymphotropic virus type 1><human T lymphotropic virus I><human T-cell leukemia virus type 1><human model><in silico><in vivo><killer T cell><leukemia><lung development><lung disorder><lung injury><mRNA><mRNA vaccine><mRNA-based vaccine><model of human><monocyte><mortality><myelopathy><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuronal degeneration><pathogen><pathway><persistent infection><prevent><preventing><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><resistant><response><social role><therapeutic evaluation><therapeutic testing><thymus derived lymphocyte><translation><viral infection><viral rescue><viral transmission><virus infection><virus protein><virus transmission><virus-induced disease>