The relative contributions of infectious and mitotic spread to HTLV-1 persistence
| العنوان: | The relative contributions of infectious and mitotic spread to HTLV-1 persistence |
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| المؤلفون: | Charles R. M. Bangham, Vikram Sunkara, Daniel J. Laydon, Becca Asquith, Lies Boelen |
| المساهمون: | Commission of the European Communities, Wellcome Trust, European Commission Directorate-General for Research and Innovation |
| المصدر: | PLoS Computational Biology PLoS Computational Biology, Vol 16, Iss 9, p e1007470 (2020) |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, RNA viruses, 0301 basic medicine, Epidemiology, viruses, Disease, Pathology and Laboratory Medicine, Malignant transformation, White Blood Cells, 0302 clinical medicine, Proviruses, Animal Cells, Tropical spastic paraparesis, Medicine and Health Sciences, Public and Occupational Health, species richness, Biology (General), Human T-lymphotropic virus 1, 0303 health sciences, Cell Death, Ecology, T Cells, Cancer Risk Factors, dynamics, Viral Load, Vaccination and Immunization, 3. Good health, medicine.anatomical_structure, Oncology, Computational Theory and Mathematics, Medical Microbiology, Cell Processes, Viral Pathogens, 030220 oncology & carcinogenesis, Modeling and Simulation, Host-Pathogen Interactions, Viruses, Physical Sciences, asymptomatic carriers, Pathogens, Cellular Types, Research Article, Bioinformatics, QH301-705.5, proviral load, Virus Integration, Immune Cells, T cell, Immunology, Mitosis, Antiretroviral Therapy, clonal expansion, estimators, Biology, Research and Analysis Methods, Models, Biological, Microbiology, Virus, Leukemia-virus type-1, 03 medical and health sciences, Cellular and Molecular Neuroscience, Antiviral Therapy, Retroviruses, Genetics, medicine, Humans, T-cell Leukemia/Lymphoma, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, 01 Mathematical Sciences, Ecology, Evolution, Behavior and Systematics, Cell Proliferation, 030304 developmental biology, Blood Cells, Organisms, Biology and Life Sciences, Htlv-1, Cell Biology, 06 Biological Sciences, Probability Theory, Probability Distribution, medicine.disease, HTLV-I Infections, Virology, Lymphoma, Chronic infection, 030104 developmental biology, Medical Risk Factors, 08 Information and Computing Sciences, Preventive Medicine, Asymptomatic carrier, Mathematics, 030217 neurology & neurosurgery, Cloning |
| الوصف: | Human T-lymphotropic virus type-1 (HTLV-1) persists within hosts via infectious spread (de novo infection) and mitotic spread (infected cell proliferation), creating a population structure of multiple clones (infected cell populations with identical genomic proviral integration sites). The relative contributions of infectious and mitotic spread to HTLV-1 persistence are unknown, and will determine the efficacy of different approaches to treatment. The prevailing view is that infectious spread is negligible in HTLV-1 persistence beyond early infection. However, in light of recent high-throughput data on the abundance of HTLV-1 clones, and recent estimates of HTLV-1 clonal diversity that are substantially higher than previously thought (typically between 104 and 105 HTLV-1+ T cell clones in the body of an asymptomatic carrier or patient with HTLV-1-associated myelopathy/tropical spastic paraparesis), ongoing infectious spread during chronic infection remains possible. We estimate the ratio of infectious to mitotic spread using a hybrid model of deterministic and stochastic processes, fitted to previously published HTLV-1 clonal diversity estimates. We investigate the robustness of our estimates using three alternative estimators. We find that, contrary to previous belief, infectious spread persists during chronic infection, even after HTLV-1 proviral load has reached its set point, and we estimate that between 100 and 200 new HTLV-1 clones are created and killed every day. We find broad agreement between all estimators. The risk of HTLV-1-associated malignancy and inflammatory disease is strongly correlated with proviral load, which in turn is correlated with the number of HTLV-1-infected clones, which are created by de novo infection. Our results therefore imply that suppression of de novo infection may reduce the risk of malignant transformation. Author summary There is no effective antiretroviral treatment for infection with Human T-lymphotropic virus type-1 (HTLV-1), which causes a range of inflammatory diseases and the aggressive malignancy Adult T-cell Leukaemia/Lymphoma (ATL) in approximately 10% of infected people. Within hosts the virus spreads via infectious spread (de novo infection) and mitotic spread (infected cell division). The relative contributions of each mechanism are unknown, and have major implications for drug development and clinical management of infection. We estimate the ratio of infectious to mitotic spread during the infection’s chronic phase using three methods. Each method indicates infectious spread at low but persistent levels after proviral load has reached set point, contrary to the prevailing view that infectious spread features in early infection only. Risk of disease in HTLV-1 infection is known to increase with proviral load, via mutations accrued from repeated infected cell division. Our analyses suggest that ongoing infectious spread may provide an additional mechanism whereby chronic infection becomes malignant. Further, because antiretroviral drugs against Human Immunodeficiency Virus (HIV) inhibit HTLV-1 infectious spread, they may reduce the risk of HTLV-1 malignancy. |
| اللغة: | English |
| DOI: | 10.1101/799197 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8675747ea74c04e6623f6dd280331c84 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8675747ea74c04e6623f6dd280331c84 |
| قاعدة البيانات: | OpenAIRE |
| DOI: | 10.1101/799197 |
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