Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling

The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Us...

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Published inPLoS pathogens Vol. 15; no. 11; p. e1008164
Main Authors Miura, Michi, Dey, Supravat, Ramanayake, Saumya, Singh, Abhyudai, Rueda, David S., Bangham, Charles R. M.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 18.11.2019
Public Library of Science (PLoS)
Subjects
Activation
Analysis
Antisense RNA
Biology and life sciences
Cells, Cultured
Cellular stress response
Cloning
Computer engineering
Computer simulation
Gene Expression Regulation, Viral
Genomes
Health aspects
HTLV-I Infections - genetics
HTLV-I Infections - virology
Human T-lymphotropic virus 1 - physiology
Humans
In Situ Hybridization, Fluorescence
Incubation
Infection
Infectious diseases
Insertion
Kinetics
Latency
Leukemia
Leukocytes (mononuclear)
Leukocytes, Mononuclear - virology
Lymphocytes
Lymphocytes T
Medicine
Medicine and Health Sciences
Parameter estimation
Peripheral blood mononuclear cells
Population
Proteins
Reaction kinetics
Research and Analysis Methods
Ribonucleic acid
RNA
Single-Cell Analysis - methods
Software
Stochastic models
Stochastic Processes
Stochasticity
T cells
Transcription
Transcription (Genetics)
Viral Proteins - genetics
Virus Activation - genetics
Virus Latency - genetics
Virus Replication
Viruses
United Kingdom > UK
Delaware
United States > US
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Abstract The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.
AbstractList The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1.sup.+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1.sup.+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1.sup.+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1.sup.+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.
The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1 + individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo . We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1 + PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1 + clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1 + cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ -negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts. Human retroviruses such as HIV-1 and HTLV-1 (human T cell leukemia virus) can establish a latent infection in the host cell. However, these viruses need to be able to produce viral genome to propagate in a new host. HTLV-1-infected cells are transmitted through breastfeeding, blood transfusion and sexual contact, and HTLV-1 restores transcription once the infected cells are drawn from infected individuals. We measured the kinetics of the HTLV-1 transcriptional reactivation in blood cells isolated from HTLV-1 + individuals by single-molecule RNA FISH. Viral transcripts were visualized as diffraction-limited spots and their abundance was quantified at one-hour intervals. The onset of the virus transcription peaked after one to three hours of incubation. In each cell, a short period of slow HTLV-1 transcription was followed by a phase of rapid transcription. Computer simulation, based on experimental data on PBMCs from a leukemic patient with a single dominant HTLV-1-infected T cell clone, indicated that this rapid transcription from the HTLV-1 sense-strand promoter activated by Tax was terminated in less than an hour. The HTLV-1 antisense transcript HBZ was constantly produced at a low level, and 50% ± 20% of HTLV-1 + cells were negative for HBZ at a given time. These results demonstrate how rapidly HTLV-1 is reactivated and potentially becomes infectious, once HTLV-1 + cells are transmitted into a new host.
The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.
The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given time in each cell. However, cellular stress responses trigger the reactivation of HTLV-1, enabling the virus to transmit to a new host cell. Using single-molecule RNA FISH, we measured the kinetics of the HTLV-1 transcriptional reactivation in peripheral blood mononuclear cells (PBMCs) isolated from HTLV-1+ individuals. The abundance of the HTLV-1 sense and antisense transcripts was quantified hourly during incubation of the HTLV-1-infected PBMCs ex vivo. We found that, in each cell, the sense-strand transcription occurs in two distinct phases: the initial low-rate transcription is followed by a phase of rapid transcription. The onset of transcription peaked between 1 and 3 hours after the start of in vitro incubation. The variance in the transcription intensity was similar in polyclonal HTLV-1+ PBMCs (with tens of thousands of distinct provirus insertion sites), and in samples with a single dominant HTLV-1+ clone. A stochastic simulation model was developed to estimate the parameters of HTLV-1 proviral transcription kinetics. In PBMCs from a leukemic subject with one dominant T-cell clone, the model indicated that the average duration of HTLV-1 sense-strand activation by Tax (i.e. the rapid transcription) was less than one hour. HTLV-1 antisense transcription was stable during reactivation of the sense-strand. The antisense transcript HBZ was produced at an average rate of ~0.1 molecules per hour per HTLV-1+ cell; however, between 20% and 70% of HTLV-1-infected cells were HBZ-negative at a given time, the percentage depending on the individual subject. HTLV-1-infected cells are exposed to a range of stresses when they are drawn from the host, which initiate the viral reactivation. We conclude that whereas antisense-strand transcription is stable throughout the stress response, the HTLV-1 sense-strand reactivation is highly heterogeneous and occurs in short, self-terminating bursts.
Audience Academic
Author Singh, Abhyudai
Bangham, Charles R. M.
Rueda, David S.
Ramanayake, Saumya
Miura, Michi
Dey, Supravat
AuthorAffiliation 1 Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
3 Single Molecule Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom
University of Illinois at Chicago College of Medicine, UNITED STATES
2 Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware, United States of America
AuthorAffiliation_xml – name: 2 Department of Electrical and Computer Engineering, University of Delaware, Newark, Delaware, United States of America
– name: 1 Department of Infectious Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
– name: University of Illinois at Chicago College of Medicine, UNITED STATES
– name: 3 Single Molecule Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, London, United Kingdom
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  orcidid: 0000-0002-6943-3782
  surname: Miura
  fullname: Miura, Michi
– sequence: 2
  givenname: Supravat
  surname: Dey
  fullname: Dey, Supravat
– sequence: 3
  givenname: Saumya
  orcidid: 0000-0003-4718-8728
  surname: Ramanayake
  fullname: Ramanayake, Saumya
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  orcidid: 0000-0002-1451-2838
  surname: Singh
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  surname: Bangham
  fullname: Bangham, Charles R. M.
BackLink https://www.ncbi.nlm.nih.gov/pubmed/31738810$$D View this record in MEDLINE/PubMed
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Copyright COPYRIGHT 2019 Public Library of Science
2019 Miura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
2019 Miura et al 2019 Miura et al
Copyright_xml – notice: COPYRIGHT 2019 Public Library of Science
– notice: 2019 Miura et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
– notice: 2019 Miura et al 2019 Miura et al
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DocumentTitleAlternate Single-cell quantification of HTLV-1 reactivation kinetics
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Current address: Department of Microbiology, The University of Hong Kong, Hong Kong
The authors have declared that no competing interests exist.
ORCID 0000-0003-4718-8728
0000-0002-6943-3782
0000-0003-4657-6323
0000-0002-1451-2838
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Snippet The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given...
The human T cell leukemia virus HTLV-1 establishes a persistent infection in vivo in which the viral sense-strand transcription is usually silent at a given...
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StartPage e1008164
SubjectTerms Activation
Analysis
Antisense RNA
Biology and life sciences
Cells, Cultured
Cellular stress response
Cloning
Computer engineering
Computer simulation
Gene Expression Regulation, Viral
Genomes
Health aspects
HTLV-I Infections - genetics
HTLV-I Infections - virology
Human T-lymphotropic virus 1 - physiology
Humans
In Situ Hybridization, Fluorescence
Incubation
Infection
Infectious diseases
Insertion
Kinetics
Latency
Leukemia
Leukocytes (mononuclear)
Leukocytes, Mononuclear - virology
Lymphocytes
Lymphocytes T
Medicine
Medicine and Health Sciences
Parameter estimation
Peripheral blood mononuclear cells
Population
Proteins
Reaction kinetics
Research and Analysis Methods
Ribonucleic acid
RNA
Single-Cell Analysis - methods
Software
Stochastic models
Stochastic Processes
Stochasticity
T cells
Transcription
Transcription (Genetics)
Viral Proteins - genetics
Virus Activation - genetics
Virus Latency - genetics
Virus Replication
Viruses
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Title Kinetics of HTLV-1 reactivation from latency quantified by single-molecule RNA FISH and stochastic modelling
URI https://www.ncbi.nlm.nih.gov/pubmed/31738810
https://www.proquest.com/docview/2327509078
https://www.proquest.com/docview/2315972209
https://pubmed.ncbi.nlm.nih.gov/PMC6886867
https://doaj.org/article/8424ea5d518e46b796bd07217988a3a8
http://dx.doi.org/10.1371/journal.ppat.1008164
Volume 15
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