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Quantifying the Turnover of Transcriptional Subclasses of HIV-1-Infected Cells

Journal Article · · PLoS Computational Biology (Online)
 [1];  [2];  [3];  [2];  [4]
  1. Univ. of Bern (Switzerland). Inst. of Social and Preventative Medicine (ISPM); DOE/OSTI
  2. Univ. Hospital of Zurich (Switzerland). Div. of Infectious Diseases and Hospital Epidemiology
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
  4. Imperial College, London (United Kingdom)
+ Show Author Affiliations
HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection. We find that a substantial fraction of cells can become defectively infected. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size on the order of 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells, and indicates that cells containing solely unspliced viral RNA are a good marker for viral latency. The model illustrates how the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.
Research Organization:
Los Alamos National Lab., NM (United States)
Sponsoring Organization:
Abbott Inc.; National Institutes of Health (NIH); Novartis Foundation; Roche Research Foundation; Swiss National Science Foundation (SNSF); USDOE National Nuclear Security Administration (NNSA)
Grant/Contract Number:
89233218CNA000001
OSTI ID:
1627240
Journal Information:
PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 10 Vol. 10; ISSN 1553-7358
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (84)

Modeling HIV Infection of CD4+ T-cell Subpopulations journal October 1994
Practical Identifiability of HIV Dynamics Models journal June 2007
Stochastic Fate Selection in HIV-Infected Patients journal October 2013
Establishment and molecular mechanisms of HIV-1 latency in T cells journal December 2013
Redefining the Viral Reservoirs that Prevent HIV-1 Eradication journal September 2012
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis journal November 1999
The search for an HIV cure: tackling latent infection journal July 2013
Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy journal January 2010
Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection journal December 2013
Modelling viral and immune system dynamics journal January 2002
Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques journal November 2007
Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy journal March 2008
Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule journal June 2011
Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection journal May 2012
Nonlinear partial differential equations and applications: In vivo dynamics of T cell activation, proliferation, and death in HIV-1 infection: Why are CD4+ but not CD8+ T cells depleted? journal November 2002
Turnover of CD4 + and CD8 + T Lymphocytes in HIV-1 Infection as Measured by Ki-67 Antigen journal April 1998
Constant Mean Viral Copy Number per Infected Cell in Tissues Regardless of High, Low, or Undetectable Plasma HIV RNA journal May 1999
Viral Dynamics of Acute HIV-1 Infection journal September 1999
Dynamics of Total, Linear Nonintegrated, and Integrated HIV‐1 DNA In Vivo and In Vitro journal February 2008
Determination of simian immunodeficiency virus production by infected activated and resting cells journal January 2007
Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy journal January 2010
Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards journal January 2012
Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing replication in eradication trials journal November 2012
HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time journal March 1996
Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue journal November 1996
Sexual Transmission and Propagation of SIV and HIV in Resting and Activated CD4+ T Cells journal November 1999
Highly Sensitive Methods Based on Seminested Real-Time Reverse Transcription-PCR for Quantitation of Human Immunodeficiency Virus Type 1 Unspliced and Multiply Spliced RNA and Proviral DNA journal July 2008
Estimation of the Initial Viral Growth Rate and Basic Reproductive Number during Acute HIV-1 Infection journal March 2010
Productive Human Immunodeficiency Virus Type 1 Infection in Peripheral Blood Predominantly Takes Place in CD4/CD8 Double-Negative T Lymphocytes journal September 2007
Pol-Specific CD8+ T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation journal August 2007
Reassessing the Human Immunodeficiency Virus Type 1 Life Cycle through Age-Structured Modeling: Life Span of Infected Cells, Viral Generation Time, and Basic Reproductive Number, R 0 journal August 2009
Contribution of Follicular Dendritic Cells to Persistent HIV Viremia journal October 2013
Decelerating Decay of Latently Infected Cells during Prolonged Therapy for Human Immunodeficiency Virus Type 1 Infection journal September 2002
Cell-associated HIV RNA: a dynamic biomarker of viral persistence journal April 2013
Dynamics of Immune Escape during HIV/SIV Infection journal July 2008
Modeling Latently Infected Cell Activation: Viral and Latent Reservoir Persistence, and Viral Blips in HIV-infected Patients on Potent Therapy journal October 2009
Current Estimates for HIV-1 Production Imply Rapid Viral Clearance in Lymphoid Tissues journal September 2010
Profound Depletion of HIV-1 Transcription in Patients Initiating Antiretroviral Therapy during Acute Infection journal October 2010
Implications of CTL-Mediated Killing of HIV-Infected Cells during the Non-Productive Stage of Infection journal February 2011
Early Antiretroviral Therapy During Primary HIV-1 Infection Results in a Transient Reduction of the Viral Setpoint upon Treatment Interruption journal November 2011
24 Hours in the Life of HIV-1 in a T Cell Line journal January 2013
Regularization Paths for Generalized Linear Models via Coordinate Descent journal January 2010
Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA journal January 2011
The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection journal August 2013
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis journal November 1999
The search for an HIV cure: tackling latent infection journal July 2013
Abortive HIV Infection Mediates CD4 T Cell Depletion and Inflammation in Human Lymphoid Tissue journal November 2010
Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure journal October 2013
Decay characteristics of HIV-1-infected compartments during combination therapy journal May 1997
The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy journal January 2000
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells journal May 2003
Quantifying Residual HIV-1 Replication in Patients Receiving Combination Antiretroviral Therapy journal May 1999
Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy journal May 1999
Cellular Viral Rebound after Cessation of Potent Antiretroviral Therapy Predicted by Levels of Multiply Spliced HIV‐1 RNA Encoding nef journal December 2004
Effect of Treatment, during Primary Infection, on Establishment and Clearance of Cellular Reservoirs of HIV-1 journal May 2005
Differences in HIV Burden and Immune Activation within the Gut of HIV‐Positive Patients Receiving Suppressive Antiretroviral Therapy journal November 2010
Residual HIV-RNA Levels Persist for Up to 2.5 Years in Peripheral Blood Mononuclear Cells of Patients on Potent Antiretroviral Therapy journal August 2000
A Simplex Method for Function Minimization journal January 1965
Viral Persistence in HIV Infection: Much Known, Much to Learn journal August 2013
Levels of HIV-infected peripheral blood cells remain stable throughout the natural history of HIV-1 infection journal January 1998
Quantification of In Vivo Replicative Capacity of HIV-1 in Different Compartments of Infected Cells journal January 2001
Determination of simian immunodeficiency virus production by infected activated and resting cells journal January 2007
Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy journal January 2010
Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards journal January 2012
Maximum Likelihood Estimation in Dynamical Models of HIV journal May 2007
Highly Sensitive Methods Based on Seminested Real-Time Reverse Transcription-PCR for Quantitation of Human Immunodeficiency Virus Type 1 Unspliced and Multiply Spliced RNA and Proviral DNA journal July 2008
Estimation of the Initial Viral Growth Rate and Basic Reproductive Number during Acute HIV-1 Infection journal March 2010
Productive Human Immunodeficiency Virus Type 1 Infection in Peripheral Blood Predominantly Takes Place in CD4/CD8 Double-Negative T Lymphocytes journal September 2007
Contribution of Follicular Dendritic Cells to Persistent HIV Viremia journal May 2013
Pol-Specific CD8+ T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation journal August 2007
Reassessing the Human Immunodeficiency Virus Type 1 Life Cycle through Age-Structured Modeling: Life Span of Infected Cells, Viral Generation Time, and Basic Reproductive Number, R 0 journal August 2009
Decelerating Decay of Latently Infected Cells during Prolonged Therapy for Human Immunodeficiency Virus Type 1 Infection journal September 2002
A Novel Antiviral Intervention Results in More Accurate Assessment of Human Immunodeficiency Virus Type 1 Replication Dynamics and T-Cell Decay In Vivo journal April 2003
Mathematical Analysis of Age‐Structured HIV‐1 Dynamics with Combination Antiretroviral Therapy journal January 2007
Mathematical Analysis of HIV-1 Dynamics in Vivo journal January 1999
Residual Cell-Associated Unspliced HIV-1 Rna in Peripheral Blood of Patients on Potent Antiretroviral Therapy Represents Intracellular Transcripts journal February 2001
Cellular and molecular mechanisms involved in the establishment of HIV-1 latency journal February 2013
A novel acute HIV infection staging system based on 4thgeneration immunoassay journal May 2013
Biphasic decay kinetics suggest progressive slowing in turnover of latently HIV-1 infected cells during antiretroviral therapy journal January 2008
CD8+ T Cell Control of HIV—A Known Unknown journal January 2010
Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies journal February 2013
Solving Differential Equations in R : Package deSolve journal January 2010
Effect of early antiretroviral therapy during primary HIV-1 infection on cell-associated HIV-1 DNA and plasma HIV-1 RNA journal January 2011
Gag-Specific CD8 + T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression journal February 2007

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Notwithstanding Circumstantial Alibis, Cytotoxic T Cells Can Be Major Killers of HIV-1-Infected Cells journal May 2016
A Computational Model of Inhibition of HIV-1 by Interferon-Alpha journal March 2016
HIV dynamics linked to memory CD4+ T cell homeostasis journal October 2017
Stochastic Dynamics of the Latently Infected Cell Reservoir During HIV Infection journal October 2018
Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART journal April 2017
Phylogenetic approach to recover integration dates of latent HIV sequences within-host journal September 2018
Prevalence and correlates of persistent intracellular HIV transcription in individuals on efavirenz versus atazanavir-based regimens: A prospective cohort study journal March 2018

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59 BASIC BIOLOGICAL SCIENCES
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Mathematical & Computational Biology