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Title: Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy

Abstract

Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation,more » the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the ‘‘critical efficacy’’ irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.« less

Authors:
 [1];  [1]
+ Show Author Affiliations
  1. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1627181
Grant/Contract Number:  
AC52-06NA25396; W-7405-ENG-36; AI28433; RR06555
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 2; Journal Issue: 10; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; viral replication; T-cells; viral load; viral persistence and latency; HIV-1; opportunistic infections; eigenvalues; blood plasma

Citation Formats

Kim, Hwijin, and Perelson, Alan S. Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy. United States: N. p., 2006. Web. doi:10.1371/journal.pcbi.0020135.
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Kim, Hwijin, & Perelson, Alan S. Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy. United States. https://doi.org/10.1371/journal.pcbi.0020135
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Kim, Hwijin, and Perelson, Alan S. Fri . "Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy". United States. https://doi.org/10.1371/journal.pcbi.0020135. https://www.osti.gov/servlets/purl/1627181.
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@article{osti_1627181,
title = {Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy},
author = {Kim, Hwijin and Perelson, Alan S.},
abstractNote = {Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the ‘‘critical efficacy’’ irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence.},
doi = {10.1371/journal.pcbi.0020135},
journal = {PLoS Computational Biology (Online)},
number = 10,
volume = 2,
place = {United States},
year = {Fri Oct 13 00:00:00 EDT 2006},
month = {Fri Oct 13 00:00:00 EDT 2006}
}
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journal, February 1998

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journal, December 1999

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CD4+ T Cell Depletion during all Stages of HIV Disease Occurs Predominantly in the Gastrointestinal Tract
journal, September 2004

  • Brenchley, Jason M.; Schacker, Timothy W.; Ruff, Laura E.
  • Journal of Experimental Medicine, Vol. 200, Issue 6
  • DOI: 10.1084/jem.20040874

Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract
journal, September 2004

  • Mehandru, Saurabh; Poles, Michael A.; Tenner-Racz, Klara
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journal, December 2000

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Approaching Eradication of Highly Active Antiretroviral Therapy–Persistent Human Immunodeficiency Virus Type 1 Reservoirs with Immune Activation Therapy
journal, December 2002

  • Kulkosky, Joseph; Pomerantz, Roger J.
  • Clinical Infectious Diseases, Vol. 35, Issue 12
  • DOI: 10.1086/344959

Determining the Relative Efficacy of Highly Active Antiretroviral Therapy
journal, March 2003

  • Louie, Michael; Hogan, Christine; Di Mascio, Michele
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Factors Influencing Increases in CD4 Cell Counts of HIV‐Positive Persons Receiving Long‐Term Highly Active Antiretroviral Therapy
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The potential for CD4 cell increases in HIV-positive individuals who control viraemia with highly active antiretroviral therapy
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Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis
journal, June 2008

HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time
journal, March 1996

Immunological Memory and Protective Immunity: Understanding Their Relation
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Quantitative Image Analysis of HIV-1 Infection in Lymphoid Tissue
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Kinetics of Response in Lymphoid Tissues to Antiretroviral Therapy of HIV-1 Infection
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journal, October 2003

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A Novel Assay Allows Genotyping of the Latent Reservoir for Human Immunodeficiency Virus Type 1 in the Resting CD4+ T Cells of Viremic Patients
journal, April 2005

T C ELL M EMORY
journal, April 2002

The Challenge of Viral Reservoirs in HIV-1 Infection
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A stable latent reservoir for HIV-1 in resting CD4+ T lymphocytes in infected children
journal, April 2000

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Reservoirs, Sanctuaries, and Residual Disease: The Hiding Spots of HIV-1
journal, March 2003

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    • Immunological Reviews, Vol. 254, Issue 1
    • DOI: 10.1111/imr.12065

    Characterization of HIV-1 RNA forms in the plasma of patients undergoing successful HAART
    journal, April 2010

    Modelling and analysis of dynamics of viral infection of cells and of interferon resistance
    journal, August 2008

    • Getto, Ph.; Kimmel, M.; Marciniak-Czochra, A.
    • Journal of Mathematical Analysis and Applications, Vol. 344, Issue 2
    • DOI: 10.1016/j.jmaa.2008.02.069

    Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy
    journal, January 2010

    • Althaus, Christian L.; De Boer, Rob J.
    • Molecular Systems Biology, Vol. 6, Issue 1
    • DOI: 10.1038/msb.2010.4

    The transcription cofactor CRTC1 protects from aberrant hepatic lipid accumulation
    journal, November 2016

    Low-level HIV-1 replication and the dynamics of the resting CD4+T cell reservoir for HIV-1 in the setting of HAART
    journal, January 2008

    • Sedaghat, Ahmad R.; Siliciano, Robert F.; Wilke, Claus O.
    • BMC Infectious Diseases, Vol. 8, Issue 1
    • DOI: 10.1186/1471-2334-8-2

    Modeling the within-host dynamics of HIV infection
    journal, September 2013

    Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients
    journal, January 2007

    • Petitjean, Gaël; Al Tabaa, Yassine; Tuaillon, Edouard
    • Retrovirology, Vol. 4, Issue 1
    • DOI: 10.1186/1742-4690-4-60

    Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies
    journal, December 2009

    An RNAi in silico approach to find an optimal shRNA cocktail against HIV-1
    journal, December 2010

    • Méndez-Ortega, María C.; Restrepo, Silvia; Rodríguez-R, Luis M.
    • Virology Journal, Vol. 7, Issue 1
    • DOI: 10.1186/1743-422x-7-369

    Viral dynamics of an HIV model with latent infection incorporating antiretroviral therapy
    journal, August 2016

    Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population
    journal, December 2015

    • Immonen, Taina T.; Conway, Jessica M.; Romero-Severson, Ethan O.
    • PLOS Computational Biology, Vol. 11, Issue 12
    • DOI: 10.1371/journal.pcbi.1004625

    Modeling the Dynamics and Migratory Pathways of Virus-Specific Antibody-Secreting Cell Populations in Primary Influenza Infection
    journal, August 2014

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