Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration
Abstract
The kinetics of HIV-1 decay under treatment depends on the class of antiretrovirals used. Mathematical models are useful to interpret the different profiles, providing quantitative information about the kinetics of virus replication and the cell populations contributing to viral decay. We modeled proviral integration in short- and long-lived infected cells to compare viral kinetics under treatment with and without the integrase inhibitor raltegravir (RAL). We fitted the model to data obtained from participants treated with RAL-containing regimes or with a four-drug regimen of protease and reverse transcriptase inhibitors. Our model explains the existence and quantifies the three phases of HIV-1 RNA decay in RAL-based regimens vs. the two phases observed in therapies without RAL. Our findings indicate that HIV-1 infection is mostly sustained by short-lived infected cells with fast integration and a short viral production period, and by long-lived infected cells with slow integration but an equally short viral production period. We propose that these cells represent activated and resting infected CD4+ T-cells, respectively, and estimate that infection of resting cells represent ~4% of productive reverse transcription events in chronic infection. RAL reveals the kinetics of proviral integration, showing that in short-lived cells the pre-integration population has a half-life ofmore »
- Authors:
-
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- The Johns Hopkins Univ., Baltimore, MD (United States)
- Univ. of Pittsburgh School of Medicine, PA (United States)
- Harvard Medical School, Boston, MA (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. de Lisboa, Lisboa (Portugal)
- Vaccine Research Center (United States)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- National Institutes of Health (NIH); USDOE
- OSTI Identifier:
- 1398914
- Report Number(s):
- LA-UR-16-27244
Journal ID: ISSN 1553-7374
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS Pathogens
- Additional Journal Information:
- Journal Volume: 13; Journal Issue: 7; Journal ID: ISSN 1553-7374
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science; Viral load; HIV-1; T cells; HIV; Macrophages; Mathematical models; Protease inhibitors; Antiretrovirals
Citation Formats
Cardozo, Erwing Fabian, Andrade, Adriana, Mellors, John W., Kuritzkes, Daniel R., Perelson, Alan S., Ribeiro, Ruy Miguel, and Douek, Daniel C. Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration. United States: N. p., 2017.
Web. doi:10.1371/journal.ppat.1006478.
Cardozo, Erwing Fabian, Andrade, Adriana, Mellors, John W., Kuritzkes, Daniel R., Perelson, Alan S., Ribeiro, Ruy Miguel, & Douek, Daniel C. Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration. United States. https://doi.org/10.1371/journal.ppat.1006478
Cardozo, Erwing Fabian, Andrade, Adriana, Mellors, John W., Kuritzkes, Daniel R., Perelson, Alan S., Ribeiro, Ruy Miguel, and Douek, Daniel C. Wed .
"Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration". United States. https://doi.org/10.1371/journal.ppat.1006478. https://www.osti.gov/servlets/purl/1398914.
@article{osti_1398914,
title = {Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration},
author = {Cardozo, Erwing Fabian and Andrade, Adriana and Mellors, John W. and Kuritzkes, Daniel R. and Perelson, Alan S. and Ribeiro, Ruy Miguel and Douek, Daniel C.},
abstractNote = {The kinetics of HIV-1 decay under treatment depends on the class of antiretrovirals used. Mathematical models are useful to interpret the different profiles, providing quantitative information about the kinetics of virus replication and the cell populations contributing to viral decay. We modeled proviral integration in short- and long-lived infected cells to compare viral kinetics under treatment with and without the integrase inhibitor raltegravir (RAL). We fitted the model to data obtained from participants treated with RAL-containing regimes or with a four-drug regimen of protease and reverse transcriptase inhibitors. Our model explains the existence and quantifies the three phases of HIV-1 RNA decay in RAL-based regimens vs. the two phases observed in therapies without RAL. Our findings indicate that HIV-1 infection is mostly sustained by short-lived infected cells with fast integration and a short viral production period, and by long-lived infected cells with slow integration but an equally short viral production period. We propose that these cells represent activated and resting infected CD4+ T-cells, respectively, and estimate that infection of resting cells represent ~4% of productive reverse transcription events in chronic infection. RAL reveals the kinetics of proviral integration, showing that in short-lived cells the pre-integration population has a half-life of ~7 hours, whereas in long-lived cells this half-life is ~6 weeks. We also show that the efficacy of RAL can be estimated by the difference in viral load at the start of the second phase in protocols with and without RAL. Altogether, we provide a mechanistic model of viral infection that parsimoniously explains the kinetics of viral load decline under multiple classes of antiretrovirals.},
doi = {10.1371/journal.ppat.1006478},
journal = {PLoS Pathogens},
number = 7,
volume = 13,
place = {United States},
year = {Wed Jul 05 00:00:00 EDT 2017},
month = {Wed Jul 05 00:00:00 EDT 2017}
}
Web of Science
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