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Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration

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  • E Fabian Cardozo
  • Adriana Andrade
  • John W Mellors
  • Daniel R Kuritzkes
  • Alan S Perelson
  • Ruy M Ribeiro

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 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. Overall, we provide a mechanistic model of viral infection that parsimoniously explains the kinetics of viral load decline under multiple classes of antiretrovirals.Author summary: Antiretroviral therapy in HIV-1 infection leads to characteristic viral load decay profiles. Interpretation of this profile with mathematical models has provided important insights into the dynamics of the viral lifecycle (e.g., the turnover of infected cells). Here we develop a unified model and analyze viral load data from HIV-infected participants under treatment with and without an integrase inhibitor. Our model offers a new explanation for the observed differences in the decay profiles, and strongly supports the hypothesis that the second phase of viral decay is due to the loss of long-lived resting CD4+ T-cells with slow proviral integration. We estimate parameters of this decay and estimate the efficacy of an integrase inhibitor.

Suggested Citation

  • E Fabian Cardozo & Adriana Andrade & John W Mellors & Daniel R Kuritzkes & Alan S Perelson & Ruy M Ribeiro, 2017. "Treatment with integrase inhibitor suggests a new interpretation of HIV RNA decay curves that reveals a subset of cells with slow integration," PLOS Pathogens, Public Library of Science, vol. 13(7), pages 1-18, July.
  • Handle: RePEc:plo:ppat00:1006478
    DOI: 10.1371/journal.ppat.1006478
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    References listed on IDEAS

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    1. James B Gilmore & Anthony D Kelleher & David A Cooper & John M Murray, 2013. "Explaining the Determinants of First Phase HIV Decay Dynamics through the Effects of Stage-dependent Drug Action," PLOS Computational Biology, Public Library of Science, vol. 9(3), pages 1-12, March.
    2. Alan S. Perelson & Avidan U. Neumann & Martin Markowitz & John M. Leonard & David D. Ho, 1996. "HIV-1 Dynamics In Vivo: Virion Clearance Rate, Infected Cell Lifespan, and Viral Generation Time," Working Papers 96-02-004, Santa Fe Institute.
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    1. Benjamin B. Policicchio & Erwing Fabian Cardozo-Ojeda & Cuiling Xu & Dongzhu Ma & Tianyu He & Kevin D. Raehtz & Ranjit Sivanandham & Adam J. Kleinman & Alan S. Perelson & Cristian Apetrei & Ivona Pand, 2023. "CD8+ T cells control SIV infection using both cytolytic effects and non-cytolytic suppression of virus production," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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