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Treatment-mediated alterations in HIV fitness preserve CD4+ T cell counts but have minimal effects on viral load.

Vaidya NK, Rong L, Marconi VC, Kuritzkes DR, Deeks SG, Perelson AS - PLoS Comput. Biol. (2010)

Bottom Line: To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor.Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits.This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

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CD4 count and the proportion of uninfected and infected cells.(a) Predicted temporal variation of the CD4 count during ENF interruption (red) and with ENF re-administration (green). Parameters used are the average values in Tables 1 and 3. The vertical dashed line indicates the time of ENF re-administration. (b) Bar diagram showing the percentage change of CD4 count at the end of one year without ENF (red) and at the end of 3 months with ENF re-administration (green). (c) Change over time of the proportion of uninfected cells, T (blue), cells infected with drug-sensitive virus, Is (green), and cells infected with drug-resistant virus, Ir (red). The vertical dashed line indicates the time of ENF re-administration.
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pcbi-1001012-g006: CD4 count and the proportion of uninfected and infected cells.(a) Predicted temporal variation of the CD4 count during ENF interruption (red) and with ENF re-administration (green). Parameters used are the average values in Tables 1 and 3. The vertical dashed line indicates the time of ENF re-administration. (b) Bar diagram showing the percentage change of CD4 count at the end of one year without ENF (red) and at the end of 3 months with ENF re-administration (green). (c) Change over time of the proportion of uninfected cells, T (blue), cells infected with drug-sensitive virus, Is (green), and cells infected with drug-resistant virus, Ir (red). The vertical dashed line indicates the time of ENF re-administration.

Mentions: The changes over time of the CD4 count, and of the proportion of uninfected cells, cell infected with sensitive virus, and cell infected with resistant virus are shown in Figs. 6a and 6c, respectively. After ENF re-administration, the proportion of uninfected cells increases, reaches a peak and then decays to a steady-state level higher than the level before ENF re-administration. In a study by Deeks et al. [11] on a larger cohort of individuals, the subjects received an ENF-based regimen (the same as the one received by individuals in this study) for 34 weeks (approximately the same period as in our study) followed by the interruption of ENF. During a screening period of 4 weeks just before the interruption began, they found a negligible change in CD4+ T cell counts (mean change: 0.13 cells/µl/week) suggesting that steady state was reached by the end of this long-term treatment. They also observed the steady state T cell level after a long period of ENF interruption. Below we calculate from our model the steady state level of uninfected CD4+ T cells to understand how the uninfected target cell level differs between long-term ENF interruption and long-term ENF re-administration.


Treatment-mediated alterations in HIV fitness preserve CD4+ T cell counts but have minimal effects on viral load.

Vaidya NK, Rong L, Marconi VC, Kuritzkes DR, Deeks SG, Perelson AS - PLoS Comput. Biol. (2010)

CD4 count and the proportion of uninfected and infected cells.(a) Predicted temporal variation of the CD4 count during ENF interruption (red) and with ENF re-administration (green). Parameters used are the average values in Tables 1 and 3. The vertical dashed line indicates the time of ENF re-administration. (b) Bar diagram showing the percentage change of CD4 count at the end of one year without ENF (red) and at the end of 3 months with ENF re-administration (green). (c) Change over time of the proportion of uninfected cells, T (blue), cells infected with drug-sensitive virus, Is (green), and cells infected with drug-resistant virus, Ir (red). The vertical dashed line indicates the time of ENF re-administration.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2991251&req=5

pcbi-1001012-g006: CD4 count and the proportion of uninfected and infected cells.(a) Predicted temporal variation of the CD4 count during ENF interruption (red) and with ENF re-administration (green). Parameters used are the average values in Tables 1 and 3. The vertical dashed line indicates the time of ENF re-administration. (b) Bar diagram showing the percentage change of CD4 count at the end of one year without ENF (red) and at the end of 3 months with ENF re-administration (green). (c) Change over time of the proportion of uninfected cells, T (blue), cells infected with drug-sensitive virus, Is (green), and cells infected with drug-resistant virus, Ir (red). The vertical dashed line indicates the time of ENF re-administration.
Mentions: The changes over time of the CD4 count, and of the proportion of uninfected cells, cell infected with sensitive virus, and cell infected with resistant virus are shown in Figs. 6a and 6c, respectively. After ENF re-administration, the proportion of uninfected cells increases, reaches a peak and then decays to a steady-state level higher than the level before ENF re-administration. In a study by Deeks et al. [11] on a larger cohort of individuals, the subjects received an ENF-based regimen (the same as the one received by individuals in this study) for 34 weeks (approximately the same period as in our study) followed by the interruption of ENF. During a screening period of 4 weeks just before the interruption began, they found a negligible change in CD4+ T cell counts (mean change: 0.13 cells/µl/week) suggesting that steady state was reached by the end of this long-term treatment. They also observed the steady state T cell level after a long period of ENF interruption. Below we calculate from our model the steady state level of uninfected CD4+ T cells to understand how the uninfected target cell level differs between long-term ENF interruption and long-term ENF re-administration.

Bottom Line: To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor.Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits.This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

View Article: PubMed Central - PubMed

Affiliation: Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.

ABSTRACT
For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment.

Show MeSH
Related in: MedlinePlus