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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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Simulation results during ENF interruption.Plasma HIV-1 RNA level (a–d), and V38A mutant virus proportion (e–h), for different V38A mutant virus fitness costs (a,e), initial V38A mutant virus proportion (b,f), initial T cell counts (c,g) and T cell source rate (d,h). Parameters used are the average values of P1, P2, P3 in Table 1.
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pcbi-1001012-g004: Simulation results during ENF interruption.Plasma HIV-1 RNA level (a–d), and V38A mutant virus proportion (e–h), for different V38A mutant virus fitness costs (a,e), initial V38A mutant virus proportion (b,f), initial T cell counts (c,g) and T cell source rate (d,h). Parameters used are the average values of P1, P2, P3 in Table 1.

Mentions: We first studied the effect of ENF-resistant virus fitness cost on plasma viral load. In Figs. 4a and 5a, we show the plasma viral load obtained from our model for different fitness costs during ENF interruption and ENF re-administration, respectively, with other parameter values held to their estimated values. When we varied the fitness cost from 5 to 50% we did not find any observable change in plasma viral load. This suggests that the fitness cost has a minor role in determining the total viral load. We next studied the effect of different initial proportions of the mutant virus at the time of ENF interruption (Fig. 4b) and ENF re-administration (Fig. 5b). The initial proportion of ENF-resistant virus does not seem to have any effect on plasma viral load either.


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)

Simulation results during ENF interruption.Plasma HIV-1 RNA level (a–d), and V38A mutant virus proportion (e–h), for different V38A mutant virus fitness costs (a,e), initial V38A mutant virus proportion (b,f), initial T cell counts (c,g) and T cell source rate (d,h). Parameters used are the average values of P1, P2, P3 in Table 1.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991251&req=5

pcbi-1001012-g004: Simulation results during ENF interruption.Plasma HIV-1 RNA level (a–d), and V38A mutant virus proportion (e–h), for different V38A mutant virus fitness costs (a,e), initial V38A mutant virus proportion (b,f), initial T cell counts (c,g) and T cell source rate (d,h). Parameters used are the average values of P1, P2, P3 in Table 1.
Mentions: We first studied the effect of ENF-resistant virus fitness cost on plasma viral load. In Figs. 4a and 5a, we show the plasma viral load obtained from our model for different fitness costs during ENF interruption and ENF re-administration, respectively, with other parameter values held to their estimated values. When we varied the fitness cost from 5 to 50% we did not find any observable change in plasma viral load. This suggests that the fitness cost has a minor role in determining the total viral load. We next studied the effect of different initial proportions of the mutant virus at the time of ENF interruption (Fig. 4b) and ENF re-administration (Fig. 5b). The initial proportion of ENF-resistant virus does not seem to have any effect on plasma viral load either.

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