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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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Schematic diagram of the viral dynamic model.
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pcbi-1001012-g001: Schematic diagram of the viral dynamic model.

Mentions: A schematic diagram of the model is shown in Fig. 1. The model contains five variables: uninfected target cells, T, cells infected by ENF-sensitive virus, Is, cells infected by ENF-resistant virus, Ir, ENF-sensitive virus, Vs, and ENF-resistant virus, Vr. The model assumes that target cells are produced at a constant rate, λ, and die at rate dT. ENF-sensitive virus infects target cells to produce infected cells, Is, at rate βsTVs, among which a fraction μsβsTVs, become ENF-resistant during the process of reverse transcription of viral RNA to DNA due to mutation at rate μs. Similarly, the infection by ENF-resistant virus produces infected cells, Ir, at rate βrTVr, with a fraction μrβrTVr undergoing backward mutation to the drug sensitive strain at rate μr. Cells infected by ENF-sensitive and ENF-resistant virus produce new virions at rates psIs and prIr, and die at rates δIs and δIr, respectively. Both viruses are cleared at the same rate c per virion. Whether the V38A mutation in gp41 affects viral production remains unclear. For simplicity, we assume ps = pr, and describe the resistance-associated fitness loss only by a reduced infectivity rate, i.e., βr = (1−α) βs, where the fitness cost of the mutant virus, α, satisfies 0≤α≤1. ENF is a fusion inhibitor and reduces infection of target cells by free virus. We assume εs and εr are the efficacies of ENF against ENF-sensitive and ENF-resistant virus, respectively, with 0≤εs, εr≤1.


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)

Schematic diagram of the viral dynamic model.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001012-g001: Schematic diagram of the viral dynamic model.
Mentions: A schematic diagram of the model is shown in Fig. 1. The model contains five variables: uninfected target cells, T, cells infected by ENF-sensitive virus, Is, cells infected by ENF-resistant virus, Ir, ENF-sensitive virus, Vs, and ENF-resistant virus, Vr. The model assumes that target cells are produced at a constant rate, λ, and die at rate dT. ENF-sensitive virus infects target cells to produce infected cells, Is, at rate βsTVs, among which a fraction μsβsTVs, become ENF-resistant during the process of reverse transcription of viral RNA to DNA due to mutation at rate μs. Similarly, the infection by ENF-resistant virus produces infected cells, Ir, at rate βrTVr, with a fraction μrβrTVr undergoing backward mutation to the drug sensitive strain at rate μr. Cells infected by ENF-sensitive and ENF-resistant virus produce new virions at rates psIs and prIr, and die at rates δIs and δIr, respectively. Both viruses are cleared at the same rate c per virion. Whether the V38A mutation in gp41 affects viral production remains unclear. For simplicity, we assume ps = pr, and describe the resistance-associated fitness loss only by a reduced infectivity rate, i.e., βr = (1−α) βs, where the fitness cost of the mutant virus, α, satisfies 0≤α≤1. ENF is a fusion inhibitor and reduces infection of target cells by free virus. We assume εs and εr are the efficacies of ENF against ENF-sensitive and ENF-resistant virus, respectively, with 0≤εs, εr≤1.

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