Limits...
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.

Show MeSH

Related in: MedlinePlus

Dynamics during ENF interruption.(a) Wild-type (green) and ENF-resistant (red) HIV-1, (b) the total plasma viral load (blue), and (c) CD4+ T cells (blue), predicted by the model using estimated parameters (solid curve) and experimentally observed data (•).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2991251&req=5

pcbi-1001012-g002: Dynamics during ENF interruption.(a) Wild-type (green) and ENF-resistant (red) HIV-1, (b) the total plasma viral load (blue), and (c) CD4+ T cells (blue), predicted by the model using estimated parameters (solid curve) and experimentally observed data (•).

Mentions: The estimated viral dynamic parameters during ENF interruption along with their mean and sample standard deviation, and their 95% confidence interval are summarized in Table 1 and Table 2, respectively. Using the estimated parameters, we found the predictions of the model agree well with the data for each of the study participants (Fig. 2). All the parameters are approximately the same for two ENF-interruptions in P3, suggesting that the viral dynamic parameters remain stable over time.


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)

Dynamics during ENF interruption.(a) Wild-type (green) and ENF-resistant (red) HIV-1, (b) the total plasma viral load (blue), and (c) CD4+ T cells (blue), predicted by the model using estimated parameters (solid curve) and experimentally observed data (•).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001012-g002: Dynamics during ENF interruption.(a) Wild-type (green) and ENF-resistant (red) HIV-1, (b) the total plasma viral load (blue), and (c) CD4+ T cells (blue), predicted by the model using estimated parameters (solid curve) and experimentally observed data (•).
Mentions: The estimated viral dynamic parameters during ENF interruption along with their mean and sample standard deviation, and their 95% confidence interval are summarized in Table 1 and Table 2, respectively. Using the estimated parameters, we found the predictions of the model agree well with the data for each of the study participants (Fig. 2). All the parameters are approximately the same for two ENF-interruptions in P3, suggesting that the viral dynamic parameters remain stable over time.

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