Document Detail


Treatment-mediated alterations in HIV fitness preserve CD4+ T cell counts but have minimal effects on viral load.
MedLine Citation:
PMID:  21124866     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Naveen K Vaidya; Libin Rong; Vincent C Marconi; Daniel R Kuritzkes; Steven G Deeks; Alan S Perelson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-11-24
Journal Detail:
Title:  PLoS computational biology     Volume:  6     ISSN:  1553-7358     ISO Abbreviation:  PLoS Comput. Biol.     Publication Date:  2010  
Date Detail:
Created Date:  2010-12-02     Completed Date:  2011-03-29     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  101238922     Medline TA:  PLoS Comput Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1001012     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
CD4 Lymphocyte Count
CD4-Positive T-Lymphocytes / drug effects*
Drug Resistance, Viral
HIV Envelope Protein gp41 / administration & dosage*
HIV Fusion Inhibitors / administration & dosage*
HIV Infections / drug therapy*,  immunology,  virology
HIV-1 / physiology*
Host-Pathogen Interactions
Humans
Models, Biological
Peptide Fragments / administration & dosage*
Prognosis
Treatment Outcome
Viral Load / drug effects
Grant Support
ID/Acronym/Agency:
AI052745/AI/NIAID NIH HHS; AI055273/AI/NIAID NIH HHS; AI28433/AI/NIAID NIH HHS; K24AI069994/AI/NIAID NIH HHS; P0 AI27763/AI/NIAID NIH HHS; P30 EB011339/EB/NIBIB NIH HHS; P30 EB011339-02/EB/NIBIB NIH HHS; P30-EB011339/EB/NIBIB NIH HHS; R01 AI028433/AI/NIAID NIH HHS; RR06555/RR/NCRR NIH HHS; UL1 RR024131/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/HIV Envelope Protein gp41; 0/HIV Fusion Inhibitors; 0/Peptide Fragments; 19OWO1T3ZE/enfuvirtide
Comments/Corrections

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