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Treatment-Mediated Alterations in HIV Fitness Preserve CD4+ T Cell Counts but Have Minimal Effects on Viral Load

Journal Article · · PLoS Computational Biology (Online)
 [1];  [2];  [3];  [4];  [5];  [6]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group; DOE/OSTI
  2. Oakland Univ., Rochester, MI (United States). Dept. of Mathematics and Statistics
  3. Emory Univ., Atlanta, GA (United States). School of Medicine. Division of Infectious Diseases
  4. Harvard Medical School, Boston, MA (United States). Bringham and Women's Hospital. Division of AIDS. Section of Retrovial Therapeutics
  5. Univ. of California, San Francisco, CA (United States). Dept. of Medicine; San Francisco General Hospital, San Francisco, CA (United States)
  6. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group
+ Show Author Affiliations
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 readministered. 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 1763% 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.
Research Organization:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627208
Journal Information:
PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 11 Vol. 6; ISSN 1553-7358
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (6)

Modeling the within-host dynamics of HIV infection journal September 2013
Estimating HIV-1 Fitness Characteristics from Cross-Sectional Genotype Data journal November 2014
Recombination Enhances HIV-1 Envelope Diversity by Facilitating the Survival of Latent Genomic Fragments in the Plasma Virus Population journal December 2015
Residual Viremia in Treated HIV+ Individuals journal January 2016
Immune Activation, Cd4+ T Cell Counts, and Viremia Exhibit Oscillatory Patterns over Time in Patients with Highly Resistant HIV Infection journal June 2011
The Majority of CD4+ T-Cell Depletion during Acute Simian-Human Immunodeficiency Virus SHIV89.6P Infection Occurs in Uninfected Cells journal January 2014

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