Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Accelerated Immunodeficiency by Anti-CCR5 Treatment in HIV Infection

Journal Article · · PLoS Computational Biology (Online)
 [1];  [2];  [2];  [3]
  1. Univ. of California, Berkeley, CA (United States). Biophysics Graduate Group; Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.; DOE/OSTI
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Div.
  3. Univ. of California, La Jolla, CA (United States). Dept. of Chemistry and Biochemistry
+ Show Author Affiliations
In 50% of progressing HIV-1 patients, CXCR4-tropic (X4) virus emerges late in infection, often overtaking CCR5-tropic (R5) virus as the dominant viral strain. This ‘‘phenotypic switch’’ is strongly associated with rapidly declining CD4+ T cell counts and AIDS onset, yet its causes remain unknown. Here, we analyze a mathematical model for the mechanism of X4 emergence in late-stage HIV infection and use this analysis to evaluate the utility of a promising new class of antiretroviral drugs—CCR5 inhibitors—in dual R5, X4 infection. The model shows that the R5-to-X4 switch occurs as CD4+ T cell activation levels increase above a threshold and as CD4+ T cell counts decrease below a threshold during late-stage HIV infection. Importantly, the model also shows that highly active antiretroviral therapy (HAART) can inhibit X4 emergence but that monotherapy with CCR5 blockers can accelerate X4 onset and immunodeficiency if X4 infection of memory CD4+ T cells occurs at a high rate. Fortunately, when CXCR4 blockers or HAART are used in conjunction with CCR5 blockers, this risk of accelerated immunodeficiency is eliminated. The results suggest that CCR5 blockers will be more effective when used in combination with CXCR4 blockers and caution against CCR5 blockers in the absence of an effective HAART regimen or during HAART failure.
Research Organization:
Los Alamos National Laboratory (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:
1629291
Journal Information:
PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 8 Vol. 5; ISSN 1553-7358
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (42)

Modeling Within-Host Evolution of HIV: Mutation, Competition and Strain Replacement journal June 2007
Effect of a CCR5 inhibitor on viral loads in macaques dual-infected with R5 and X4 primate immunodeficiency viruses journal October 2004
Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1 journal October 2005
Maraviroc for Previously Treated Patients with R5 HIV-1 Infection journal October 2008
Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection journal April 2004
Resting naive CD4+ T cells are massively infected and eliminated by X4-tropic simian-human immunodeficiency viruses in macaques journal May 2005
CD8+ T cell-mediated CXC chemokine receptor 4-simian/human immunodeficiency virus suppression in dually infected rhesus macaques journal September 2003
Nonlinear partial differential equations and applications: Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection journal November 2002
Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages journal April 1999
Antigen-independent activation of naive and memory resting T cells by a cytokine combination. journal September 1994
Turnover of CD4 + and CD8 + T Lymphocytes in HIV-1 Infection as Measured by Ki-67 Antigen journal April 1998
Increased Turnover of T Lymphocytes in HIV-1 Infection and Its Reduction by Antiretroviral Therapy journal October 2001
Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection journal October 2005
Human naive T cells activated by cytokines differentiate into a split phenotype with functional features intermediate between naive and memory T cells journal January 1995
HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries? journal January 2002
Persistent immune activation in HIV-1 infection is associated with progression to AIDS journal January 2003
Enhanced Replication of R5 HIV-1 Over X4 HIV-1 in CD4+CCR5+CXCR4+ T Cells journal January 2005
Coreceptor Competition for Association with CD4 May Change the Susceptibility of Human Cells to Infection with T-Tropic and Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1 journal January 2000
Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population journal March 1995
R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L − CD4 + T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors journal January 2006
POPULATION BIOLOGY OF HIV-1 INFECTION: Viral and CD4 + T Cell Demographics and Dynamics in Lymphatic Tissues journal April 1999
T C ELL D YNAMICS IN HIV-1 I NFECTION journal April 2003
Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy journal February 2001
Generation of CD4 + CD45RA + Effector T Cells by Stimulation in the Presence of Cyclic Adenosine 5′-Monophosphate- Elevating Agents journal August 2002
Viral dynamics in human immunodeficiency virus type 1 infection journal January 1995
Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection journal January 1995
Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells journal March 2005
Maraviroc for Previously Treated Patients with R5 HIV-1 Infection journal October 2008
Natural Infection of a Homozygous Δ24 CCR5 Red-capped Mangabey with an R2b-Tropic Simian Immunodeficiency Virus journal December 1998
Link between the X4 Phenotype in Human Immunodeficiency Virus Type 1–Infected Mothers and Their Children, Despite the Early Presence of R5 in the Child
  • Casper, Charlotte H. E.; Clevestig, Peter; Carlenor, Elisabeth
  • The Journal of Infectious Diseases, Vol. 186, Issue 7 https://doi.org/10.1086/342948
journal October 2002
Genetic Deficiency of Chemokine Receptor CCR5 Is a Strong Risk Factor for Symptomatic West Nile Virus Infection: A Meta‐Analysis of 4 Cohorts in the US Epidemic journal January 2008
The CCR5 and CXCR4 Coreceptors—Central to Understanding the Transmission and Pathogenesis of Human Immunodeficiency Virus Type 1 Infection journal January 2004
Syncytium-inducing (SI) phenotype suppression at seroconversion after intramuscular inoculation of a non-syncytium-inducing/SI phenotypically mixed human immunodeficiency virus population journal March 1995
Coreceptor Competition for Association with CD4 May Change the Susceptibility of Human Cells to Infection with T-Tropic and Macrophagetropic Isolates of Human Immunodeficiency Virus Type 1 journal June 2000
Cooperation of Multiple CCR5 Coreceptors Is Required for Infections by Human Immunodeficiency Virus Type 1 journal August 2000
Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir journal May 2006
Naïve and Memory Cell Turnover as Drivers of CCR5-to-CXCR4 Tropism Switch in Human Immunodeficiency Virus Type 1: Implications for Therapy journal January 2006
R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L − CD4 + T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors journal January 2006
CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and Disease journal April 1999
Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy journal February 2001
T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART) journal January 2000
The Case for Selection at CCR5-Δ32 journal November 2005

Cited By (2)

Evolutionary dynamics of HIV at multiple spatial and temporal scales journal May 2012
A Quantitative Comparison of Anti-HIV Gene Therapy Delivered to Hematopoietic Stem Cells versus CD4+ T Cells journal June 2014

Similar Records

Selective elimination of HIV-1-infected cells by Env-directed, HIV-1-based virus-like particles
Journal Article · Sat Feb 04 23:00:00 EST 2006 · Virology · OSTI ID:20779455
Ezrin, Radixin, and Moesin (ERM) proteins function as pleiotropic regulators of human immunodeficiency virus type 1 infection
Journal Article · Sun May 25 00:00:00 EDT 2008 · Virology · OSTI ID:21140991
Enhanced CD4+ cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection
Journal Article · Tue Jan 19 23:00:00 EST 2010 · Virology · OSTI ID:21357585

Related Subjects

60 APPLIED LIFE SCIENCES
AIDS
CCR5 coreceptor
HIV
T cells
competitive inhibitors
highly-active antiretroviral therapy
immune deficiency
viral load