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
Open Access
- 15 May 2006
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 80 (10), 4909-4920
- https://doi.org/10.1128/jvi.80.10.4909-4920.2006
Abstract
Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log 10 copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope ( Env ) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.Keywords
This publication has 37 references indexed in Scilit:
- Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 ActivityAntimicrobial Agents and Chemotherapy, 2005
- Molecular and Clinical Epidemiology of CXCR4‐Using HIV‐1 in a Large Population of Antiretroviral‐Naive IndividualsThe Journal of Infectious Diseases, 2005
- Epidemiology and Predictive Factors for Chemokine Receptor Use in HIV‐1 InfectionThe Journal of Infectious Diseases, 2005
- Improved Coreceptor Usage Prediction and GenotypicMonitoring of R5-to-X4 Transition by Motif Analysis of HumanImmunodeficiency Virus Type 1 env V3 LoopSequencesJournal of Virology, 2003
- T Cell Dynamics in HIV-1 InfectionAnnual Review of Immunology, 2003
- Impact of antiretroviral treatment on the tropism of HIV-1 plasma virus populationsAIDS, 2003
- Variability in the Human Immunodeficiency Virus Type 1 gp120 Env Protein Linked to Phenotype-Associated Changes in the V3 LoopJournal of Virology, 2002
- Conversion Rate towards a Syncytium‐Inducing (SI) Phenotype during Different Stages of Human Immunodeficiency Virus Type 1 Infection and Prognostic Value of SI Phenotype for Survival after AIDS DiagnosisThe Journal of Infectious Diseases, 1999
- Genetic Restriction of HIV-1 Infection and Progression to AIDS by a Deletion Allele of the CKR5 Structural GeneScience, 1996
- CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choiceNucleic Acids Research, 1994