Establishment of pharmacological evaluation system for non-nucleoside reverse-transcriptase inhibitors resistant HIV-1.
- Author:
Ying-li CAO
1
;
Shao-xiong LI
;
Hong CHEN
;
Ying GUO
Author Information
1. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
- Publication Type:Journal Article
- MeSH:
Anti-HIV Agents;
pharmacology;
Benzoxazines;
pharmacology;
Cell Line;
Delavirdine;
pharmacology;
Drug Evaluation, Preclinical;
methods;
Drug Resistance, Viral;
Genetic Vectors;
HIV Reverse Transcriptase;
antagonists & inhibitors;
genetics;
metabolism;
HIV-1;
drug effects;
genetics;
Humans;
Membrane Glycoproteins;
genetics;
Nevirapine;
pharmacology;
Plasmids;
genetics;
Point Mutation;
Reverse Transcriptase Inhibitors;
pharmacology;
Stavudine;
pharmacology;
Transfection;
Viral Envelope Proteins;
genetics;
Virion;
genetics;
metabolism;
Virus Replication;
Zidovudine;
pharmacology
- From:
Acta Pharmaceutica Sinica
2009;44(4):355-361
- CountryChina
- Language:Chinese
-
Abstract:
Consistent non-nucleoside reverse-transcriptase inhibitors (NNRTIs) resistant HIV-1 strains occurred due to the clinical use for more than ten years of efavirenz (EFV), nevirapine (NVP), and delavirdine (DLV). In this study, we established nine cell-based pharmacological models according to most NNRTIs-resistant clinical tested strains, Resistant mutations were introduced into vector, pNL4-3.Luc.R-E-, by overlapping PCR. Then, pseudovirions were produced by co-transfection of VSV-G plasmid and pNL4-3.Luc.R-E- -mut. All nine recombinant VSVG/HIV-mut pseudovirions (VSVG/HIV-wt, VSVG/HIV(-K103N), VSVG/HIV(-Y181C), VSVG/HIV(-L100I,K103N), VSVG/HIV(-Y188L), VSVG/HIV(-K103N,Y181C), VSVG/HIV(-K103N,P225H), VSVG/HIV(-K103N,Y188L), VSVG/HIV(-K103N,G109A) and VSVG/HIV(-K103N,V108I)) had high efficient infectivity. Furthermore, they all showed resistant characteristics to EFV and NVP with IC50 changes consisting with clinical reports, not to nucleoside reverse-transcriptase inhibitors (AZT and d4T). This series safe cell-based model, which could be carried out in BSL-2 laboratory, can be used for evaluating NNRTIs candidates.
