ABSTRACT
In this study, we examined the occurrence of acquired and transmitted drug resistance to integrase strand transfer inhibitor (INSTI) in HIV-1 strains in Chongqing (China) for guiding for the routine testing of INSTI-associated HIV-1 genotype resistance. Plasma samples were obtained from HIV-1 patients at Chongqing Public Health Medical Center from July 2019 to August 2022. Besides, amplification, sequence, and analysis of the portion of the HIV-1 pol gene that encodes the integrase protein were implemented to identify INSTI resistance. Integrase sequence data was harvested for a comprehensive cohort of 1032 patients infected with HIV-1. This cohort consisted of 564 ART-naive patients, 465 ART-treated patients, and 3 patients with an unknown treatment history. Within the study group, we identified INSTI resistance in 21 patients (2.03%, 21/1032), including 17 ART-treated patients (3.66%, 17/465). Among the ART-treated patients, 12 were INSTI-treated (11.76%, 12/102), 5 were INSTI-naive (1.38%, 5/363), and 4 were ART-ineffective patients (0.71%, 4/564). The prevalent major resistance mutation was Q148R (0.48%, 5/1032), while the most prevalent accessory resistance mutation was E157Q (1.65%, 17/1032). In light of the above, it is recommended that the incidence of accessory genotype analysis should be considered before starting any future INSTI-based therapy, especially in patients with drug resistance to NRTIs and NNRTIs and the reduction of INSTI sensitivity should be carefully monitored and investigated. Regular monitoring for resistance should be implemented after the use of INSTIs, and, importantly, ongoing monitoring of the decreasing susceptibility to INSTIs is crucial following the initiation of treatment with INSTIs.
Subject(s)
HIV Infections , HIV Integrase Inhibitors , HIV Integrase , HIV-1 , Humans , HIV-1/genetics , HIV Integrase Inhibitors/pharmacology , HIV Integrase Inhibitors/therapeutic use , HIV Infections/drug therapy , HIV Infections/epidemiology , Prevalence , HIV Integrase/genetics , HIV Integrase/pharmacology , Drug Resistance, Viral/genetics , Mutation , Genotype , China/epidemiologyABSTRACT
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of human immunodeficiency virus (HIV) infection. These regimens are extremely effective in suppressing virus replication. Recently, our research group identified some N1-aryl-2-arylthioacetamido-benzimidazoles as a novel class of NNRTIs. In this research work we report the design, the synthesis and the structure-activity relationship studies of new compounds (20-34) in which some structural modifications have been introduced in order to investigate their effects on reverse transcriptase (RT) inhibition and to better define the features needed to increase the antiviral activity. Most of the new compounds proved to be highly effective in inhibiting both RT enzyme at nanomolar concentrations and HIV-1 replication in MT4 cells with minimal cytotoxicity. Among them, the most promising N1-aryl-2-arylthioacetamido-benzimidazoles and N1-aryl-2-aryloxyacetamido-benzimidazoles were also tested toward a panel of single- and double-mutants strain responsible for resistance to NNRTIs, showing in vitro antiviral activity toward single mutants L100I, K103N, Y181C, Y188L and E138K. The best results were observed for derivatives 29 and 33 active also against the double mutants F227L and V106A. Computational approaches were applied in order to rationalize the potency of the new synthesized inhibitors.
Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , HIV-1/drug effects , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Virus Replication/drug effects , Benzimidazoles/toxicity , Binding Sites , Cell Line , Cell Survival/drug effects , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/genetics , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , HIV-1/genetics , Humans , Hydrogen Bonding , Molecular Docking Simulation , Mutagenesis, Site-Directed , Protein Structure, Tertiary , Reverse Transcriptase Inhibitors/toxicity , Structure-Activity RelationshipABSTRACT
Objective To analyze the subtypes and characteristics of HIV-1 among men who have sex with men (MSM) in Zhejiang province from the year 2004 to 2011.Methods Blood DNA/RNA was extracted from the MSM HIV -1 infected individuals and then HIV-1 gag and pol fragments were amplified by nested polymerase chain reaction (nested-PCR)or RT-PCR.The positive PCR products were sequenced and the obtained sequences were analyzed by phylogenetic inference.Results A total of 117 HIV-1 infected MSMindividuals were analyzed,covering 21 provinces according to their household registry.Totally,three major strains were identified including CRF01_AE (84.62%,n =99 ),B (5.98%,n=7)and CRF07_BC (5.13%,n=6). Moreover,3 novel 01B recombinant stains,1 CRF59_01B and 1 CRF08_BC were found.According to the neighbor-joining tree by pol fragments,there were more than 30 sub clusters with bootstrap value higher than 70% among the 84 CRF01_AE sequences.Conclusion CRF01_AE is the major HIV-1 infection strain among MSMin Zhejiang province.CRF59_01B and other novel 01B recombinant stains are first reported among MSM individuals in Zhejiang province.