scholarly journals The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains

2019 ◽  
Author(s):  
Shengjia Li ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Temporal Association ◽  
Compensatory Mutation ◽  
Phenotypic Resistance ◽  
K65r Mutation ◽  
Replication Fitness ◽  
Generation Sequencing ◽  
Hiv 1

Abstract Background The rate of S68G mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has increased and is closely related to the K65R mutation among CRF01_AE-infected patients who failed treatment. We aimed to explore the temporal association of S68G and K65R mutations and disclose the role of the former on susceptibility to nucleotide/nucleoside reverse transcriptase inhibitor (NRTI) and viral replication with the K65R double mutations among CRF01_AE-infected patients who failed treatment. Methods The occurrence of S68G and K65R mutations was evaluated among HIV-1 of various subtypes in the global HIV Drug Resistance Database. The temporal association of S68G and K65R mutations was analyzed through next-generation sequencing in four CRF01_AE-infected patients who failed treatment with tenofovir/lamivudine/efavirenz. The impact of the S68G mutation on susceptibility to NRTI and replication fitness was analyzed using pseudovirus phenotypic resistance assays and growth competition assays, respectively. Results The frequency of the S68G mutation increased by 1.4–9.7% in almost all HIV subtypes and circulating recombinant forms in treatment-experienced patients, except subtype F. The S68G mutation often occurred in conjunction with the K65R mutation among RTI-treated patients, with frequencies ranging 21.1%–61.7% in various subtypes. Next-generation sequencing revealed that the S68G mutation occurred following the K65R mutation in three of the four CRF01_AE-infected patients. In these three patients, there was no significant change detected in the half maximal inhibitory concentration for zidovudine, tenofovir, or lamivudine between the K65R and K65R/S68G mutations, as demonstrated by the phenotypic resistance assays. Virus stocks of the K65R and K65R/S68G mutations were mixed with 4:6, 1:1, and 9:1 and cultured for 13 days, the K65R/S68G mutants outgrew those of the K65R mutants irrespective of the input ratio. Conclusions S68G may be a natural polymorphism and compensatory mutation of K65R selected by NRTIs in the CRF01_AE strain of HIV-1. This mutation does not affect susceptibility to NRTI; however, it improves the replication fitness of K65R mutants. This study deciphers the role of the S68G mutation in the HIV reverse transcriptase of the CRF01_AE strain and provides new evidence for the interpretation of drug-resistant mutations in non-B subtypes of HIV-1.

scholarly journals The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains

2020 ◽  
Author(s):  
Shengjia Li ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Temporal Association ◽  
Compensatory Mutation ◽  
Phenotypic Resistance ◽  
K65r Mutation ◽  
Replication Fitness ◽  
Generation Sequencing ◽  
Hiv 1

Abstract Background The rate of S68G mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has increased and is closely related to the K65R mutation among CRF01_AE-infected patients who failed treatment. We aimed to explore the temporal association of S68G and K65R mutations and disclose the role of the former on susceptibility to nucleotide/nucleoside reverse transcriptase inhibitor (NRTI) and viral replication with the K65R double mutations among CRF01_AE-infected patients who failed treatment. Methods The occurrence of S68G and K65R mutations was evaluated among HIV-1 of various subtypes in the global HIV Drug Resistance Database. The temporal association of S68G and K65R mutations was analyzed through next-generation sequencing in four CRF01_AE-infected patients who failed treatment with tenofovir/lamivudine/efavirenz. The impact of the S68G mutation on susceptibility to NRTI and replication fitness was analyzed using pseudovirus phenotypic resistance assays and growth competition assays, respectively. Results The frequency of the S68G mutation increased by 1.4–9.7% in almost all HIV subtypes and circulating recombinant forms in treatment-experienced patients, except subtype F. The S68G mutation often occurred in conjunction with the K65R mutation among RTI-treated patients, with frequencies ranging 21.1%–61.7% in various subtypes. Next-generation sequencing revealed that the S68G mutation occurred following the K65R mutation in three of the four CRF01_AE-infected patients. In these three patients, there was no significant change detected in the half maximal inhibitory concentration for zidovudine, tenofovir, or lamivudine between the K65R and K65R/S68G mutations, as demonstrated by the phenotypic resistance assays. Virus stocks of the K65R and K65R/S68G mutations were mixed with 4:6, 1:1, and 9:1 and cultured for 13 days, the K65R/S68G mutants outgrew those of the K65R mutants irrespective of the input ratio. Conclusions S68G may be a natural polymorphism and compensatory mutation of K65R selected by NRTIs in the CRF01_AE strain of HIV-1. This mutation does not affect susceptibility to NRTI; however, it improves the replication fitness of K65R mutants. This study deciphers the role of the S68G mutation in the HIV reverse transcriptase of the CRF01_AE strain and provides new evidence for the interpretation of drug-resistant mutations in non-B subtypes of HIV-1.

scholarly journals The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains

2020 ◽  
Author(s):  
Shengjia Li ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Temporal Association ◽  
Compensatory Mutation ◽  
Phenotypic Resistance ◽  
K65r Mutation ◽  
Replication Fitness ◽  
Generation Sequencing ◽  
Hiv 1

Abstract Background The rate of S68G mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has increased and is closely related to the K65R mutation among CRF01_AE-infected patients who failed treatment. We aimed to explore the temporal association of S68G and K65R mutations and disclose the role of the former on susceptibility to nucleotide/nucleoside reverse transcriptase inhibitor (NRTI) and viral replication with the K65R double mutations among CRF01_AE-infected patients who failed treatment. Methods The occurrence of S68G and K65R mutations was evaluated among HIV-1 of various subtypes in the global HIV Drug Resistance Database. The temporal association of S68G and K65R mutations was analyzed through next-generation sequencing in four CRF01_AE-infected patients who failed treatment with tenofovir/lamivudine/efavirenz. The impact of the S68G mutation on susceptibility to NRTI and replication fitness was analyzed using pseudovirus phenotypic resistance assays and growth competition assays, respectively. Results The frequency of the S68G mutation increased by 1.4–9.7% in almost all HIV subtypes and circulating recombinant forms in treatment-experienced patients, except subtype F. The S68G mutation often occurred in conjunction with the K65R mutation among RTI-treated patients, with frequencies ranging 21.1%–61.7% in various subtypes. Next-generation sequencing revealed that the S68G mutation occurred following the K65R mutation in three of the four CRF01_AE-infected patients. In these three patients, there was no significant change detected in the half maximal inhibitory concentration for zidovudine, tenofovir, or lamivudine between the K65R and K65R/S68G mutations, as demonstrated by the phenotypic resistance assays. Virus stocks of the K65R and K65R/S68G mutations were mixed with 4:6, 1:1, and 9:1 and cultured for 13 days, the K65R/S68G mutants outgrew those of the K65R mutants irrespective of the input ratio. Conclusions S68G may be a natural polymorphism and compensatory mutation of K65R selected by NRTIs in the CRF01_AE strain of HIV-1. This mutation does not affect susceptibility to NRTI; however, it improves the replication fitness of K65R mutants. This study deciphers the role of the S68G mutation in the HIV reverse transcriptase of the CRF01_AE strain and provides new evidence for the interpretation of drug-resistant mutations in non-B subtypes of HIV-1.

scholarly journals The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains

2019 ◽  
Author(s):  
Shengjia Li ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Reverse Transcriptase ◽  
Temporal Association ◽  
Compensatory Mutation ◽  
Double Mutation ◽  
Phenotypic Resistance ◽  
K65r Mutation ◽  
The Impact ◽  
Hiv 1

Abstract Background: The rate of S68G mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase has increased and is closely related to the K65R mutation among treatment-failure CRF01_AE-infected patients. We aim to explore the temporal association of S68G and K65R mutations among treatment-failure CRF01_AE-infected patients and disclose the role of the S68G mutation on nucleotide/nucleoside reverse transcriptase inhibitor (NRTI) susceptibility and viral replication with the K65R double mutation. Methods: Occurrence of S68G and K65R mutations was evaluated among HIV-1 of various subtypes in the global HIV Drug Resistance Database. The temporal association of S68G and K65R mutations was analyzed by next-generation sequencing (NGS). The impact of the S68G mutation on NRTI susceptibility and replication adaptability was analyzed with pseudovirus phenotypic resistance assays and growth competition assays, respectively. Results: The frequency of the S68G mutation increased significantly in all HIV subtypes and circulating recombinant forms in treatment-experienced patients (except for subtype F), as did the frequency of the K65R/S68G double mutation. NGS revealed that the S68G mutation occurred following K65R mutation among three out of four patients. No significant difference in fold-change for tenofovir, lamivudine or efavirenz was detected between K65R and K65R/S68G mutations in phenotypic resistance assays. The K65R/S68G double mutant outgrew the K65R mutant within 13 days of co-culture for any input ratio among all patients. Conclusions: S68G might be a natural polymorphism and compensatory mutation of K65R selected by NRTIs among the CRF01_AE strain of HIV-1, which does not affect NRTI susceptibility, but improves the replication adaptability on K65R mutants.

The algorithm used for the interpretation of doravirine transmitted drug resistance strongly influences clinical practice and guideline recommendations

2020 ◽  
Vol 75 (5) ◽  
pp. 1294-1300 ◽  
Author(s):  
Carlos Guerrero-Beltrán ◽  
Javier Martínez-Sanz ◽  
Marta Álvarez ◽  
Julián Olalla ◽  
Mónica García-Álvarez ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Practice ◽  
Reverse Transcriptase ◽  
Prevalence Study ◽  
Transmitted Drug Resistance ◽  
National Agency ◽  
Treatment Naïve ◽  
Aids Research ◽  
Hiv 1

Abstract Objectives We report the results of the reverse transcriptase (RT)/protease (PR) transmitted drug resistance (TDR) prevalence study in 2018, focusing on doravirine resistance-associated mutations and the differences observed when Stanford or French National Agency for AIDS Research (ANRS)/Spanish Network of AIDS Research (RIS)/IAS-USA resistance interpretation algorithms are used to describe clinically relevant resistance. Methods We used the WHO 2009 list to investigate the prevalence of NNRTI, NRTI and PI TDR, in treatment-naive HIV-1-infected patients, adding mutations E138A/G/K/Q/R, V106I, V108I, V179L, G190Q, H221Y, F227C/L/V, M230IDR, L234I, P236L and Y318F in RT. The prevalence of doravirine resistance-associated mutations, as described by Soulie et al. in 2019, was evaluated. Clinically relevant TDR was investigated using the latest versions of ANRS, RIS, IAS-USA and Stanford algorithms. Results NNRTI mutations were detected in 82 of 606 (13.5%) patients. We found 18 patients (3.0%) with NRTI mutations and 5 patients (0.8%) with PI mutations. We detected 11 patients harbouring doravirine resistance-associated mutations (prevalence of 1.8%). Furthermore, we observed important differences in clinically relevant resistance to doravirine when ANRS/RIS (0.7%), IAS-USA (0.5%) or Stanford algorithms (5.0%) were used. V106I, which was detected in 3.8% of the patients, was the main mutation driving these differences. V106I detection was not associated with any of the clinical, demographic or virological characteristics of the patients. Conclusions The prevalence of NRTI and PI TDR remains constant in Spain. Doravirine TDR is very infrequent by RIS/ANRS/IAS-USA algorithms, in contrast with results using the Stanford algorithm. Further genotype–phenotype studies are necessary to elucidate the role of V106I in doravirine resistance.

scholarly journals Structural Basis for the Role of the K65R Mutation in HIV-1 Reverse Transcriptase Polymerization, Excision Antagonism, and Tenofovir Resistance

2009 ◽  
Vol 284 (50) ◽  
pp. 35092-35100 ◽  
Author(s):  
Kalyan Das ◽  
Rajiv P. Bandwar ◽  
Kirsten L. White ◽  
Joy Y. Feng ◽  
Stefan G. Sarafianos ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Structural Basis ◽  
K65r Mutation ◽  
Hiv 1

The role of HIV-1 on genetic diversity, drug resistance, response to anti-retroviral, disease progression, and on In vivo HIV control as potential target for therapeutic vaccines Development (Part Seventeen)

2021 ◽  
Vol 12 (11) ◽  
pp. 1094-1110
Author(s):  
Dr. Zelalem Kiros Bitsue
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Viral Proteins ◽  
Current Treatment ◽  
Therapeutic Vaccines ◽  
Resistance Response ◽  
Hiv 1

Current treatment of HIV/AIDS consists of a combination of three to five agents targeting different viral proteins, i.e. the reverse transcriptase, protease, integrase and envelope, and aims to suppress viral replication below detectable levels.

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