The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains
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...
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| Format: | Article |
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BMC
2020-02-01
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| Series: | BMC Infectious Diseases |
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| Online Access: | https://doi.org/10.1186/s12879-020-4836-z |
| _version_ | 1818615574467444736 |
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| author | Shengjia Li Jinming Ouyang Bin Zhao Minghui An Lin Wang Haibo Ding Min Zhang Xiaoxu Han |
| author_facet | Shengjia Li Jinming Ouyang Bin Zhao Minghui An Lin Wang Haibo Ding Min Zhang Xiaoxu Han |
| author_sort | Shengjia Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T16:36:04Z |
| format | Article |
| id | doaj.art-d4a7b710c9534b38bcf479b2c25f0eb6 |
| institution | Directory Open Access Journal |
| issn | 1471-2334 |
| language | English |
| last_indexed | 2024-12-16T16:36:04Z |
| publishDate | 2020-02-01 |
| publisher | BMC |
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| series | BMC Infectious Diseases |
| spelling | doaj.art-d4a7b710c9534b38bcf479b2c25f0eb62022-12-21T22:24:28ZengBMCBMC Infectious Diseases1471-23342020-02-012011810.1186/s12879-020-4836-zThe S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strainsShengjia Li0Jinming Ouyang1Bin Zhao2Minghui An3Lin Wang4Haibo Ding5Min Zhang6Xiaoxu Han7NHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityDepartment of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityNHC Key Laboratory of AIDS Immunology (China Medical University), Department of Laboratory Medicine, The First Affiliated Hospital of China Medical UniversityAbstract 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.https://doi.org/10.1186/s12879-020-4836-zCRF01_AEPolymorphismDrug resistanceReplication fitness |
| spellingShingle | Shengjia Li Jinming Ouyang Bin Zhao Minghui An Lin Wang Haibo Ding Min Zhang Xiaoxu Han The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains BMC Infectious Diseases CRF01_AE Polymorphism Drug resistance Replication fitness |
| title | The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains |
| title_full | The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains |
| title_fullStr | The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains |
| title_full_unstemmed | The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains |
| title_short | The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains |
| title_sort | s68g polymorphism is a compensatory mutation associated with the drug resistance mutation k65r in crf01 ae strains |
| topic | CRF01_AE Polymorphism Drug resistance Replication fitness |
| url | https://doi.org/10.1186/s12879-020-4836-z |
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