Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Rhee, Soo-Yon; Varghese, Vici; Holmes, Susan; Zyl, Gert van; Steegen, Kim; Boyd, Mark; Cooper, David A.; Nsanzimana, Sabin; Saravanan, S.; Charpentier, Charlotte; Oliveira, Túlio de; Etiebet, Mary-Ann; García, Féderico; Goedhals, Dominique; Gómes, Perpétua; Günthard, Huldrych F.; Hamers, Raph L; Hoffmann, Christopher J.; Hunt, Gillian; Jiamsakul, Awachana; Kaleebu, Pontiano; Kanki, Phyllis J.; Kantor, Rami; Kerschberger, Bernhard; Marconi, Vincent C.; Ndahimana, Jean d’Amour; Ndembi, Nicaise; Ngo‐Giang‐Huong, Nicole; Rokx, Casper; Santoro, Maria Mercedes; Schapiro, Jonathan; Schmidt, Daniel; Seu, Lillian; Sigaloff, Kim C.E.; Sirivichayakul, Sunee; Skhosana, Lindiwe; Sunpath, Henry; Tang, Michele W.; Yang, Chunfu; Carmona, Sergio; Rk, Gupta; Shafer, Robert W.

doi:10.1016/j.ebiom.2017.03.024

“…We found that the mutation rate of S68G increased in almost all HIV-1 subtypes in drug-experienced populations, with the greatest increase noted among CRF01_AE strains. This finding is supported by several studies on non-subtype B HIV-1 [17,18]. Based on the available evidence, it is suggested that S68G may be new mutation associated with the development of drug resistance.…”

Section: Discussionmentioning

confidence: 62%

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

Li¹,

Ouyang²,

Zhao³

et al. 2019

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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.

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“…Moreover, previous studies showed that patients infected with subtype B and non-B subtype HIV-1, who failed ART and developed the K65R mutation, also acquired the S68G mutation [18][19][20][21][22].…”

Section: Discussionmentioning

confidence: 99%

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

Li¹,

Ouyang²,

Zhao³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

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.

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“…The viral pol gene was amplified and sequenced. The ChromatQuan Internet tool was used to calculate the viral ratio at each time point [16].…”

Section: Growth Competition Assaymentioning

confidence: 99%

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

Li¹,

Ouyang²,

Zhao³

et al. 2019

Preprint

0

View full text Add to dashboard Cite

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.

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Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

Cited by 39 publications

References 28 publications

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

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

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

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

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