Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia

Dawit Assefa Arimide; Zsófia Ilona Szojka; Kidist Zealiyas; Atsbeha Gebreegziabxier; Fekadu Adugna; Sviataslau Sasinovich; Per Björkman; Patrik Medstrand

doi:10.3390/v14040729

Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia

Dawit Assefa Arimide, Zsófia Ilona Szojka, Kidist Zealiyas, Atsbeha Gebreegziabxier, Fekadu Adugna, Sviataslau Sasinovich, Per Björkman, Patrik Medstrand

Research output: Contribution to journal › Article › peer-review

Abstract

Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-naïve (n = 373 ART-naïve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-naïve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease-and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.

Original language	English
Article number	729
Journal	Viruses
Volume	14
Issue number	4
DOIs	https://doi.org/10.3390/v14040729
Publication status	Published - 2022 Apr

Bibliographical note

Funding Information:
Author Contributions: Conceptualization, D.A.A., P.B., and P.M.; Data curation, D.A.A.; Formal analysis, D.A.A., S.S., and P.M.; Funding acquisition, F.A, P.B. and P.M.; Investigation, D.A.A., Z.I.S.,K.Z., A.G.,F.A., S.S., and P.M.; Project administration, D.A.A.; and P.M. Supervision, D.A.A. and P.M.; Visualization, Z.I.S.; Writing—original draft, D.A.A..; Writing—review and editing, D.A.A.,S.S, P.B., and P.M. All authors revised the manuscript, provided important intellectual content, and approved the manuscript Funding: This research was supported by the WHO Ethiopia Country Office. The Swedish Research Council (grant numbers 2019-05235 and 2020-02344), the Österlund Foundation, and a donation to P.M. and P.B. through the Medical Faculty, Lund University, also supported the research. The computations were enabled by resources from project SNIC 2021-5-69 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973.

Funding Information:
Acknowledgments: We express our deep appreciation to the study participants and all staff involved in the survey. We acknowledge the support given by the WHO and the National Institute of Respiratory Diseases-Mexico (INER) laboratory for HIVDR genotyping. We also acknowledge Mauno Vihinen (Protein Bioinformatics. Lund University) for his assistance with the Chimera software.

Publisher Copyright:
© 2022 by the author. Licensee MDPI, Basel, Switzerland.

Subject classification (UKÄ)

Infectious Medicine

Free keywords

docking
dolutegravir
Ethiopia
genetic barrier
HIV drug resistance (HIVDR)
integrase strand transfer inhibitor (INSTI)
naturally occurring polymorphisms (NOPs)
pretreatment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/v14040729Licence: CC BY

1 Doctoral Thesis (compilation)

The HIV-1 epidemic in Ethiopia – transmission patterns, antiretroviral drug resistance and treatment outcomes
Assefa, D., 2022, Lund: Lund University, Faculty of Medicine. 130 p.
Research output: Thesis › Doctoral Thesis (compilation)

Open Access
File

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1 Active

The HIV-1 epidemic in Ethiopia – transmission patterns, antiretroviral drug resistance and treatment outcomes
Assefa, D., Medstrand, P., Björkman, P. & Esbjörnsson, J.
2014/01/03 → …
Project: Dissertation
The HIV epidemic in Ethiopia – dynamics of viral transmissions and prevalence of transmitted drug resistance
Assefa, D., Medstrand, P., Björkman, P. & Esbjörnsson, J.
2014/01/03 → 2022/09/15
Project: Dissertation

Cite this

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title = "Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia",

abstract = "Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-na{\"i}ve (n = 373 ART-na{\"i}ve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-na{\"i}ve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease-and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.",

keywords = "docking, dolutegravir, Ethiopia, genetic barrier, HIV drug resistance (HIVDR), integrase strand transfer inhibitor (INSTI), naturally occurring polymorphisms (NOPs), pretreatment",

author = "Arimide, {Dawit Assefa} and Szojka, {Zs{\'o}fia Ilona} and Kidist Zealiyas and Atsbeha Gebreegziabxier and Fekadu Adugna and Sviataslau Sasinovich and Per Bj{\"o}rkman and Patrik Medstrand",

note = "Funding Information: Author Contributions: Conceptualization, D.A.A., P.B., and P.M.; Data curation, D.A.A.; Formal analysis, D.A.A., S.S., and P.M.; Funding acquisition, F.A, P.B. and P.M.; Investigation, D.A.A., Z.I.S.,K.Z., A.G.,F.A., S.S., and P.M.; Project administration, D.A.A.; and P.M. Supervision, D.A.A. and P.M.; Visualization, Z.I.S.; Writing—original draft, D.A.A..; Writing—review and editing, D.A.A.,S.S, P.B., and P.M. All authors revised the manuscript, provided important intellectual content, and approved the manuscript Funding: This research was supported by the WHO Ethiopia Country Office. The Swedish Research Council (grant numbers 2019-05235 and 2020-02344), the {\"O}sterlund Foundation, and a donation to P.M. and P.B. through the Medical Faculty, Lund University, also supported the research. The computations were enabled by resources from project SNIC 2021-5-69 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Funding Information: Acknowledgments: We express our deep appreciation to the study participants and all staff involved in the survey. We acknowledge the support given by the WHO and the National Institute of Respiratory Diseases-Mexico (INER) laboratory for HIVDR genotyping. We also acknowledge Mauno Vihinen (Protein Bioinformatics. Lund University) for his assistance with the Chimera software. Publisher Copyright: {\textcopyright} 2022 by the author. Licensee MDPI, Basel, Switzerland.",

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AU - Arimide, Dawit Assefa

AU - Szojka, Zsófia Ilona

AU - Zealiyas, Kidist

AU - Gebreegziabxier, Atsbeha

AU - Adugna, Fekadu

AU - Sasinovich, Sviataslau

AU - Björkman, Per

AU - Medstrand, Patrik

N1 - Funding Information: Author Contributions: Conceptualization, D.A.A., P.B., and P.M.; Data curation, D.A.A.; Formal analysis, D.A.A., S.S., and P.M.; Funding acquisition, F.A, P.B. and P.M.; Investigation, D.A.A., Z.I.S.,K.Z., A.G.,F.A., S.S., and P.M.; Project administration, D.A.A.; and P.M. Supervision, D.A.A. and P.M.; Visualization, Z.I.S.; Writing—original draft, D.A.A..; Writing—review and editing, D.A.A.,S.S, P.B., and P.M. All authors revised the manuscript, provided important intellectual content, and approved the manuscript Funding: This research was supported by the WHO Ethiopia Country Office. The Swedish Research Council (grant numbers 2019-05235 and 2020-02344), the Österlund Foundation, and a donation to P.M. and P.B. through the Medical Faculty, Lund University, also supported the research. The computations were enabled by resources from project SNIC 2021-5-69 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. Funding Information: Acknowledgments: We express our deep appreciation to the study participants and all staff involved in the survey. We acknowledge the support given by the WHO and the National Institute of Respiratory Diseases-Mexico (INER) laboratory for HIVDR genotyping. We also acknowledge Mauno Vihinen (Protein Bioinformatics. Lund University) for his assistance with the Chimera software. Publisher Copyright: © 2022 by the author. Licensee MDPI, Basel, Switzerland.

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N2 - Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-naïve (n = 373 ART-naïve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-naïve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease-and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.

AB - Dolutegravir-based antiretroviral therapy (ART) has been scaled up in many developing countries, including Ethiopia. However, subtype-dependent polymorphic differences might influence the occurrence of HIV-drug-resistance mutations (HIVDRMs). We analyzed the prevalence of pre-treatment integrase strand transfer inhibitor (INSTI) HIVDRMs and naturally occurring polymorphisms (NOPs) of the integrase gene, using plasma samples collected as part of the national HIVDR survey in Ethiopia in 2017. We included a total of 460 HIV-1 integrase gene sequences from INSTI-naïve (n = 373 ART-naïve and n = 87 ART-experienced) patients. No dolutegravir-associated HIVDRMs were detected, regardless of previous exposure to ART. However, we found E92G in one ART-naïve patient specimen and accessory mutations in 20/460 (4.3%) of the specimens. Moreover, among the 288 integrase amino acid positions of the subtype C, 187/288 (64.9%) were conserved (<1.0% variability). Analysis of the genetic barrier showed that the Q148H/K/R dolutegravir resistance pathway was less selected in subtype C. Docking analysis of the dolutegravir showed that protease-and reverse-transcriptase-associated HIVDRMs did not affect the native structure of the HIV-1 integrase. Our results support the implementation of a wide scale-up of dolutegravir-based regimes. However, the detection of polymorphisms contributing to INSTI warrants the continuous surveillance of INSTI resistance.

KW - docking

KW - dolutegravir

KW - Ethiopia

KW - genetic barrier

KW - HIV drug resistance (HIVDR)

KW - integrase strand transfer inhibitor (INSTI)

KW - naturally occurring polymorphisms (NOPs)

KW - pretreatment

U2 - 10.3390/v14040729

DO - 10.3390/v14040729

M3 - Article

C2 - 35458459

AN - SCOPUS:85128401756

SN - 1999-4915

VL - 14

JO - Viruses

JF - Viruses

IS - 4

M1 - 729

ER -

Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Research output

The HIV-1 epidemic in Ethiopia – transmission patterns, antiretroviral drug resistance and treatment outcomes

Projects

The HIV-1 epidemic in Ethiopia – transmission patterns, antiretroviral drug resistance and treatment outcomes

The HIV epidemic in Ethiopia – dynamics of viral transmissions and prevalence of transmitted drug resistance

Cite this