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

Arimide, Dawit Assefa LU orcid ; Szojka, Zsófia Ilona LU ; Zealiyas, Kidist ; Gebreegziabxier, Atsbeha ; Adugna, Fekadu ; Sasinovich, Sviataslau LU ; Björkman, Per LU orcid and Medstrand, Patrik LU orcid (2022) In Viruses 14(4).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
docking, dolutegravir, Ethiopia, genetic barrier, HIV drug resistance (HIVDR), integrase strand transfer inhibitor (INSTI), naturally occurring polymorphisms (NOPs), pretreatment
in
Viruses
volume
14
issue
4
article number
729
publisher
MDPI AG
external identifiers
  • scopus:85128401756
  • pmid:35458459
ISSN
1999-4915
DOI
10.3390/v14040729
project
The HIV epidemic in Ethiopia – dynamics of viral transmissions and prevalence of transmitted drug resistance
The HIV-1 epidemic in Ethiopia – transmission patterns, antiretroviral drug resistance and treatment outcomes
language
English
LU publication?
yes
additional info
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.
id
cbbec6f9-782e-4e9a-bc46-1a8a2ddf18f4
date added to LUP
2022-06-09 22:26:40
date last changed
2024-04-18 12:07:26
@article{cbbec6f9-782e-4e9a-bc46-1a8a2ddf18f4,
  abstract     = {{<p>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 (&lt;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.</p>}},
  author       = {{Arimide, Dawit Assefa and Szojka, Zsófia Ilona and Zealiyas, Kidist and Gebreegziabxier, Atsbeha and Adugna, Fekadu and Sasinovich, Sviataslau and Björkman, Per and Medstrand, Patrik}},
  issn         = {{1999-4915}},
  keywords     = {{docking; dolutegravir; Ethiopia; genetic barrier; HIV drug resistance (HIVDR); integrase strand transfer inhibitor (INSTI); naturally occurring polymorphisms (NOPs); pretreatment}},
  language     = {{eng}},
  number       = {{4}},
  publisher    = {{MDPI AG}},
  series       = {{Viruses}},
  title        = {{Pre-Treatment Integrase Inhibitor Resistance and Natural Polymorphisms among HIV-1 Subtype C Infected Patients in Ethiopia}},
  url          = {{http://dx.doi.org/10.3390/v14040729}},
  doi          = {{10.3390/v14040729}},
  volume       = {{14}},
  year         = {{2022}},
}