Publication

Structural Implications of Genotypic Variations in HIV-1 Integrase From Diverse Subtypes

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Last modified
  • 05/23/2025
Type of Material
Authors
    Leonard Rogers, University of MissouriAdetayo E. Obasa, Stellenbosch UniversityGraeme B. Jacobs, Stellenbosch UniversityStefan Sarafianos, Emory UniversityAnders Sonnerborg, Karolinska InstituteUjjwal Neogi, Karolinska InstituteKamalendra Singh, University of Missouri
Language
  • English
Date
  • 2018-08-02
Publisher
  • Frontiers Media
Publication Version
Copyright Statement
  • © 2018 Rogers, Obasa, Jacobs, Sarafianos, Sönnerborg, Neogi and Singh.
License
Final Published Version (URL)
Title of Journal or Parent Work
ISSN
  • 1664-302X
Volume
  • 9
Issue
  • AUG
Start Page
  • 1754
End Page
  • 1754
Grant/Funding Information
  • KS acknowledges support from NIH CTSA grant UL1 TR002345.
  • Part of this research was supported by National Institute of Health grant GM118012 (SS).
  • The study is partially funded by the Swedish Research Council Establishment grant (2017-01330) and Jeanssons Stiftelser (JS2016–0185) to UN, the Swedish Research Council grant 2016- 01675 to AS and ALF-grant from Stockholm County Council (ALF 20160074) to UN and AS.
Abstract
  • Human immunodeficiency virus type 1 (HIV-1) integrase (IN) integrates viral DNA into the host genome using its 3'-end processing and strand-transfer activities. Due to the importance of HIV-1 IN, it is targeted by the newest class of approved drugs known as integrase strand transfer inhibitors (INSTIs). INSTIs are efficient in maintaining low viral load; however, as with other approved antivirals, resistance mutations emerge in patients receiving INSTI-containing therapy. As INSTIs are becoming increasingly accessible worldwide, it is important to understand the mechanism(s) of INSTI susceptibility. There is strong evidence suggesting differences in the patterns and mechanisms of drug resistance between HIV-1 subtype B, which dominates in United States, Western Europe and Australia, and non-B infections that are most prevalent in countries of Africa and Asia. IN polymorphisms and other genetic differences among diverse subtypes are likely responsible for these different patterns, but lack of a full-length high-resolution structure of HIV-1 IN has been a roadblock in understanding the molecular mechanisms of INSTI resistance and the impact of polymorphisms on therapy outcome. A recently reported full-length medium-resolution cryoEM structure of HIV-1 IN provides insights into understanding the mechanism of integrase function and the impact of genetic variation on the effectiveness of INSTIs. Here we use molecular modeling to explore the structural impact of IN polymorphisms on the IN reaction mechanism and INSTI susceptibility.
Author Notes
Keywords
Research Categories
  • Health Sciences, Immunology
  • Biology, Microbiology

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