Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis
- Washington University School of Medicine, United States
- University of Colorado School of Medicine, United States
- Department of Cancer Immunology and Virology, United States
- Dana-Farber Cancer Institute, United States
Abstract
A number of human immunodeficiency virus 1 integrase (IN) alterations, referred to as class II substitutions, exhibit pleotropic effects during virus replication. However, the underlying mechanism for the class II phenotype is not known. Here we demonstrate that all tested class II IN substitutions compromised IN-RNA binding in virions by one of three distinct mechanisms: i) markedly reducing IN levels thus precluding formation of IN complexes with viral RNA; ii) adversely affecting functional IN multimerization and consequently impairing IN binding to viral RNA; iii) directly compromising IN-RNA interactions without substantially affecting IN levels or functional IN multimerization. Inhibition of IN-RNA interactions resulted in mislocalization of the viral ribonucleoprotein complexes outside the capsid lattice, which led to premature degradation of the viral genome and IN in target cells. Collectively, our studies uncover causal mechanisms for the class II phenotype and highlight an essential role of IN-RNA interactions for accurate virion maturation.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Mamuka Kvaratskhelia
Sebla Bulent Kutluay
Funding
National Institutes of Health (GM103297)
- Sebla Bulent Kutluay
National Institutes of Health (GM122458)
- Sebla Bulent Kutluay
National Institutes of Health (AI143389)
- Jennifer L Elliott
National Institutes of Health (AI062520)
- Mamuka Kvaratskhelia
- Sebla Bulent Kutluay
National Institutes of Health (AI150472)
- Mamuka Kvaratskhelia
National Institutes of Health (AI070042)
- Alan N Engelman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Viviana Simon, Icahn School of Medicine at Mount Sinai, United States
Version history
- Received: December 10, 2019
- Accepted: September 22, 2020
- Accepted Manuscript published: September 22, 2020 (version 1)
- Version of Record published: November 17, 2020 (version 2)
Copyright
© 2020, Elliott et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis
eLife 9:e54311.
https://doi.org/10.7554/eLife.54311
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