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Cited by 59HIV Research and TreatmentHIV/AIDS drug development and treatmentVirus-based gene therapy research

Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis

Open access
Elliott, Jennifer L, Eschbach, Jenna E, Koneru, Pratibha C, Li, Wen, Puray-Chavez, Maritza, Townsend, Dana, Lawson, Dana Q, Engelman, Alan N +2 more·2020·eLife
DOI 10.7554/elife.54311PMC PMC7671690

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Abstract

A large number of human immunodeficiency virus 1 (HIV-1) integrase (IN) alterations, referred to as class II substitutions, exhibit pleiotropic 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 the three distinct mechanisms: (i) markedly reducing IN levels thus precluding the formation of IN complexes with viral RNA; (ii) adversely affecting functional IN multimerization and consequently impairing IN binding to viral RNA; and (iii) directly compromising IN-RNA interactions without substantially affecting IN levels or functional IN multimerization. Inhibition of IN-RNA interactions resulted in the mislocalization of 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.

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Crossref · 10.7554/elife.54311

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  • Examined class II HIV-1 integrase mutant proteins fail to engage genomic RNA due to defects in virion incorporation, tetramerization, and/or RNA binding.

    “Examined class II HIV-1 IN mutant proteins failed to engage genomic RNA, though for varying reasons including defects in virion incorporation, tetramerization, and/or RNA binding132.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [132]

    The Introduction attributes loss of IN–viral RNA interaction to reduced or absent IN in virions, impaired tetramerization, or likely direct interference with RNA binding. However, the Results section “Class II IN mutants abolish IN binding to RNA” says nearly all tested mutants failed to bind viral RNA: E96A reduced binding but did not abolish it. The claim overstates the finding by saying the examined mutants all failed to engage RNA. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Many HIV-1 integrase point mutants retain enzymatic activity yet fail to support viral replication.

    “The literature is replete with examples of HIV-1 IN point mutants that retain enzymatic activity yet fail to support viral replication (REF.132 and references therein).”

    From Structure and function of retroviral integrase (2022) · cites this paper as [132]

  • Mislocalisation of viral genomic material may explain why class II mutants fail to synthesize normal vDNA levels.

    “The mislocalisation of the viral genomic material provides an attractive explanation as to why class II mutants fail to synthetize normal levels of vDNA upon infection132.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [132]

  • HIV-1 integrase directly interacts with viral genomic RNA.

    “Strikingly, recent cross-linking immunoprecipitation experiments demonstrated that HIV-1 IN directly interacts with viral genomic RNA132,141.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [132]

  • Class II integrase mutations alter viral particle morphology, with ribonucleoprotein material outside the capsid shell, often associated with the viral membrane.

    “Class II IN mutations additionally affected viral particle morphology, with the ribonucleoprotein material found outside of the capsid shell, oftentimes in association with the viral membrane131,132,139–142.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [132]

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Authors
Elliott, J. L., Eschbach, J. E., Koneru, P. C., Li, W., Puray-Chavez, M., Townsend, D., Lawson, D. Q., Engelman, A. N., Kvaratskhelia, M., & Kutluay, S. B.
Affiliations
  • Washington University in St. Louis (US)
  • University of Colorado Anschutz (US)
  • Harvard University (US)
  • Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, United States
Corresponding author
Kutluay, Sebla B
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-09-22
Volume
9
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.54311
PMC
PMC7671690
OpenAlex
W3087190549
Cited by
59
References
111
Citations by year
2026: 11 · 2025: 6 · 2024: 8 · 2023: 4 · 2022: 16 · 2021: 9 · 2020: 4 · 2019: 1
FWCI
4.35
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (GM103297, GM122458, AI143389, AI062520, AI150472, AI070042)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HIV-1 integrase, viral morphogenesis, integrase multimerization, viral ribonucleoprotein, capsid lattice
MeSH terms
Capsid, Humans, Phenotype, Protein Binding, Ribonucleoproteins, RNA, Viral, Virion, Virus Replication, HIV-1, HIV Infections, Virus Integration, Genome, Viral, HIV Integrase, Protein Multimerization, HEK293 Cells

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