1. Microbiology and Infectious Disease
Download icon

HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

  1. Pratibha C Koneru
  2. Ashwanth C Francis
  3. Nanjie Deng
  4. Stephanie V Rebensburg
  5. Ashley C Hoyte
  6. Jared Lindenberger
  7. Daniel Adu-Ampratwum
  8. Ross C Larue
  9. Michael F Wempe
  10. Alan N Engelman
  11. Dmitry Lyumkis
  12. James R Fuchs
  13. Ronald M Levy
  14. Gregory B Melikyan
  15. Mamuka Kvaratskhelia  Is a corresponding author
  1. University of Colorado School of Medicine, United States
  2. Emory University, United States
  3. Pace University, United States
  4. The Ohio State University, United States
  5. University of Colorado Denver, United States
  6. Dana-Farber Cancer Institute, United States
  7. Salk Institute for Biological Studies, United States
  8. Temple University, United States
Research Article
  • Cited 13
  • Views 1,386
  • Annotations
Cite this article as: eLife 2019;8:e46344 doi: 10.7554/eLife.46344

Abstract

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10-fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.

Article and author information

Author details

  1. Pratibha C Koneru

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ashwanth C Francis

    Department of Pediatrics, Infectious Diseases, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nanjie Deng

    Department of Chemistry and Physical Sciences, Pace University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stephanie V Rebensburg

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ashley C Hoyte

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jared Lindenberger

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Adu-Ampratwum

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9392-2431
  8. Ross C Larue

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael F Wempe

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alan N Engelman

    Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Dmitry Lyumkis

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8124-7472
  12. James R Fuchs

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ronald M Levy

    Department of Chemistry, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8696-5177
  14. Gregory B Melikyan

    Department of Pediatrics, Infectious Diseases, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Mamuka Kvaratskhelia

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    MAMUKA.KVARATSKHELIA@UCDENVER.EDU
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3800-0033

Funding

National Institutes of Health (U54GM103368)

  • Mamuka Kvaratskhelia

National Institutes of Health (R01AI062520)

  • Mamuka Kvaratskhelia

National Institutes of Health (KL2 TR001068)

  • Ross C Larue

National Institutes of Health (R37AI039394)

  • Alan N Engelman

National Institutes of Health (R01AI143649)

  • Mamuka Kvaratskhelia

National Institutes of Health (R01AI129862)

  • Gregory B Melikyan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: February 23, 2019
  2. Accepted: May 22, 2019
  3. Accepted Manuscript published: May 23, 2019 (version 1)
  4. Version of Record published: June 18, 2019 (version 2)
  5. Version of Record updated: June 21, 2019 (version 3)
  6. Version of Record updated: July 15, 2020 (version 4)

Copyright

© 2019, Koneru 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.

Metrics

  • 1,386
    Page views
  • 314
    Downloads
  • 13
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Ecology
    2. Microbiology and Infectious Disease
    Lara Urban et al.
    Research Article

    While traditional microbiological freshwater tests focus on the detection of specific bacterial indicator species, including pathogens, direct tracing of all aquatic DNA through metagenomics poses a profound alternative. Yet, in situ metagenomic water surveys face substantial challenges in cost and logistics. Here, we present a simple, fast, cost-effective and remotely accessible freshwater diagnostics workflow centred around the portable nanopore sequencing technology. Using defined compositions and spatiotemporal microbiota from surface water of an example river in Cambridge (UK), we provide optimised experimental and bioinformatics guidelines, including a benchmark with twelve taxonomic classification tools for nanopore sequences. We find that nanopore metagenomics can depict the hydrological core microbiome and fine temporal gradients in line with complementary physicochemical measurements. In a public health context, these data feature relevant sewage signals and pathogen maps at species level resolution. We anticipate that this framework will gather momentum for new environmental monitoring initiatives using portable devices.

    1. Microbiology and Infectious Disease
    Philip P Adams et al.
    Research Article

    Many bacterial genes are regulated by RNA elements in their 5´ untranslated regions (UTRs). However, the full complement of these elements is not known even in the model bacterium Escherichia coli. Using complementary RNA-sequencing approaches, we detected large numbers of 3´ ends in 5´ UTRs and open reading frames (ORFs), suggesting extensive regulation by premature transcription termination. We documented regulation for multiple transcripts, including spermidine induction involving Rho and translation of an upstream ORF for an mRNA encoding a spermidine efflux pump. In addition to discovering novel sites of regulation, we detected short, stable RNA fragments derived from 5´ UTRs and sequences internal to ORFs. Characterization of three of these transcripts, including an RNA internal to an essential cell division gene, revealed that they have independent functions as sRNA sponges. Thus, these data uncover an abundance of cis- and trans-acting RNA regulators in bacterial 5´ UTRs and internal to ORFs.