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Structure and function of retroviral integrase. ​

Literature Information ​

DOI10.1038/s41579-021-00586-9
PMID34244677
JournalNature reviews. Microbiology
Impact Factor103.3
JCR QuartileQ1
Publication Year2022
Times Cited51
KeywordsRetroviral Integrase, Integrase Inhibitors, Viral Integration Mechanism
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1740-1526
Pages20-34
Issue20(1)
AuthorsGoedele N Maertens, Alan N Engelman, Peter Cherepanov

TL;DR ​

This review discusses the structural insights gained from X-ray crystallography and cryogenic electron microscopy studies of retroviral DNA integration, focusing on the role of integrase and the formation of the intasome core for viral genome incorporation. It highlights the development of allosteric integrase inhibitors as a promising new therapeutic strategy against HIV, while also addressing remaining questions and future directions in understanding retroviral integration mechanisms.

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Retroviral Integrase · Integrase Inhibitors · Viral Integration Mechanism

Abstract ​

A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome. Integrase is the viral enzyme responsible for the catalytic steps involved in this process, and integrase strand transfer inhibitors are widely used to treat people living with HIV. Over the past decade, a series of X-ray crystallography and cryogenic electron microscopy studies have revealed the structural basis of retroviral DNA integration. A variable number of integrase molecules congregate on viral DNA ends to assemble a conserved intasome core machine that facilitates integration. The structures additionally informed on the modes of integrase inhibitor action and the means by which HIV acquires drug resistance. Recent years have witnessed the development of allosteric integrase inhibitors, a highly promising class of small molecules that antagonize viral morphogenesis. In this Review, we explore recent insights into the organization and mechanism of the retroviral integration machinery and highlight open questions as well as new directions in the field.

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Primary Questions Addressed ​

  1. What are the specific structural features of retroviral integrase that contribute to its function in DNA integration?
  2. How do the mechanisms of action of allosteric integrase inhibitors differ from traditional integrase strand transfer inhibitors?
  3. What role does the intasome core machine play in the integration process of retroviral DNA into host chromosomes?
  4. In what ways does HIV acquire drug resistance to integrase inhibitors, and what are the implications for treatment strategies?
  5. What recent advancements in cryogenic electron microscopy have provided new insights into the retroviral integration machinery?

Key Findings ​

Research Background and Objectives ​

Retroviruses, including HIV, require the integration of their viral DNA into the host cell's genome for replication. This process is mediated by the viral enzyme integrase (IN), which has become a key target for antiretroviral therapies. The objective of this review is to summarize recent advances in understanding the structure and function of retroviral integrase, particularly focusing on the mechanisms of integration, the action of integrase inhibitors, and the implications for drug resistance and future therapeutic strategies.

Main Methods/Materials/Experimental Design ​

The review synthesizes findings from various structural biology studies, including X-ray crystallography and cryogenic electron microscopy (cryo-EM), to elucidate the mechanisms of retroviral DNA integration.

Mermaid diagram

Key Results and Findings ​

  1. Integrase Structure: Retroviral integrases consist of three main domains (N-terminal, catalytic core, and C-terminal) and function as multimers to form the intasome, a complex essential for DNA integration.
  2. Integration Mechanism: The integration process involves two key enzymatic reactions—3' processing of the viral DNA and strand transfer to the host chromosome. The structural studies have revealed the active sites and the role of metal ions in these reactions.
  3. Inhibitor Action: Integrase strand transfer inhibitors (INSTIs) target the active site of integrase, preventing the integration of viral DNA. New allosteric inhibitors (ALLINIs) have been developed that interfere with integrase function by promoting aberrant multimerization rather than directly inhibiting the catalytic activity.

Main Conclusions/Significance/Innovation ​

The review highlights the intricate mechanisms of retroviral integration and the structural basis for the action of integrase inhibitors. It underscores the importance of understanding the molecular details of integrase function and inhibitor interactions to inform the design of more effective therapies against HIV. The discovery of allosteric inhibitors represents a novel approach to antiviral drug development.

Research Limitations and Future Directions ​

  • Research Limitations: While significant progress has been made in understanding integrase, many aspects of the integration process, particularly the interactions with host chromatin and the dynamics of the pre-integration complex, remain poorly characterized.
  • Future Directions: Future research should focus on the in vivo dynamics of integrase and its complexes, the development of safer and more effective allosteric inhibitors, and strategies to overcome drug resistance. Enhanced imaging techniques, such as in situ cryo-EM, may provide insights into the integration process within the native cellular environment.
AspectSummary
Research FocusMechanisms of retroviral DNA integration and integrase function
Methods UsedX-ray crystallography, cryo-EM, structural biology
Key FindingsStructure of integrase, mechanism of action, role of inhibitors
Future Research NeedsUnderstanding host interactions, developing new inhibitors, addressing drug resistance

References ​

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Literatures Citing This Work ​

  1. The KT Jeang Retrovirology prize 2021: Peter Cherepanov. - - Retrovirology (2021)
  2. Clonal Expansion of Infected CD4+ T Cells in People Living with HIV. - John M Coffin;Stephen H Hughes - Viruses (2021)
  3. Multivalent interactions essential for lentiviral integrase function. - Allison Ballandras-Colas;Vidya Chivukula;Dominika T Gruszka;Zelin Shan;Parmit K Singh;Valerie E Pye;Rebecca K McLean;Gregory J Bedwell;Wen Li;Andrea Nans;Nicola J Cook;Hind J Fadel;Eric M Poeschla;David J Griffiths;Javier Vargas;Ian A Taylor;Dmitry Lyumkis;Hasan Yardimci;Alan N Engelman;Peter Cherepanov - Nature communications (2022)
  4. Cabotegravir, the Long-Acting Integrase Strand Transfer Inhibitor, Potently Inhibits Human T-Cell Lymphotropic Virus Type 1 Transmission in vitro. - Bethany S Schneiderman;Michal S Barski;Goedele N Maertens - Frontiers in medicine (2022)
  5. Multimodal Functionalities of HIV-1 Integrase. - Alan N Engelman;Mamuka Kvaratskhelia - Viruses (2022)
  6. The C-Terminal Domain of HIV-1 Integrase: A Swiss Army Knife for the Virus? - Cecilia Rocchi;Patrice Gouet;Vincent Parissi;Francesca Fiorini - Viruses (2022)
  7. Commercially Available Flavonols Are Better SARS-CoV-2 Inhibitors than Isoflavone and Flavones. - Otávio Augusto Chaves;Natalia Fintelman-Rodrigues;Xuanting Wang;Carolina Q Sacramento;Jairo R Temerozo;André C Ferreira;Mayara Mattos;Filipe Pereira-Dutra;Patrícia T Bozza;Hugo Caire Castro-Faria-Neto;James J Russo;Jingyue Ju;Thiago Moreno L Souza - Viruses (2022)
  8. Integrase deficient lentiviral vector: prospects for safe clinical applications. - Chee-Hong Takahiro Yew;Narmatha Gurumoorthy;Fazlina Nordin;Gee Jun Tye;Wan Safwani Wan Kamarul Zaman;Jun Jie Tan;Min Hwei Ng - PeerJ (2022)
  9. HIV-1 Preintegration Complex Preferentially Integrates the Viral DNA into Nucleosomes Containing Trimethylated Histone 3-Lysine 36 Modification and Flanking Linker DNA. - Nicklas Sapp;Nathaniel Burge;Khan Cox;Prem Prakash;Muthukumar Balasubramaniam;Santosh Thapa;Devin Christensen;Min Li;Jared Linderberger;Mamuka Kvaratskhelia;Jui Pandhare;Robert Craigie;Michael G Poirier;Chandravanu Dash - Journal of virology (2022)
  10. Complex Relationships between HIV-1 Integrase and Its Cellular Partners. - Anna Rozina;Andrey Anisenko;Tatiana Kikhai;Maria Silkina;Marina Gottikh - International journal of molecular sciences (2022)

... (41 more literatures)

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