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Structure and function of retroviral integrase

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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Fig. 1: The retroviral integration process.
Fig. 2: Prototype foamy virus intasome structures and integrase active site mechanics.
Fig. 3: Diversity of retroviral intasome architectures.
Fig. 4: Integration into nucleosomal DNA.
Fig. 5: Integrase strand transfer inhibitors.
Fig. 6: Allosteric HIV-1 integrase inhibitors.

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Acknowledgements

The authors apologize to colleagues whose work they were unable to cite due to space constraints. This work was supported by US National Institutes of Health grants P50 AI150481 (P.C. and A.N.E.) and R01 AI070042 (A.N.E.), Wellcome Trust Investigator Award 107005/Z/15Z (G.N.M.) and the Francis Crick Institute (P.C), which receives its core funding from Cancer Research UK (FC001061), the UK Medical Research Council (FC001061) and the Wellcome Trust (FC001061).

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A.N.E. consults for ViiV Healthcare Co. The other authors declare no competing interests.

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Maertens, G.N., Engelman, A.N. & Cherepanov, P. Structure and function of retroviral integrase. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-00586-9

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