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Conference Papers Year : 2020

HIV-1 Pre-Integration Complexes. Structures, Functions and Drug Design

Abstract

After retroviral infection of a target cell, during the early phase of replication, the HIV-1 genomic RNA is reverse transcribed by the viral reverse transcriptase to generate the double-stranded viral DNA that interact with viral and cellular proteins to form the pre-integration complex (PIC). Viral integrase (IN) is the key component of the PIC and is involved in several steps of viral replication notably in reverse transcription, nuclear import, chromatin targeting and integration. Viral components such as IN cannot perform these functions on their own and need to recruit host cell proteins to carry out the different processes. IN is a flexible protein with intrinsically disordered regions allowing its interaction with multiple partners and enabling its multiple functions. To study the molecular mechanisms of viral integration we use a bottom - up strategy by assembling in vitro and/or incellulo multiprotein complexes around the integrase protein (core protein of the PIC). Several complexes have been characterized in our team (IN/LEDGF, IN/LEDGF/INI1-IBD, IN/LEDGF/CA, IN/LEDGF/TNPO3, IN/LEDGF/Nucleosome). To reveal the structure - function relationships of PIC complexes, we combine X-ray, NMR and Cryo-EM structures with biochemical and biological data. Two cryo-EM structures of the IN/LEDGF/DNA and IN/LEDGF/INI1-IBD/DNA complexes have been solved at low resolution (Michel et al., EMBO J., 2009; Maillot et al. PLoS ONE, 2013). With the recent progress of the cryo-EM techniques and our improvement in the complex preparations (Levy et al. Nature Comm. 2016; Eiler et al., Methods in Molecular Biology, 2018) new cryoEM datasets are collected (IN/LEDGF/DNA-pal, IN/LEDGF/Nucleosome) to increase the structure quality to near atomic resolution. In addition, the use of molecular structures together with in vitro assays allows us to develop a screening platform for interaction/allosteric inhibitors with the pre-integration complexes as targets.
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Dates and versions

hal-03433618 , version 1 (17-11-2021)

Identifiers

  • HAL Id : hal-03433618 , version 1

Cite

Julien Batisse, Eduardo Bruch, Nicolas Lévy, Sylvia Eiler, Sylvie Duclaud, et al.. HIV-1 Pre-Integration Complexes. Structures, Functions and Drug Design. 64th meeting of the Biophysical society, Feb 2020, San Diego, United States. ⟨hal-03433618⟩
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