The capsid revolution

Taylor, Ian A; Fassati, Ariberto

doi:10.1093/jmcb/mjad076

Cited by 2 publications

References 119 publications

(179 reference statements)

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A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import

Boulay,

Quevarec,

Malet

et al. 2024

EMBO Mol Med

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HIV-1 capsids cross nuclear pore complexes (NPCs) by engaging with the nuclear import machinery. To identify compounds that inhibit HIV-1 nuclear import, we screened drugs in silico on a three-dimensional model of a CA hexamer bound by Transportin-1 (TRN-1). Among hits, compound H27 inhibited HIV-1 with a low micromolar IC50. Unlike other CA-targeting compounds, H27 did not alter CA assembly or disassembly, inhibited nuclear import specifically, and retained antiviral activity against PF74- and Lenacapavir-resistant mutants. The differential sensitivity of divergent primate lentiviral capsids, capsid stability and H27 escape mutants, together with structural analyses, suggest that H27 makes multiple low affinity contacts with assembled capsid. Interaction experiments indicate that H27 may act by preventing CA from engaging with components of the NPC machinery such as TRN-1. H27 exhibited good metabolic stability in vivo and was efficient against different subtypes and circulating recombinant forms from treatment-naïve patients as well as strains resistant to the four main classes of antiretroviral drugs. This work identifies compounds that demonstrate a novel mechanism of action by specifically blocking HIV-1 nuclear import.

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A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import

Boulay,

Quevarec,

Malet

et al. 2024

EMBO Mol Med

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Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with the nuclear speckle

Tomasini,

Cuche,

et al. 2024

Preprint

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SummaryViruses rely on host cellular machinery for replication. After entering the nucleus, the HIV genome accumulates in nuclear niches where it undergoes reverse transcription and integrates into neighboring chromatin, promoting high transcription rates and new virus progeny. Despite anti-retroviral treatment, viral genomes can persist in these nuclear niches and reactivate if treatment is interrupted, likely contributing to the formation of viral reservoirs. The post-nuclear entry dynamics of HIV remain unclear, and understanding these steps is critical for revealing how viral reservoirs are established.In this study, we elucidate the formation of HIV-induced CPSF6 puncta and the domains of CPSF6 essential for this process. We also explore the roles of nuclear speckle scaffold factors, SON and SRRM2, in the biogenesis of these puncta. Through genetic manipulation and depletion experiments, we demonstrate the key role of the intrinsically disordered region of SRRM2 in enlarging nuclear speckles in the presence of the HIV capsid. We identify the FG domain of CPSF6 as essential for both puncta formation and binding to the viral core, which serves as the scaffold for CPSF6 puncta. While the low-complexity regions (LCRs) modulate CPSF6 binding to the viral capsid, they do not contribute to puncta formation, nor do the disordered mixed charge domains (MCDs) of CPSF6. These results demonstrate how HIV evolved to hijack host nuclear factors, enabling its persistence in the host. Of note, this study provides new insights into the underlying interactions between host factors and viral components, advancing our understanding of HIV nuclear dynamics and offering potential therapeutic targets for preventing viral persistence.HighlightsThe formation of HIV-induced CPSF6 puncta is critical for restoring HIV-1 nuclear reverse transcription (RT).CPSF6 protein lacking the FG peptide cannot bind to the viral core, thereby failing to form HIV-induced CPSF6 puncta.The FG peptide, rather than low-complexity regions (LCRs) or the mixed charge domains (MCDs) of the CPSF6 protein, drives the formation of HIV-induced CPSF6 puncta.HIV-induced CPSF6 puncta form individually and later fuse with nuclear speckles (NS) via the intrinsically disordered region (IDR) of SRRM2.

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The capsid revolution

Cited by 2 publications

References 119 publications

A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import

A new class of capsid-targeting inhibitors that specifically block HIV-1 nuclear import

Decoding the biogenesis of HIV-induced CPSF6 puncta and their fusion with the nuclear speckle

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