BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

@article{Fricke2014BI2DH,
  title={BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid},
  author={T. Fricke and Cindy Buffone and S. Opp and J. Valle-Casuso and F. Diaz-Griffero},
  journal={Retrovirology},
  year={2014},
  volume={11}
}
BackgroundThe recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74.FindingsThis work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor… Expand
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References

SHOWING 1-10 OF 26 REFERENCES
Human Cytosolic Extracts Stabilize the HIV-1 Core
TLDR
Interestingly, stabilization of in vitro-assembled HIV-1 CA-NC complexes is not due solely to macromolecular crowding, suggesting the presence of specific cellular factors that stabilize the HIV- 1 core. Expand
CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication
TLDR
A novel protein-protein interface in the N-terminal domain of HIV-1 CA is determined by X-ray crystallography, which mediates both viral restriction and host cofactor dependence, and is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. Expand
Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization
TLDR
The data suggest that PF74 triggers premature HIV-1 uncoating in target cells, thereby mimicking the activity of the retrovirus restriction factor TRIM5α, and highlights un coating as a step in the HIV- 1 life cycle that is susceptible to small molecule intervention. Expand
Inhibition of Reverse Transcriptase Activity Increases Stability of the HIV-1 Core
TLDR
It is shown that inhibition of reverse transcriptase (RT) during HIV-1 infection by pharmacologic or genetic means increased the stability of the HIV- 1 core during infection, implying that the surface of the AIDS-1 core is dynamic and changes upon the ongoing processes within the core. Expand
Discovery of Novel Small-Molecule HIV-1 Replication Inhibitors That Stabilize Capsid Complexes
TLDR
A novel class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6-one ( pyrrolopyrazolone) HIV-1 inhibitors, exemplified by two compounds: BI-1 and BI-2, which may inhibit viral replication by stabilizing the viral capsid. Expand
Specific recognition and accelerated uncoating of retroviral capsids by the TRIM5alpha restriction factor.
TLDR
It is demonstrated that TRIM5alpha variants from Old World monkeys specifically associate with the HIV type 1 (HIV-1) capsid and that this interaction depends on the TRIM 5alpha B30.2 domain. Expand
Flexible use of nuclear import pathways by HIV-1.
TLDR
A fragment of the cleavage and polyadenylation factor 6, CPSF6, is identified as a potent inhibitor of HIV-1 infection and highlights a single residue in CA as essential in regulating interactions with NUPs. Expand
The fate of HIV-1 capsid: a biochemical assay for HIV-1 uncoating.
TLDR
This assay is based on the biochemical separation of soluble capsid protein from particulate capsid cores and provides information about the fate of the capsid during infection. Expand
HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention
TLDR
It is shown that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells and revealing HIV CA as a tractable drug target for HIV therapy. Expand
TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm
TLDR
TNPO3 promotes HIV-1 infectivity indirectly, by shifting the CA-binding protein CPSF6 to the nucleus, thus preventing the excessive HIV- 1 CA stability that would otherwise result from cytoplasmic accumulation of CPSF4 and targeting CPSF 6 by fusion to a heterologous nuclear localization signal rescued HIV-2 from the inhibitory effects of TNPO3 knockdown. Expand
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1
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3
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