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

  title={BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid},
  author={Thomas Fricke and Cindy Buffone and Silvana Opp and Jos{\'e} Carlos Valle-Casuso and Felipe Diaz-Griffero},
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… 

PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating

Atomic force microscopy is applied to show that binding of PF74 to recombinant capsid-like assemblies and to HIV-1 isolated cores stabilizes the capsid in a concentration-dependent manner, thereby permitting reverse transcription while interfering with a late step in uncoating.

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Understanding of the interactions between the viral capsid core and several cellular factors that enable efficient HIV-1 genome replication, timely core disassembly, nuclear import and the integration of the viral genome into the genome of the target cell are described.

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The role of the HIV-1 capsid protein in the virus life cycle is detailed, antiviral compounds are categorized based on their targeting of five sites within theAIDS capsid, and their molecular interactions and mechanisms of action are discussed.

Comparison of Biochemical Properties of HIV-1 and HIV-2 Capsid Proteins

Results imply that distinct in vitro polymerization abilities of the two HIV-1 and HIV-2 CA proteins are related to their structural instability/stability, which is one of the decisive factors for viral replication potential.

PF74 Inhibits HIV-1 Integration by Altering the Composition of the Preintegration Complex

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It is shown that the decreased infectivity of HIV-1-N74D in CD4+ T cells is due to a loss of Cyp A protection from TRIM5αhu restriction activity.

Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

This work reveals that the dose-response curve of PF74 consists of two distinct inhibitory phases that are differentially regulated by CA-interacting host proteins, which provides novel insights into both the mechanism of action ofPF74 and the roles of host factors during the early steps of HIV-1 infection.

Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein

It is shown that C1 acts during HIV-1 maturation to prevent assembly of a mature viral capsid, and the binding site for C1 represents a new pharmacological vulnerability in the capsid assembly stage of the HIV- 1 life cycle.

Novel Intersubunit Interaction Critical for HIV-1 Core Assembly Defines a Potentially Targetable Inhibitor Binding Pocket

A specific interaction that is primarily present in pentameric interfaces in the HIV-1 capsid core was identified and is reported to be important for CA assembly and could lead to the development of antivirals which disrupt this interaction and affect capsid assembly.

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This review covers the current understanding of the role of the viral capsid in the HIV-1 life cycle and its interaction with different host factors that enable reverse transcription, trafficking towards the nucleus, nuclear import and integration into host chromosomes.



Human Cytosolic Extracts Stabilize the HIV-1 Core

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CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication

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.

Small-Molecule Inhibition of Human Immunodeficiency Virus Type 1 Infection by Virus Capsid Destabilization

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.

Inhibition of Reverse Transcriptase Activity Increases Stability of the HIV-1 Core

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.

Discovery of Novel Small-Molecule HIV-1 Replication Inhibitors That Stabilize Capsid Complexes

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.

Flexible use of nuclear import pathways by HIV-1.

The fate of HIV-1 capsid: a biochemical assay for HIV-1 uncoating.

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.

HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention

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.

TNPO3 protects HIV-1 replication from CPSF6-mediated capsid stabilization in the host cell cytoplasm

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.

RING Domain Mutations Uncouple TRIM5α Restriction of HIV-1 from Inhibition of Reverse Transcription and Acceleration of Uncoating

It is suggested that TRIM5αrh blocks HIV-1 reverse transcription by inducing premature viral uncoating in target cells by correlated the block of reverse transcription with the ability of TRim5α to accelerate un coating.