Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

Nunzio, Francesca Di; Fricke, Thomas; Miccio, Annarita; Valle-Casuso, José Carlos; Pérez, Pablo; Souque, Philippe; Rizzi, Ermanno; Mavilio, Fulvio; Charneau, Pierre; Díaz-Griffero, Felipe

doi:10.1186/1742-4690-10-s1-p111

Cited by 11 publications

(15 citation statements)

References 64 publications

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“…A role for CA in the nuclear import of the PIC is well established, in part through the interactions of CA with nucleoporins (47)(48)(49)(50)(51)(52). We speculate that BI pyrrolopyrazolones binding to CA site 2 may disrupt the interaction of some host factors with capsid cores.…”

Section: Discussionmentioning

confidence: 91%

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

Lamorte

Titolo

Lemke

et al. 2013

Antimicrob Agents Chemother

107

142

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The identification of novel antiretroviral agents is required to provide alternative treatment options for HIV-1-infected patients. The screening of a phenotypic cell-based viral replication assay led to the identification of 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. These compounds inhibited early postentry stages of viral replication at a step(s) following reverse transcription but prior to 2 long terminal repeat (2-LTR) circle formation, suggesting that they may block nuclear targeting of the preintegration complex. Selection of viruses resistant to BI-2 revealed that substitutions at residues A105 and T107 within the capsid (CA) amino-terminal domain (CA NTD ) conferred high-level resistance to both compounds, implicating CA as the antiviral target. Direct binding of BI-1 and/or BI-2 to CA NTD was demonstrated using isothermal titration calorimetry and nuclear magnetic resonance (NMR) chemical shift titration analyses. A high-resolution crystal structure of the BI-1:CA NTD complex revealed that the inhibitor bound within a recently identified inhibitor binding pocket (CA NTD site 2) between CA helices 4, 5, and 7, on the surface of the CA NTD , that also corresponds to the binding site for the host factor CPSF-6. The functional consequences of BI-1 and BI-2 binding differ from previously characterized inhibitors that bind the same site since the BI compounds did not inhibit reverse transcription but stabilized preassembled CA complexes. Hence, this new class of antiviral compounds binds CA and may inhibit viral replication by stabilizing the viral capsid.

show abstract

Section: Discussionmentioning

confidence: 91%

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

Lamorte

Titolo

Lemke

et al. 2013

Antimicrob Agents Chemother

107

142

View full text Add to dashboard Cite

show abstract

“…This pathway was initially linked to the binding of the cleavage and polyadenylation specificity factor 6 (CPSF6) protein, a pre-mRNA splicing factor and member of the serine/arginine-rich (SR) protein family, to the viral capsid before the PIC translocation to the host cell nucleus (6 -10). In particular, mutating the CPSF6 binding site in capsid was shown to activate an alternative mode (11)(12)(13) for PIC trafficking that leads to integration away from gene-dense regions and to decreased integration into genes (12,14). Recent studies revealed that disruption of CPSF6 expression by RNA interference or CRISPR-mediated gene knock-out resulted in a redistribution of HIV-1 integration sites away from gene bodies and gene dense chromosomal regions, thus validating the key role of CPSF6 in HIV-1 integration targeting (15).…”

mentioning

confidence: 99%

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes

Rasheedi

Shun

Serrao

et al. 2016

Journal of Biological Chemistry

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HIV-1 favors integration into active genes and gene-enriched regions of host cell chromosomes, thus maximizing the probability of provirus expression immediately after integration. This requires cleavage and polyadenylation specificity factor 6 (CPSF6), a cellular protein involved in pre-mRNA 3 end processing that binds HIV-1 capsid and connects HIV-1 preintegration complexes to intranuclear trafficking pathways that link integration to transcriptionally active chromatin. CPSF6 together with CPSF5 and CPSF7 are known subunits of the cleavage factor I (CFI m ) 3 end processing complex; however, CPSF6 could participate in additional protein complexes. The molecular mechanisms underpinning the role of CPSF6 in HIV-1 infection remain to be defined. Here, we show that a majority of cellular CPSF6 is incorporated into the CFI m complex. HIV-1 capsid recruits CFI m in a CPSF6-dependent manner, which suggests that the CFI m complex mediates the known effects of CPSF6 in HIV-1 infection. To dissect the roles of CPSF6 and other CFI m complex subunits in HIV-1 infection, we analyzed virologic and integration site targeting properties of a CPSF6 variant with mutations that prevent its incorporation into CFI m . We show, somewhat surprisingly, that CPSF6 incorporation into CFI m is not required for its ability to direct preferential HIV-1 integration into genes. The CPSF5 and CPSF7 subunits appear to have only a minor, if any, role in this process even though they appear to facilitate CPSF6 binding to capsid. Thus, CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin.

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“…This preference becomes part of the 5-bp repeat at each end of the integration (89 (67). HIV infects nondividing cells, and nuclear import by the PIC is specific, requiring interactions between PIC components, including the HIV capsid, and cellular proteins, such as nucleoporins (76)(77)(78)(79)(80)(81)(82). Not all of the newly synthesized viral DNA molecules are integrated into the host genome; a subset of DNA molecules form circular molecules that include one or both LTRs ( Figure 1).…”

Section: Integration: a Central Event In Retrovirus Replicationmentioning

confidence: 99%

The role of HIV integration in viral persistence: no more whistling past the proviral graveyard

Maldarelli¹

2016

Journal of Clinical Investigation

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Nup153 and Nup98 bind the HIV-1 core and contribute to the early steps of HIV-1 replication

Cited by 11 publications

References 64 publications

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

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

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes

The role of HIV integration in viral persistence: no more whistling past the proviral graveyard

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