2018
DOI: 10.1128/jvi.00845-18
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PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating

Abstract: The RNA genome of human immunodeficiency virus type 1 (HIV-1) is enclosed in a cone-shaped capsid shell that disassembles following cell entry via a process known as uncoating. During HIV-1 infection, the capsid is important for reverse transcription and entry of the virus into the target cell nucleus. The small molecule PF74 inhibits HIV-1 infection at early stages by binding to the capsid and perturbing uncoating. However, the mechanism by which PF74 alters capsid stability and reduces viral infection is pre… Show more

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Cited by 72 publications
(86 citation statements)
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References 42 publications
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“…These data clearly support the observation that a PF74 inhibitor stabilized the mature hexameric lattice and thus inhibited the processes connected to uncoating. A similar conclusion was reported based on the measurement of HIV-1 CA cores stiffness, which was enhanced in the presence of PF74 [52].…”
Section: Dith Analysissupporting
confidence: 88%
See 1 more Smart Citation
“…These data clearly support the observation that a PF74 inhibitor stabilized the mature hexameric lattice and thus inhibited the processes connected to uncoating. A similar conclusion was reported based on the measurement of HIV-1 CA cores stiffness, which was enhanced in the presence of PF74 [52].…”
Section: Dith Analysissupporting
confidence: 88%
“…Some experiments proved that PF74 decreased the stability of the HIV-1 core and thus accelerated its disassembly [49]. However, another paper documented that PF74 strengthened the stability of the HIV-1 CA cores, and thus slowed down the disassembly process [51,52,57]. Our data, obtained using an in vitro stabilization assay (DITH) supported the model in which PF74 acted as a stabilizer of the HIV-1 mature hexameric lattice [51].…”
Section: Nmr Analysis Of the Binding Mode Of D10supporting
confidence: 78%
“…High doses of PF74 have been shown to block reverse transcription in studies described in the literature, but their effects on the capsid vary between studies (26,27,54,55,(57)(58)(59)(60)(61)(62)(63)(64). PF74 was shown to stabilize or destabilize the capsid, depending on the method used.…”
Section: Fig 11mentioning
confidence: 99%
“…In the present work, we exploited PF-3450074 (PF74), a capsid-binding smallmolecule compound (57), as a tool to study capsid functions. PF74 was shown to destabilize the viral capsid in certain assay systems (55,(58)(59)(60)(61), although the compound did not affect capsid stability and even stabilized cores in imaging-based assays (27,54,62). We used the capsid-targeting activity of PF74, together with cell-free and cellbased assays, to reveal a novel naturally occurring phenotype of capsid stability that drastically alters cGAS-dependent sensing of HIV-1 DNA and highlights an underappreciated capacity of HIV-1 to accommodate phenotypic variation in the viral capsid.…”
mentioning
confidence: 99%
“…PF74 binds at the NTD-CTD subunit interface and occupies a similar pocket used by the host proteins CPFS6 and Nup153, two nuclear import factors known to enhance infectivity by increasing nuclear import and integration ( Figures 7 and 8, Table 1) [103][104][105]. PF74 stabilizes the CA core structure upon infection, which inhibits the uncoating process and, subsequently, HIV-1 reverse transcription [101,106,107] in the early stage and destabilizes CA in the late-stage causing aberrant virus morphologies that do not undergo maturation. PF74, however, suffers from extremely poor drug-like properties due to its peptidic nature, most notably its poor metabolic stability, which limits its clinical utility.…”
Section: Capsid (Ca P24)mentioning
confidence: 99%