Evidence for Direct Involvement of the Capsid Protein in HIV Infection of Nondividing Cells

Yamashita, Masahiro; Pérez, Omar García; Hope, Thomas J.; Emerman, Michael

doi:10.1371/journal.ppat.0030156

Cited by 182 publications

(266 citation statements)

References 41 publications

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“…A third major outcome of these studies is that A3F-YFP labeling of PICs can provide a valuable tool for analyzing the early stage of HIV-1 infection. The use of GFP-Vpr for analysis of viral postentry events, pioneered by Hope and colleagues (33), has provided numerous valuable insights into postentry events during HIV-1 replication (22,24,(34)(35)(36). However, GFP-Vpr dissociates from the RTCs/PICs shortly after infection and has not been observed in the nuclei of infected cells (33,36,37).…”

Section: Discussionmentioning

confidence: 99%

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Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Burdick

Pathak

2013

Proc. Natl. Acad. Sci. U.S.A.

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Human cytidine deaminases APOBEC3F (A3F) and APOBEC3G (A3G) are host factors that incorporate into virions and restrict virus replication. We labeled HIV-1 particles with yellow fluorescent protein (YFP)-tagged APOBEC3 proteins and examined their association with preintegration complexes (PICs) in infected cells. Labeling of PICs with A3F-YFP, and to a lesser extent A3G-YFP, could be used to visualize PICs in the nuclei, which was dependent on nuclear pore protein Nup153 but not TNPO3. We show that reverse transcription is not required for nuclear import of PICs, indicating that a viral core uncoating event associated with reverse transcription, and the central DNA flap that forms during reverse transcription, are not required for nuclear import. We also quantify association of cytoplasmic PICs with nuclear envelope (NE) and report that capsid mutations that increase or decrease core stability dramatically reduce NE association and nuclear import of PICs. In addition, we find that nuclear PICs remain close to the NE and are not distributed throughout the nuclei. These results provide tools for tracking retroviral PICs in infected cells and reveal insights into HIV-1 replication.retrovirus | microscopy | early events

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Section: Discussionmentioning

confidence: 99%

“…To determine the effect of cell division on the nuclear import of A3F-labeled PICs, HeLa cells were arrested in the G1/S phase of the cell cycle with aphidicolin treatment (2 μg/mL), an inhibitor of DNA polymerase α (21,22), and infected with A3F-YFP-labeled WT virus or D110E virus (Fig. 4E).…”

Section: Significancementioning

confidence: 99%

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Burdick

Pathak

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The HIV-1 preintegration complex travels to the nuclear envelope via the microtubule network [127], and is subsequently actively transported through the nuclear pore, although the cis-and trans-acting factors required for nuclear uptake are still debated [128]. Genetic analyses indicate that properly assembled capsids are required for the successful completion of reverse transcription (and other early events) [47,49,50,67,71,129,130] and also for later events that accompany nuclear localization of the preintegration complex [130,131]. Moreover, mutations that either increase or decrease capsid stability can reduce viral infectivity, suggesting that the timing (or extent) of capsid disassembly is probably important for successful completion of the first half of the viral life cycle [129].…”

Section: Capsid Disassemblymentioning

confidence: 99%

The structural biology of HIV assembly

Ganser‐Pornillos

Yeager

Sundquist

2008

Current Opinion in Structural Biology

413

422

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HIV assembly and replication proceed through formation of morphologically distinct immature and mature viral capsids that are organized by the Gag polyprotein (immature) and by the fully processed CA protein (mature). The Gag polyprotein is composed of three folded polypeptides (MA, CA, and NC) and three smaller peptides (SP1, SP2, and p6) that function together to coordinate membrane binding and Gag-Gag lattice interactions in immature virions. Following budding, HIV maturation is initiated by proteolytic processing of Gag, which induces conformational changes in the CA domain and results in assembly of the distinctive conical capsid. Retroviral capsids are organized following the principles of fullerene cones, and the hexagonal CA lattice is stabilized by three distinct interfaces. Recently identified inhibitors of viral maturation act by disrupting the final stage of Gag processing, or by inhibiting formation of a critical intermolecular CA-CA interface in the mature capsid. Following release into a new host cell, the capsid disassembles and host cell factors can potently restrict this stage of retroviral replication. Here, we review the structures of immature and mature HIV virions, focusing on recent studies that have defined the global organization of the immature Gag lattice, identified sites likely to undergo conformational changes during maturation, revealed the molecular structure of the mature capsid lattice, demonstrated that capsid architectures are conserved, identified the first capsid assembly inhibitors, and begun to uncover the remarkable biology of the mature capsid.

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“…This now legendary problem remains unsolved [23,124]. Despite the initially provocative correlation between intracellular trafficking of integrase proteins expressed outside the viral context and the differential capability of these retroviruses for non-dividing cell infection -HIV IN is nuclear, MLV IN is cytoplasmic -the weight of current evidence tilts against integrase or the integrase-p75 interaction being the determinant [75,95,96,101,121,[128][129][130][131][132][133]. As is discussed below, however, a role for p75 in PIC nuclear import is not definitively excluded.…”

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

115

104

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HIV integrates a DNA copy of its genome into a host cell chromosome in each replication cycle. The essential DNA cleaving and joining chemistry of integration is known, but there is less understanding of the process as it occurs in a cell, where two complex and dynamic macromolecular entities are joined: the viral pre-integration complex and chromatin. Among implicated cellular factors, much recent attention has coalesced around LEDGF/p75, a nuclear protein that may act as a chromatin docking factor or receptor for lentiviral pre-integration complexes. LEDGF/p75 tethers HIV integrase to chromatin, protects it from degradation, and strongly influences the genome-wide pattern of HIV integration. Depleting the protein from cells and/or over-expressing its integrase-binding domain blocks viral replication. Current goals are to establish the underlying mechanisms and to determine whether this knowledge can be exploited for antiviral therapy or for targeting lentiviral vector integration in human gene therapy.

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Evidence for Direct Involvement of the Capsid Protein in HIV Infection of Nondividing Cells

Cited by 182 publications

References 41 publications

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes

The structural biology of HIV assembly

Integrase, LEDGF/p75 and HIV replication

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