Differential Effects of Human Immunodeficiency Virus Type 1 Capsid and Cellular Factors Nucleoporin 153 and LEDGF/p75 on the Efficiency and Specificity of Viral DNA Integration

Koh, Yasuhiro; Wu, Xiaolin; Ferris, Andrea L.; Matreyek, Kenneth A.; Smith, Steven J.; Lee, Kyeongeun; KewalRamani, Vineet N.; Hughes, Stephen H.; Engelman, Alan

doi:10.1128/jvi.01148-12

Cited by 112 publications

(138 citation statements)

References 65 publications

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“…CA have been shown to influence infection of nondividing cells, utilization of nuclear import pathways, and integration site selection (13)(14)(15)(16)(17)(18)(19). The E45A, Q63/67A, and N74D mutations all decrease the rate of uncoating to different degrees, with the N74D mutant virus the most similar to the wild-type virus and the Q63/ 67A mutant virus the most delayed ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…from wild-type HIV (1,2,16). The N74D mutation also alters the integration site preference of HIV (17,18). In the CsA washout assay, E45A mutant virus uncoated slower than the wild-type virus and had a significantly greater average half-life of uncoating (124 min) compared to HIV-GFP (85 min; Fig.…”

Section: Mutations In P24mentioning

confidence: 99%

“…4 and Table 1). We also examined the uncoating kinetics of N74D virus in both cell lines, as this virus has been the most well studied for its differential interaction with cellular host factors (16)(17)(18)(19)35). Similar to OMK cells, N74D mutant virus uncoated slower than the wild-type virus in HeLa-TC cells (Fig.…”

Section: Mutations In P24mentioning

confidence: 99%

“…CA mutations (E45A, N74D, G89V, P90A, A92E, and G94) that are currently actively studied due to their effects on other aspects of HIV replication, including infection of nondividing cells, utilization of nuclear import pathways, and integration site selection (13)(14)(15)(16)(17)(18)(19). Often the effect of these mutations on other steps in viral replication has been proposed to be due to changes in uncoating.…”

Section: Mutations In P24mentioning

confidence: 99%

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Identification of Capsid Mutations That Alter the Rate of HIV-1 Uncoating in Infected Cells

Hulme

Kelley

Okocha

et al. 2015

J Virol

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After viral fusion with the cell membrane, the conical capsid of HIV-1 disassembles by a process called uncoating. We recently utilized the cyclosporine (CsA) washout assay, in which TRIM-CypA-mediated restriction of viral replication is used to detect the state of the viral capsid, to study the kinetics of uncoating in HIV-1-infected cells. Here we have extended this analysis to examine the effects of p24 capsid protein (p24 CA ) mutations and cellular environment on the kinetics of uncoating in infected cells. We found that p24 CA mutations can significantly increase (A92E), delay (E45A and N74D), or have no effect (G94D) on the rate of uncoating and that these alterations are not due to changes in reverse transcription. Inhibition of reverse transcription delayed uncoating kinetics to an extent similar to that of the wild-type virus with all the p24 CA mutant viruses tested. In addition, we observed differences in uncoating in two cell lines, which suggests that the cellular environment can differentially impact the disassembly of wild-type and mutant capsids. Collectively, these experiments suggest that viral and cellular factors are important for the process of uncoating. Finally, these data support the model whereby early steps in reverse transcription facilitate HIV-1 uncoating. IMPORTANCEThe HIV-1 capsid is a cone-shaped structure, composed of the HIV-1-encoded protein p24 CA , which contains the viral RNA and other proteins needed for infection. After the virus enters a target cell, this capsid must disassemble by a process called uncoating. Uncoating is required for HIV-1 infection to progress, but the details of how this process occurs is not known. In this study, we used an in vivo assay to examine the uncoating process in HIV-1-infected cells. We determined that p24 CA mutations could increase or decrease the rate of uncoating and that this rate varied in different cell lines. We also found that reverse transcription of the viral RNA altered the process of uncoating before the p24 CA mutations. Collectively, these experiments provide a better understanding of how viral and cellular factors are involved with a poorly understood step in HIV-1 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Mutations In P24mentioning

confidence: 99%

Section: Mutations In P24mentioning

confidence: 99%

Section: Mutations In P24mentioning

confidence: 99%

See 2 more Smart Citations

Identification of Capsid Mutations That Alter the Rate of HIV-1 Uncoating in Infected Cells

Hulme

Kelley

Okocha

et al. 2015

J Virol

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“…Nup153 may interact with PICs docked on Nup358 and facilitate their transport through the NPC. Nup153 depletion does not only decrease HIV-1 nuclear entry, but also reduces the number of HIV-1 integration sites into transcriptionally active regions (Koh et al, 2013;Di Nunzio et al, 2013). It has been proposed that Nup153 is directly guiding the PIC to the genomic integration regions.…”

Section: Nup153 and Hivmentioning

confidence: 99%

The nuclear pore complex: structure and function

Duhéron¹,

Fahrenkrog²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is Nuclear pore complexes (NPCs) are large multi-protein complexes, which are embedded in the nuclear envelope and which are regulating the molecular exchange between the nucleus and the cytoplasm. While electron microscopy and cryo-electron tomography studies have provided high-resolution pictures of the NPC structure as entity, the challenge nowadays is to elucidate the organization and the functions of nuclear pore proteins (nucleoporins or Nups) inside and outside the NPC. Nucleoporins are not only involved in nucleocytoplasmic transport, but in an increasing number of other cellular processes, such as kinetochore organization, cell cycle regulation, DNA repair, and gene expression. The implication of nucleoporins in these diverse processes links them also to a wide variety of human diseases, such as cancer and autoimmune diseases. Here we review the progress made in defining the molecular arrangement of nucleoporins within the NPC and use the example of Nup153 to illustrate the versatility of individual nucleoporins and their implication in various human diseases.

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Connecting HIV‐1 integration and transcription: a step toward new treatments

Lucic

Lušić

2016

FEBS Letters

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Edited by Wilhelm JustThanks to the current combined antiretroviral therapy (cART), HIV-1 infection has become a manageable although chronic disease. The reason for this lies in the fact that long-lived cellular reservoirs persist in patients on cART. Despite numerous efforts to understand molecular mechanisms that contribute to viral latency, the important question of how and when latency is established remains unanswered. Related to this is the connection between HIV-1 integration and the capacity of the provirus to enter the latent state. In this review, we will give an overview of these nuclear events in the viral life cycle in the light of current therapeutic approaches, which aim to either reactivate the provirus or even excise the proviral DNA from the cellular genome.

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Differential Effects of Human Immunodeficiency Virus Type 1 Capsid and Cellular Factors Nucleoporin 153 and LEDGF/p75 on the Efficiency and Specificity of Viral DNA Integration

Cited by 112 publications

References 65 publications

Identification of Capsid Mutations That Alter the Rate of HIV-1 Uncoating in Infected Cells

Identification of Capsid Mutations That Alter the Rate of HIV-1 Uncoating in Infected Cells

The nuclear pore complex: structure and function

Connecting HIV‐1 integration and transcription: a step toward new treatments

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