The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

Houwer, Stéphanie De; Demeulemeester, Jonas; Thys, Wannes; Rocha, Susana; Dirix, Lieve; Gijsbers, Rik; Christ, Frauke; Debyser, Zeger

doi:10.1074/jbc.m113.533281

Cited by 29 publications

(42 citation statements)

References 61 publications

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“…3). While a direct and Ran-dependent interaction between IN and TRN-SR2 was verified in vitro 2072, no correlation between formation of IN tetramers and TRN-SR2 binding has been observed73. The FRET data agree with the hypothesis that TRN-SR2 has no direct influence on IN oligomerization73.…”

Section: Discussionsupporting

confidence: 59%

Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry

Borrenberghs

Dirix

Wit

et al. 2016

Sci Rep

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Nuclear entry is a selective, dynamic process granting the HIV-1 pre-integration complex (PIC) access to the chromatin. Classical analysis of nuclear entry of heterogeneous viral particles only yields averaged information. We now have employed single-virus fluorescence methods to follow the fate of single viral pre-integration complexes (PICs) during infection by visualizing HIV-1 integrase (IN). Nuclear entry is associated with a reduction in the number of IN molecules in the complexes while the interaction with LEDGF/p75 enhances IN oligomerization in the nucleus. Addition of LEDGINs, small molecule inhibitors of the IN-LEDGF/p75 interaction, during virus production, prematurely stabilizes a higher-order IN multimeric state, resulting in stable IN multimers resistant to a reduction in IN content and defective for nuclear entry. This suggests that a stringent size restriction determines nuclear pore entry. Taken together, this work demonstrates the power of single-virus imaging providing crucial insights in HIV replication and enabling mechanism-of-action studies.

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Section: Discussionsupporting

confidence: 59%

Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry

Borrenberghs

Dirix

Wit

et al. 2016

Sci Rep

Self Cite

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“…45−47 Among the esoteric functions of HIV-1 IN, its proposed involvement in PIC nuclear import has been the subject of considerable and yet to be resolved debate. 34,40,41,48−54 …”

Section: In and The Retroviral Life Cyclementioning

confidence: 99%

Retroviral DNA Integration

2016

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The integration of a DNA copy of the viral RNA genome into host chromatin is the defining step of retroviral replication. This enzymatic process is catalyzed by the virus-encoded integrase protein, which is conserved among retroviruses and LTR-retrotransposons. Retroviral integration proceeds via two integrase activities: 3′-processing of the viral DNA ends, followed by the strand transfer of the processed ends into host cell chromosomal DNA. Herein we review the molecular mechanism of retroviral DNA integration, with an emphasis on reaction chemistries and architectures of the nucleoprotein complexes involved. We additionally discuss the latest advances on anti-integrase drug development for the treatment of AIDS and the utility of integrating retroviral vectors in gene therapy applications.

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“…In other experiments, the mutant exhibited slightly reduced affinity for IN but strong impairment of binding to unphosphorylated ASF/SF2, indicating its lower cargo binding ability (De Houwer et al 2014). …”

Section: Cleavage and Polyadenylation Specific Factor 6 (Cpsf6)mentioning

confidence: 99%

“…Different research groups have succeeded in detecting the cellular import systems by genome-wide or yeast 2-hybrid (Y2H) screening. However, the roles of their components have not been determined by single or double mutations because viral infection is not inhibited (Cribier et al 2011;De Iaco et al 2013;De Houwer et al 2014;Ali et al 2015).…”

Section: Canonical Nuclear Import Mechanismsmentioning

confidence: 99%

Cellular and viral determinants of retroviral nuclear entry

2016

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Retroviruses must integrate their cDNA into the host genome to generate proviruses. Viral DNA-protein complexes interact with cellular proteins and produce pre-integration complexes, which carry the viral genome and cross the nuclear pore channel to enter the nucleus and integrate viral DNA into host chromosomal DNA. If the reverse transcripts fail to integrate, linear or circular DNA species such as 1-and 2-long terminal repeats are generated. Such complexes encounter numerous cellular proteins in the cytoplasm, which restrict viral infection and protect the nucleus. To overcome host cell defenses, the pathogens have evolved several evasion strategies. Viral proteins often contain nuclear localization signals, allowing entry into the nucleus. Among more than 1000 proteins identified as required for HIV infection by RNA interference screening, karyopherins, cleavage and polyadenylation specific factor 6, and nucleoporins have been predominantly studied. This review discusses current opinions about the synergistic relationship between the viral and cellular factors involved in nuclear import, with focus on the unveiled mysteries of the host-pathogen interaction, and highlights novel approaches to pinpoint therapeutic targets.

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The HIV-1 Integrase Mutant R263A/K264A Is 2-fold Defective for TRN-SR2 Binding and Viral Nuclear Import

Cited by 29 publications

References 61 publications

Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry

Dynamic Oligomerization of Integrase Orchestrates HIV Nuclear Entry

Retroviral DNA Integration

Cellular and viral determinants of retroviral nuclear entry

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