Reassessment of the Roles of Integrase and the Central DNA Flap in Human Immunodeficiency Virus Type 1 Nuclear Import

Dvorin, Jeffrey D.; Bell, P. R.; Maul, Gerd G.; Yamashita, Masahiro; Emerman, Michael; Malim, Michael H.

doi:10.1128/jvi.76.23.12087-12096.2002

Cited by 139 publications

(144 citation statements)

References 40 publications

(42 reference statements)

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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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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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“…However, some studies have shown that cPPT mutant HIV-1 can replicate in non-dividing cells including primary macrophages, albeit less efficiently than the parental virus (Dvorin et al, 2002;Limon et al, 2002b). Viral proteins are also involved in the nuclear transport of HIV-1 PIC (Fouchier and Malim, 1999).…”

Section: Nuclear Importmentioning

confidence: 99%

Macrophages and HIV-1: dangerous liaisons

Verani¹,

Gras

Pancino

2005

Molecular Immunology

102

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“…Circular DNA forms are considered to be useful indicators of viral DNA entry into the nucleus (4) but as dead-end products (nonproductive pathway) (5,17,30). Similar molecules are found in the nuclei of HIV-infected cells, both in vitro and in vivo (15,24), but this observation was recently challenged by the hypothesis that the use of LTR circle formation as a marker of virus-mediated nuclear import may be less definitive than was previously thought (14). Recently, the episomal two-LTR circles formed during a single round of HIV-1 replication were found to persist indefinitely in a transformed CD4 ϩ T-cell line (35) and in SupT1 lymphoid cells (8), decreasing in concentration only as a function of dilution resulting from cell division.…”

Section: Discussionmentioning

confidence: 98%

“…Other factors contributing to the nuclear import of HIV, such as the presence of the central DNA flap (PPTc) and a valine residue at position 165 in the nuclear localization signal of IN, were recently reported (1,53). However, the contributions of these factors are still controversial (14,29).…”

mentioning

confidence: 99%

Early Detection of a Two-Long-Terminal-Repeat Junction Molecule in the Cytoplasm of Recombinant Murine Leukemia Virus-Infected Cells

Serhan

Penaud

Petit

et al. 2004

J Virol

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We showed that a U5-U3 junction was reproducibly detected by a PCR assay as early as 1 to 2 h postinfection with a DNase-treated murine leukemia virus (MLV)-containing supernatant in aphidicolin-arrested NIH 3T3 cells, as well as in nonarrested cells. Such detection is azidothymidine sensitive and corresponded to neosynthesized products of the reverse transcriptase. This observation was confirmed in two additional human cell lines, TE671 and ARPE-19. Using cell fractionation combined with careful controls, we found that a two-longterminal-repeat (two-LTR) junction molecule was detectable in the cytoplasm as early as 2 h post virus entry. Altogether, our data indicated that the neosynthesized retroviral DNA led to the early formation of structures including true two-LTR junctions in the cytoplasm of MLV-infected cells. Thus, the classical assumption that two-LTR circles are a mitosis-dependent dead-end product accumulating in the nucleus must be reconsidered. MLV-derived products containing a two-LTR junction can no longer be used as an exclusive surrogate for the preintegration complex nuclear translocation event.

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Reassessment of the Roles of Integrase and the Central DNA Flap in Human Immunodeficiency Virus Type 1 Nuclear Import

Cited by 139 publications

References 40 publications

Integrase, LEDGF/p75 and HIV replication

Integrase, LEDGF/p75 and HIV replication

Macrophages and HIV-1: dangerous liaisons

Early Detection of a Two-Long-Terminal-Repeat Junction Molecule in the Cytoplasm of Recombinant Murine Leukemia Virus-Infected Cells

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