Coupled Integration of Human Immunodeficiency Virus Type 1 cDNA Ends by Purified Integrase In Vitro: Stimulation by the Viral Nucleocapsid Protein

Carteau, Sandrine; Gorelick, Robert J.; Bushman, Frederic D.

doi:10.1128/jvi.73.8.6670-6679.1999

Cited by 163 publications

(51 citation statements)

References 59 publications

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“…Several studies have explored the association between nucleosome packaging and integration bias. Early studies suggesting a loose association of retroviral integration sites with chromosomal sites sensitive to DNAseI digestion (reviewed in (16,19,20,34)), which led to the idea that packaging DNA in nucleosomes would inhibit integration. However, once assays were available that recapitulated integration in vitro, nucleosomal wrapping was found instead to favor integration (110)(111)(112)(113)(114).…”

Section: Retroviral Integration and Nucleosomal Associationmentioning

confidence: 99%

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Craigie

Bushman

2015

Mobile DNA III

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In order to replicate, a retrovirus must integrate a DNA copy of the viral RNA genome into a chromosome of the host cell. The study of retroviral integration has advanced considerably in the last few years. Here we focus on host factor interactions and the linked area of integration targeting. Genome-wide screens for cellular factors affecting HIV replication have identified a series of host cell proteins that may mediate subcellular trafficking of integration complexes, nuclear import, and integration target site selection. The cell transcriptional co-activator protein LEDGF/p75 has been identified as a tethering factor important for HIV integration, and recently, BET proteins (Brd2, 4, and 4) have been identified as tethering factors for the gammaretroviruses. A new class of HIV inhibitors has been developed targeting the HIV-1 IN-LEDGF binding site, though surprisingly these inhibitors appear to block assembly late during replication and do not act at the integration step. Going forward, genome-wide studies of HIV-host interactions offer many new starting points to investigate HIV replication and identify potential new inhibitor targets.

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Section: Retroviral Integration and Nucleosomal Associationmentioning

confidence: 99%

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Craigie

Bushman

2015

Mobile DNA III

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“…The mature NC protein, which is released in a late cleavage reaction (Swanstrom and Wills, 1997), plays a major role in assuring the specificity and efficiency of reverse transcription (reviewed in Bampi et al, 2004;Darlix et al, 1995;Levin et al, 2005;Rein et al, 1998; and is also important for other events in the virus life-cycle including maturation of the genomic RNA dimer (Feng et al, 1996;Muriaux et al, 1996) and integration of proviral DNA into the host genome (Carteau et al, 1999;Thomas et al, 2006). NC's function in virus replication is correlated with its ability to act as a nucleic acid chaperone.…”

Section: Introductionmentioning

confidence: 99%

Fundamental differences between the nucleic acid chaperone activities of HIV-1 nucleocapsid protein and Gag or Gag-derived proteins: Biological implications

Datta

Mitra

et al. 2010

Virology

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The HIV-1 Gag polyprotein precursor has multiple domains including nucleocapsid (NC). Although mature NC and NC embedded in Gag are nucleic acid chaperones (proteins that remodel nucleic acid structure), few studies include detailed analysis of the chaperone activity of partially processed Gag proteins and comparison with NC and Gag. Here we address this issue by using a reconstituted minus-strand transfer system. NC and NC-containing Gag proteins exhibited annealing and duplex destabilizing activities required for strand transfer. Surprisingly, unlike NC, with increasing concentrations, Gag proteins drastically inhibited the DNA elongation step. This result is consistent with “nucleic acid-driven multimerization” of Gag and the reported slow dissociation of Gag from bound nucleic acid, which prevent reverse transcriptase from traversing the template (“roadblock” mechanism). Our findings illustrate one reason why NC (and not Gag) has evolved as a critical cofactor in reverse transcription, a paradigm that might also extend to other retrovirus systems.

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“…Additional results by Gorelick et al also indicated that the integration reaction was impaired (Buckman et al, 2003;Thomas et al, 2006), supporting the view that functional interactions exist between NC and IN as it stands between NC and RT since mutating the ZF strongly diminish NC-RT interactions (Druillennec et al, 1999a;Lener et al, 1998). The existence of critical interactions between NC and IN is further supported by the fact that NC can strongly stimulate concerted LTR DNA integration by IN under physiological conditions in vitro (Buckman et al, 2003;Carteau et al, 1997Carteau et al, , 1999Poljak et al, 2003;Thomas et al, 2006).…”

Section: Impacts Of Zinc Finger Mutations On Viral Dna Synthesis and mentioning

confidence: 71%

Retrospective on the all-in-one retroviral nucleocapsid protein

et al. 2014

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This review aims at briefly presenting a retrospect on the retroviral nucleocapsid protein (NC), from an unspecific nucleic acid binding protein (NABP) to an all-in-one viral protein with multiple key functions in the early and late phases of the retrovirus replication cycle, notably reverse transcription of the genomic RNA and viral DNA integration into the host genome, and selection of the genomic RNA together with the initial steps of virus morphogenesis. In this context we will discuss the notion that NC protein has a flexible conformation and is thus a member of the growing family of intrinsically disordered proteins (IDPs) where disorder may account, at least in part, for its function as a nucleic acid (NA) chaperone and possibly as a protein chaperone vis-à-vis the viral DNA polymerase during reverse transcription. Lastly, we will briefly review the development of new anti-retroviral/AIDS compounds targeting HIV-1 NC because it represents an ideal target due to its multiple roles in the early and late phases of virus replication and its high degree of conservation.

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Coupled Integration of Human Immunodeficiency Virus Type 1 cDNA Ends by Purified Integrase In Vitro: Stimulation by the Viral Nucleocapsid Protein

Cited by 163 publications

References 59 publications

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Host Factors in Retroviral Integration and the Selection of Integration Target Sites

Fundamental differences between the nucleic acid chaperone activities of HIV-1 nucleocapsid protein and Gag or Gag-derived proteins: Biological implications

Retrospective on the all-in-one retroviral nucleocapsid protein

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