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Interactions of host proteins with the murine leukemia virus integrase.

Studamire B, Goff SP - Viruses (2010)

Bottom Line: Host factors are widely anticipated to be involved in all stages of the retroviral life cycle, and the identification of integrase interacting factors has the potential to increase our understanding of mechanisms by which the incoming virus might appropriate cellular proteins to target and capture host DNA sequences.Identification of MoMLV integrase interacting host factors may be key to designing efficient and benign retroviral-based gene therapy vectors; key to understanding the basic mechanism of integration; and key in designing efficient integrase inhibitors.In this review, we discuss current progress in the field of MoMLV integrase interacting proteins and possible roles for these proteins in integration.

View Article: PubMed Central - PubMed

Affiliation: Brooklyn College of the City University of New York, Department of Biology, 2900 Bedford Avenue, Brooklyn, NY 11210, USA; bstudamire@brooklyn.cuny.edu.

ABSTRACT
Retroviral infections cause a variety of cancers in animals and a number of diverse diseases in humans such as leukemia and acquired immune deficiency syndrome. Productive and efficient proviral integration is critical for retroviral function and is the key step in establishing a stable and productive infection, as well as the mechanism by which host genes are activated in leukemogenesis. Host factors are widely anticipated to be involved in all stages of the retroviral life cycle, and the identification of integrase interacting factors has the potential to increase our understanding of mechanisms by which the incoming virus might appropriate cellular proteins to target and capture host DNA sequences. Identification of MoMLV integrase interacting host factors may be key to designing efficient and benign retroviral-based gene therapy vectors; key to understanding the basic mechanism of integration; and key in designing efficient integrase inhibitors. In this review, we discuss current progress in the field of MoMLV integrase interacting proteins and possible roles for these proteins in integration.

No MeSH data available.


Related in: MedlinePlus

Early events in MLV infection leading to the production of the integrated provirus. Virions deliver a viral core particle into the cytoplasm, which carries out the process of reverse transcription to form the Pre-Integration Complex or PIC, containing the Integrase enzyme (red) bound to the termini of the Long Terminal Repeats or LTRs (grey boxes) of the viral DNA (green helix). The PIC enters the nucleus, likely via the dispersion of the nuclear membrane during mitosis. The incoming DNA is then integrated into the host genome (blue helix). DNAs that fail to integrate are often circularized by host repair enzymes to form circular DNAs with one or two copies of the viral LTRs.
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f1-viruses-02-01110: Early events in MLV infection leading to the production of the integrated provirus. Virions deliver a viral core particle into the cytoplasm, which carries out the process of reverse transcription to form the Pre-Integration Complex or PIC, containing the Integrase enzyme (red) bound to the termini of the Long Terminal Repeats or LTRs (grey boxes) of the viral DNA (green helix). The PIC enters the nucleus, likely via the dispersion of the nuclear membrane during mitosis. The incoming DNA is then integrated into the host genome (blue helix). DNAs that fail to integrate are often circularized by host repair enzymes to form circular DNAs with one or two copies of the viral LTRs.

Mentions: Following entry into the cytoplasm and DNA synthesis, the linear viral DNA ends are processed by integrase, which typically removes two terminal nucleotides at the 3′ ends of the long terminal repeats (LTRs). The number of nucleotides removed may vary between viruses (HIV-2 IN removes three, although this is a rare exception), as does whether or not both LTR ends are processed (i.e., foamy virus) [25,26]. Moloney murine leukemia virus produces recessed 3′ OH termini with the release of a dinucleotide at each end of the LTR [27–29]. The subsequent steps of integration have been well characterized in vitro: generally, the two free 3′-OH linear viral DNA ends, in a concerted nucleophilic attack on the host DNA, covalently join the viral and host DNA strands, leaving a gapped intermediate with free 5′-phosphodiester viral DNA ends which are repaired by host enzymes (Figure 1) [28,30]. Although the basic retroviral integration mechanism is clear, it has been challenging to identify and characterize those cofactors that will exhibit both a significant influence on viral integration events, as well as an effect on targeting. Furthermore, those few factors that have both direct interactions with integrase and exhibit effects on viral replication are primarily effective on lentiviruses [31,32]. Thus, for the simple retroviruses such as MoMLV, proteins playing equivalent roles in integration remain even more elusive. In addition, significant questions remain regarding the influence of host proteins on import of the PIC, on the selection of target sites, on the repair of integration intermediates, and on proteins affecting the efficiency of integration.


Interactions of host proteins with the murine leukemia virus integrase.

Studamire B, Goff SP - Viruses (2010)

Early events in MLV infection leading to the production of the integrated provirus. Virions deliver a viral core particle into the cytoplasm, which carries out the process of reverse transcription to form the Pre-Integration Complex or PIC, containing the Integrase enzyme (red) bound to the termini of the Long Terminal Repeats or LTRs (grey boxes) of the viral DNA (green helix). The PIC enters the nucleus, likely via the dispersion of the nuclear membrane during mitosis. The incoming DNA is then integrated into the host genome (blue helix). DNAs that fail to integrate are often circularized by host repair enzymes to form circular DNAs with one or two copies of the viral LTRs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3104679&req=5

f1-viruses-02-01110: Early events in MLV infection leading to the production of the integrated provirus. Virions deliver a viral core particle into the cytoplasm, which carries out the process of reverse transcription to form the Pre-Integration Complex or PIC, containing the Integrase enzyme (red) bound to the termini of the Long Terminal Repeats or LTRs (grey boxes) of the viral DNA (green helix). The PIC enters the nucleus, likely via the dispersion of the nuclear membrane during mitosis. The incoming DNA is then integrated into the host genome (blue helix). DNAs that fail to integrate are often circularized by host repair enzymes to form circular DNAs with one or two copies of the viral LTRs.
Mentions: Following entry into the cytoplasm and DNA synthesis, the linear viral DNA ends are processed by integrase, which typically removes two terminal nucleotides at the 3′ ends of the long terminal repeats (LTRs). The number of nucleotides removed may vary between viruses (HIV-2 IN removes three, although this is a rare exception), as does whether or not both LTR ends are processed (i.e., foamy virus) [25,26]. Moloney murine leukemia virus produces recessed 3′ OH termini with the release of a dinucleotide at each end of the LTR [27–29]. The subsequent steps of integration have been well characterized in vitro: generally, the two free 3′-OH linear viral DNA ends, in a concerted nucleophilic attack on the host DNA, covalently join the viral and host DNA strands, leaving a gapped intermediate with free 5′-phosphodiester viral DNA ends which are repaired by host enzymes (Figure 1) [28,30]. Although the basic retroviral integration mechanism is clear, it has been challenging to identify and characterize those cofactors that will exhibit both a significant influence on viral integration events, as well as an effect on targeting. Furthermore, those few factors that have both direct interactions with integrase and exhibit effects on viral replication are primarily effective on lentiviruses [31,32]. Thus, for the simple retroviruses such as MoMLV, proteins playing equivalent roles in integration remain even more elusive. In addition, significant questions remain regarding the influence of host proteins on import of the PIC, on the selection of target sites, on the repair of integration intermediates, and on proteins affecting the efficiency of integration.

Bottom Line: Host factors are widely anticipated to be involved in all stages of the retroviral life cycle, and the identification of integrase interacting factors has the potential to increase our understanding of mechanisms by which the incoming virus might appropriate cellular proteins to target and capture host DNA sequences.Identification of MoMLV integrase interacting host factors may be key to designing efficient and benign retroviral-based gene therapy vectors; key to understanding the basic mechanism of integration; and key in designing efficient integrase inhibitors.In this review, we discuss current progress in the field of MoMLV integrase interacting proteins and possible roles for these proteins in integration.

View Article: PubMed Central - PubMed

Affiliation: Brooklyn College of the City University of New York, Department of Biology, 2900 Bedford Avenue, Brooklyn, NY 11210, USA; bstudamire@brooklyn.cuny.edu.

ABSTRACT
Retroviral infections cause a variety of cancers in animals and a number of diverse diseases in humans such as leukemia and acquired immune deficiency syndrome. Productive and efficient proviral integration is critical for retroviral function and is the key step in establishing a stable and productive infection, as well as the mechanism by which host genes are activated in leukemogenesis. Host factors are widely anticipated to be involved in all stages of the retroviral life cycle, and the identification of integrase interacting factors has the potential to increase our understanding of mechanisms by which the incoming virus might appropriate cellular proteins to target and capture host DNA sequences. Identification of MoMLV integrase interacting host factors may be key to designing efficient and benign retroviral-based gene therapy vectors; key to understanding the basic mechanism of integration; and key in designing efficient integrase inhibitors. In this review, we discuss current progress in the field of MoMLV integrase interacting proteins and possible roles for these proteins in integration.

No MeSH data available.


Related in: MedlinePlus