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At least 1,693 records · Page 94Linked to original sources
PubMed1999

HIV-1 nuclear import: in search of a leader.

The ability of HIV-1 to use host cell nuclear import machinery to translocate the viral pre-integration complex into the cell nucleus is the critical determinant in the replication of the virus in non-dividing cells, such as macrophages. In this review, we describe the viral and cellular factors involved in this process. The available data suggest that the process of HIV-1 nuclear import is driven by interaction between nuclear localization signals (NLSs) present on viral proteins matrix and integrase and the cellular NLS receptor, karyopherin alpha. However, this interaction by itself is weak and insufficient to insure effective import of the pre-integration complex. Viral protein R (Vpr) functions to increase the affinity of interaction between viral NLSs and karyopherin alpha, thus substantially enhancing the karyophilic potential of the pre-integration complex. Interestingly, some cells, in particular HeLa, seem to contain a factor that can substitute for the Vpr's activity, making HIV-1 replication in such cells Vpr-independent. We also describe a class of novel anti-HIV compounds that target the NLSs of HIV-1 and effectively block viral replication in T cells and macrophages.

Biological Transport↗
PubMed1999

The Yersinia high-pathogenicity island.

A pathogenicity island present only in highly pathogenic strains of Yersinia (Y. enterocolitica 1B, Y. pseudotuberculosis I and Y. pestis) has been identified on the chromosome of Yersinia spp. and has been designated High-Pathogenicity Island (HPI). The Yersinia HPI carries a cluster of genes involved in the biosynthesis, transport and regulation of the siderophore yersiniabactin. The major function of this island is thus to acquire iron molecules essential for in vivo bacterial growth and dissemination. The presence of an integrase gene and att sites homologous to those of phage P4, together with a G + C content much higher than the chromosomal background, suggests that the HPI is of foreign origin and has been acquired by chromosomal integration of a phage. The HPI can excise from the chromosome of Y. pseudotuberculosis and is found inserted into any of the three copies of the asn tRNA loci present in this species. A unique characteristic of the HPI is its wide distribution in various enterobacteria. Although first identified in Yersinia spp., it has subsequently been detected in other genera such as E. coli, Klebsiella and Citrobacter.

Bacteriophages↗
PubMed2002

[Molecular mechanism of HIV-1 replication].

Host factors that associate retrovirus replication also play an important role in regulating cellular physiological conditions. Therefore, a discovery of HIV related cellular proteins might open up understanding mechanisms for essential cellular machinery. Recent advances in biotechnology have shed new light on the molecular mechanism of HIV replication. We choose three topics about HIV replication and discuss them; a role of ubiquitin and vacuolar protein sorting pathway during virus budding, new players, integrase and central DNA flap, that regulate the translocation of preintegration complex into nucleus, and a relationship between basic model for core formation and fullerene molecule.

Cell Nucleus↗
PubMed2002

[Progress in the study of the structure and function of Cre recombinase].

The Cre recombinase, an integrase from bacteriophage P1, catalyzes site-specific recombination between 34-bp repeats termed loxP sites, in the absence of any additional cofactors and energy. Mediated by Cre recombinase, specific DNA fragments can be excised, inversed or integrated depending on the orientation or position of loxP sites in vitro or in vivo. Because of its simplicity and high efficiency, Cre/loxP site-specific recombination system has been widely used in gene deletion and function identification, gene site-specific integration, gene trapping and chromosome engineering. It has been used as a useful tool for DNA recombination in transgenic yeast, plants, insects and mammals. Here progress in the study of the structure and function of Cre recombinase is discussed.

Integrases↗
PubMed2003

New hope from new classes of therapy.

A number of very interesting new drugs were discussed in sessions at Barcelona. Two represent new classes of therapy--entry inhibitors and integrase inhibitors--while others seek to offer improvements over drugs in existing classes. Both are welcome advances.

Anti-HIV Agents↗
PubMed2003

S-1360 Shionogi-GlaxoSmithKline.

Shionogi and GlaxoSmithKline, as the joint venture company Shionogi-GlaxoSmithKline Pharmaceuticals, is developing S-1360, an HIV integrase inhibitor as a potential treatment for HIV infection. As of October 2002, phase II trials were ongoing and launch is expected in 2004/2005.

Anti-HIV Agents↗
PubMedDate not supplied

Integration site selection by retroviruses.

Integration into the host-cell genome is a critical step in the retrovirus life cycle. In particular, the choice of the integration site is crucial for retroviral replication, since integration at a site incompatible for high-level transcription may impair production of the progeny virus. Integration is not sequence specific, thus all chromosomal sites could potentially host integration events. However, this is not what is observed in vivo, where integrated viruses are preferentially detected in chromatin regions characterized by an open structure, a hallmark of actively transcribed genes. Target site selection might be influenced by several factors, including the function of cellular proteins that interact with integrase, the viral protein that catalyzes the integration reaction. Interestingly, a common functional feature that unifies these cellular co-factors is that, to a different extent, they are all involved in the regulation of chromatin structure or transcription. Inappropriate retroviral integration might lead to insertional mutagenesis and cellular transformation, as recently observed in a gene therapy clinical trial exploiting retroviral vectors for gene transfer into hematopoietic progenitors. Thus, the deeper understanding of the molecular mechanisms regulating integration site selection is also essential for the design of safer and more effective gene transfer vectors.

Chromatin↗
PubMed2004

Transposition of IntAs into the conserved regions of IS3 family elements.

Together with the previous reports, my computer survey revealed that several bacteria contain six copies of the type group II intron IntA. The sequence analysis of IntAs showed the high level of homology in the nucleotide sequence (91.9-99.8%). The consensus sequence, 2,270 base pair long, was derived from the nucleotide sequences of all IntA members. The size of the open reading frame intA was 502 amino acids long, that is homologous to reverse transcriptase-like proteins encoded within the group II introns. It was reported that EPEC.IntA and Sf.IntA were inserted into IS911 and IS629, respectively. The sequence of the flanking region IntA was analyzed here. The data show the insertion of EC.IntA into IS629, the insertion of EHEC.IntA into IS3, the insertion of Yp.IntA into IS904-like sequence, and the insertion of EK12.IntA into IS911. Interestingly, these IS elements nested by IntAs were the members of IS3 family elements. The sequences of the IS3 members correspond to the OrfB with the DDE motif conserved in retroviral integrases. Alignment of the flanking sequences of IntAs revealed that the flanking regions -25 to +10 of insertion sites, that are generally believed to be required for the retrohoming, were not strongly conserved. The data presented here suggests that the retrohoming pathway of IntA seems to differ from those of other group II introns.

Amino Acid Motifs↗
PubMed2004

[Integrons].

The development of antimicrobial resistance has led to the discovery of many natural mobile elements like transposons and conjugative plasmids. Integrons are carried on plasmids and transposons that potentially increase the dissemination of antibiotic resistance genes among bacterial species. Integrons are genetic elements containing the determinants of a site-specific recombination system. These DNA elements mediate the integration of antibiotic resistance genes into bacteria through the site-specific recombination. Integrons consist of an integrase gene (intl), a recombination site (attl), and one or two promoters responsible for expression of the inserted gene cassettes. Class 1 integrons are the most commonly studied and largely implicated type in the dissemination of antibiotic resistance among clinical isolates. In the last few years, a variety of new gene cassettes coding antibiotic resistance have been described. Having the ability of horizontal transfer of antibiotic resistance genes between interspecies of bacteria, integrons play a dominant role in the development of multiresistance in Enterobacteriaceae. In this review article, classification, structure and expression, epidemiology and clinical importance of integrons, has been discussed.

Drug Resistance, Bacterial↗
PubMedDate not supplied

A hard way to the nucleus.

As a member of the Retrovirus family, human immunodeficiency virus (HIV), a causative agent of AIDS, replicates by integrating its genome into the host cell's nuclear DNA. However, in contrast to most retroviruses that depend on mitotic dissolution of the nuclear envelope to gain access to the host cell's genome, the HIV pre-integration complex can enter the nucleus of the target cell during the interphase. Such capacity greatly enhances HIV replication and allows the virus to productively infect terminally differentiated nonproliferating cells, such as macrophages. Infection of macrophages is a critical factor in the pathogenesis of diseases caused by HIV-1 and other lentiviruses. The mechanisms responsible for this unusual feature of HIV have enticed researchers since the early 90s, when the first characterization of the HIV-1 pre-integration complex was reported. Several viral factors, including matrix protein, integrase, viral protein R, and central DNA flap, have been proposed as regulators of HIV-1 nuclear import, only to be later shown as nonessential for this process. As a result, after more than a decade of intense research, there is still no consensus on which HIV-1 and cellular proteins control this critical step in HIV-1 replication. In this review, we will discuss recent advances and suggest possible solutions to the controversial issue of HIV-1 nuclear import.

Biological Transport↗
PubMed2005

Targeting site-specific chromosome integration.

The concept of gene therapy was introduced with great promise and high expectations. However, what appeared simple in theory has not translated into practice. Despite some success in clinical trials, the research community is still facing an old problem: namely, the need for a vector that can deliver a gene to target cells without adverse events while maintaining a long-term therapeutic effect. Some of these challenges are being addressed by the development of hybrid vectors which meld two different viral systems to incorporate efficient gene delivery and large cloning capacity with site-specific integration. The two known systems that integrate genes into specific sites in mammalian genomes are the adeno-associated virus and phage integrases. Recent experiments with hybrid vectors incorporating both of these systems are encouraging. However, extensive research should be directed towards the safety and efficacy of this approach before it will be available for gene therapy.

Animals↗
PubMed2005

New targets and new drugs in the treatment of HIV.

Antiretroviral treatment has modified the course of human immunodeficiency virus (HIV) infection transforming it into a chronic disease. However, as treatment is conceived "for life", more effective and safety drugs, overcoming the growing resistance of the virus are required. New molecules may block the known viral targets or other new ones. The mechanism of the virus union and entrance to the cell includes the new therapeutic targets that are studied more frequently. Although studies with substances that efficiently block the virus-CD4 receptors union are in very early phases, other studies of molecules capable to block the entrance co-receptors are in more advanced phases (II or III), and enfuvirtide, a substance that blocks membrane fusion, the last phase of virus entrance, has been recently marketed. Another very promising pharmacological target is the integration of the proviral DNA as we know some substances that in vitro block HIV integrase. Besides this, new drugs are increasing the three classic antiretroviral families. Among nucleoside analogs emtricitabine (recently marketed) and amdoxovir are the more prominent. Capravirine and TMC-125 are the non-nucleoside analogs whose studies are more advanced. And atazanavir, fos-amprenavir, tipranavir and TMC-114 are the new protease inhibitors recently marketed or near to be.

Anti-HIV Agents↗
PubMed2005

[New drugs--hope for salvage patients?].

New and potent drugs are urgently needed for the salvage therapy of HIV-infected patients. The protease inhibitors Tipranavir and TMC114, which have high potency against multidrug-resistant viral strains, are the most promising drugs for the near future. How important they will be in salvage therapy cannot be predicted at this time. New points of attack in the viral replication cycle have been defined. Substances belonging to the groups of integrase and maturation inhibitors are in the early stages of clinical development.

Anti-HIV Agents↗
PubMed2006

[Molecular typing of the Burkholderia pseudomallei strains with different resistance to antibiotics].

Wild type strains of Burkholderia pseudomallei, spontaneous mutants with high resistance to fluoroquinolones and ceftazidime, and Tn5-induced mutants with reduced resistance level were studied using polymorphic and gene-specific DNA fingerprinting. Cluster analysis of genomic DNA patterns obtained using PCR with arbitrary primer (5'-GTTTCGCTCC-3') and primer specific to the class I integrase intll gene (5'-CCTCCCGCACGATGATC-3') was performed. According to the DNA pattern conformity, the distinct groups submitted by high-level resistant B. pseudomallei derivatives were revealed by both typing approaches. The obtained results may be useful in searching for molecular markers associated with different types of antimicrobial resistance among pathogenic and related burkholderiae.

Anti-Bacterial Agents↗
PubMed1991

Recombination and modular exchange in the genesis of new lambdoid phages.

Comparison of the nucleotide sequence of the integrase genes of lambdoid phages 21 and 434 with the published sequences of phages HK022 and lambda shows that lambda and 434 are very closely related (98% base sequence identity), whereas HK022 and 21 respectively show 73% and 48% identity to lambda. It is likely that several homologous recombination events occurred in the int gene and flanking DNA among the progenitors of these phages. Sequence divergence to different alternative sequences at a common site (tL4) suggests that tL4 has been repeatedly used as a recombination site, despite the very limited homology it provides. A minor constitutive transcript that terminates at tL4 of lambda has been identified. We propose that the principal selective force acting to conserve tL4 is for terminator function, but that the use of tL4 as a recombination site has allowed the formation of selectively favored recombinants. By extension, we suggest that conservation of microhomologies at functional sites serves to keep lambdoid phages within a common gene pool despite extensive drift and divergence.

Bacteriophage lambda↗
PubMed1991

Escherichia coli XerC recombinase is required for chromosomal segregation at cell division.

XerC is a site-specific recombinase of the bacteriophage lambda integrase family that is encoded by xerC at 3700 kbp on the genetic map of Escherichia coli. The protein was originally identified through its role in converting multimers of plasmid ColE1 to monomers; only monomers are stably inherited. Here we demonstrate that XerC also has a role in the segregation of replicated chromosomes at cell division. xerC mutants form filaments with aberrant nucleotides that appear unable to partition correctly. A DNA segment (dif) from the replication terminus region of the E. coli chromosome binds XerC and acts as a substrate for XerC-mediated site-specific recombination when inserted into multicopy plasmids. This dif segment contains a region of 28 bp with sequence similarity to the crossover region of ColE1 cer. The cell division phenotype of xerC mutants is suppressed in strains deficient in homologous recombination, suggesting that the role of XerC/dif in chromosomal metabolism is to convert any chromosomal multimers (arising through homologous recombination) to monomers.

Aminopeptidases↗
PubMed1994

Structure of the P22 att site. Conservation and divergence in the lambda motif of recombinogenic complexes.

We have defined the bacterial and viral DNA targets (att sites) of P22 site-specific recombination and characterized their interaction with integrase (Int) protein. The bacterial DNA target, attB, is approximately 27 base pairs and consists of two core type Int binding sites as inverted repeats. The top and bottom Int cleavage sites fall within the core type Int binding sites and are separated by a 7-base pair overlap region. A similar core region is found in the viral DNA target, attP, which is approximately 260 base pairs long and contains two IHF binding sites and five arm type binding sites for Int. The results suggest that P22 Int, like lambda Int, is a heterobivalent DNA-binding protein that is capable of forming complex higher order structures with recombinogenic function. Although P22 and lambda recombination involve very similar multiprotein interactions and core region structures, there are significant differences in the arrangements of distal protein binding sites. These differences are discussed in terms of the possible flexibility of the Int protein and the specificity with which the higher order complexes assemble and/or function.

Attachment Sites, Microbiological↗
PubMedDate not supplied

Roles of electrospray mass spectrometry, counterion distribution monitoring and N-(2-hydroxy-4-methoxybenzyl) backbone protection in peptide synthesis.

The synthesis of a 36-residue fragment of HIV integrase by standard Fmoc-polyamide chemistry was unsuccessful (Trt-protected Cys) or difficult (Acm-protected Cys); after 10-12 couplings, deprotection became hindered and a major portion (30%-50%) of the growing peptide chains became inaccessible to reagents. The synthesis was repeated using N-(2-hydroxy-4-methoxybenzyl) (Hmb) backbone protection at two strategic positions in the sequence, and Acm protection of Cys. The synthesis was trouble-free and progressed smoothly to completion. Electrospray mass spectrometric analysis at each step of the cleavage and purification showed that Hmb groups become O-acetylated during treatment of the peptide with acetic anhydride in the presence of tertiary base. The acetylated Hmb was refractory to cleavage with TFA/scavenger mixtures but could be readily removed following deacetylation with piperidine. The target peptide was purified to > 98% purity and an overall yield of 15%.

Amino Acid Sequence↗