Transcriptional Coactivator LEDGF/p75 Modulates Human Immunodeficiency Virus Type 1 Integrase-Mediated Concerted Integration

Pandey, Krishan K.; Sinha, Sapna; Grandgenett, Duane P.

doi:10.1128/jvi.02322-06

Cited by 55 publications

(100 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The interaction between p75 and IN is direct [73] and it is confined to only one of the seven retroviral genera, lentivirinae [75,87,100]. A number of laboratories established the role of p75 in chromatin tethering, mapped relevant functional domains, and worked to answer the question of virological relevance [74][75][76][77][78][79][80][81][82][85][86][87][88][89][90][91]93,[95][96][97][100][101][102][103][104][105][108][109][110]. The first indication of the protein's significance was the clarification it provided about the vexing issue of the intracellular trafficking of retroviral integrase proteins.…”

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 99%

“…Since achieving the full-site reaction in vitro is thought to require the tetrameric form of the enzyme while the dimer mediates half-site integration [154,157,158], properly coupled joining may require that p75 binding occur after assembly of a mature "synaptic complex" in which tetrameric HIV-1 IN is complexed to the viral cDNA ends [104]. A note of complexity was added by Pandey et al, who found that full site integration by HIV IN was promoted at lower p75 concentrations but inhibited at higher concentrations [103].…”

Section: Modeling P75 Function In the Hiv Life Cyclementioning

confidence: 99%

See 1 more Smart Citation

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

113

104

View full text Add to dashboard Cite

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.

show abstract

Section: Interaction With Lentiviral Integrase Proteins and The Traffmentioning

confidence: 99%

Section: Modeling P75 Function In the Hiv Life Cyclementioning

confidence: 99%

Integrase, LEDGF/p75 and HIV replication

Poeschla

2008

Cell. Mol. Life Sci.

113

104

View full text Add to dashboard Cite

show abstract

“…34 Essa proteína é encontrada na célula do hospedeiro e funciona como um importante cofator da replicação viral, exercendo papel fundamental na interação da integrase com o cromossomo do hospedeiro, estimulando a integração concertada do DNA viral. 35,36 Após o processamento do terminal-3' do DNA viral, a integrase permanece ligada a cada uma dessas regiões finais, formando o complexo de pré-integração. A integrase liga-se, então, à proteína LEDGF/p75, que irá transportar o complexo até o núcleo onde ocorre a transferência de cadeia.…”

Section: Classe Das 8-hidroxiquinolinasunclassified

Integrase: An Important Therapeutic Target in the Fight Against HIV/AIDS Infection

Santos¹,

Albuquerque²,

Brito³

2014

Revista Virtual De Química

View full text Add to dashboard Cite

Among all the HIV enzymes, integrase is responsible for the insertion of viral DNA in the host DNA. The aim of this article is to describe the integrase inhibitors drugs and report cases of resistance, in addition to discussing new promising compounds that are being evaluated as integrase inhibitors. Currently, there are only three drugs in clinical use that belong to the class of integrase inhibitors: raltegravir (a pirimidinone carboxamide derivative, elvitegravir (a quinoline derivative) and dolutegravir (a diazatricyclo carboxamide derivative). However, several cases of resistance to drugs of this class are described in the literature, and the mutations of the enzyme responsible for such profile are known. Many compounds with integrase inhibitory action are under development. The use of the integrase enzyme as a target against HIV/AIDS infection is promising. In addition, the integration is a complex stage of the viral replication cycle, and new details of this process are being discovered every minute, which encourages the accomplishment of more studies for the development of new drugs of this class. Keywords: Drugs; integrase; HIV/AIDS. ResumoA síndrome da imunodeficiência humana adquirida (AIDS, acquired immunodeficiency syndrome) é causada pelo vírus da imunodeficiência humana (HIV, human immunodeficiency virus) que infecta as células do sistema imune, destruindo-as ou causando prejuízos ao seu funcionamento. Dentre as enzimas do HIV, a integrase é responsável pela inserção do DNA viral no DNA do hospedeiro. O objetivo desse artigo é descrever os fármacos inibidores de integrase e relatar os casos de resistência, além de discutir novos compostos promissores que estão sendo avaliados como inibidores de integrase. Atualmente, existem apenas três fármacos em uso clínico pertencentes à classe dos inibidores de integrase: raltegravir (um derivado pirimidinona carboxamida), elvitegravir (um derivado quinolina) e dolutegravir (um derivado diazatriciclo carboxamida). Entretanto, diversos casos de resistência a estes fármacos são descritos na literatura e as mutações da enzima responsáveis por este perfil são conhecidas. Muitos compostos com ação inibidora de integrase estão em desenvolvimento. A utilização da enzima integrase como alvo no combate ao vírus HIV mostra-se promissora. Além disso, a integração é uma etapa complexa do ciclo de replicação viral e novos detalhes desse processo têm sido descobertos a todo instante, o que estimula a realização de mais estudos para o desenvolvimento de novos fármacos desta classe.Palavras-chave: Fármaco; integrase; HIV/AIDS.

show abstract

“…Results of chemical cross-linking (48), solution biochemistry (24,25,49,50), and structure-based approaches (18,43,51) confirm that a tetramer of IN catalyzes DNA strand transfer activity, although somewhat less clear is the multimeric nature of the 3Ј-processing protagonist. Although a dimer of IN may suffice to process an individual LTR end in vitro (48,52), some substitutions that affect the ability of HIV-1 IN to tetramerize compromise 3Ј-processing activity severely (31).…”

Section: Retroviral In-dna Nucleoprotein Complexesmentioning

confidence: 99%

Retroviral Integrase Proteins and HIV-1 DNA Integration

Krishnan

Engelman

2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Retroviral integrases catalyze two reactions, 3-processing of viral DNA ends, followed by integration of the processed ends into chromosomal DNA. X-ray crystal structures of integrase-DNA complexes from prototype foamy virus, a member of the Spumavirus genus of Retroviridae, have revealed the structural basis of integration and how clinically relevant integrase strand transfer inhibitors work. Underscoring the translational potential of targeting virus-host interactions, small molecules that bind at the host factor lens epithelium-derived growth factor/ p75-binding site on HIV-1 integrase promote dimerization and inhibit integrase-viral DNA assembly and catalysis. Here, we review recent advances in our knowledge of HIV-1 DNA integration, as well as future research directions.Retroviral replication proceeds through an obligate proviral or integrated DNA recombination intermediate. Integration provides a favorable environment for efficient gene expression, ensures inheritance of the virus in both daughter cells during mitosis, and forms the basis for latent HIV-1 reservoirs that persist in the face of highly active antiretroviral therapy. The early events of retroviral replication take place within the context of nucleoprotein complexes that are derived from the core of the infecting virus particle (1, 2). Within the confines of the reverse transcription complex (RTC), 2 the reverse transcriptase enzyme copies single-stranded viral RNA into a linear double-stranded DNA molecule containing a copy of the LTR sequence at each end. The viral integrase (IN) engages the LTR ends prior to catalyzing two spatially and temporally distinct chemical reactions. Soon after their synthesis (3), IN site-specifically processes each LTR end adjacent to an invariant CA dinucleotide (4, 5), yielding CA OH 3Ј-hydroxyl groups that serve as the nucleophiles for the second reaction, DNA strand transfer. Because the viral replication intermediate at this point gains the ability to catalyze DNA strand transfer activity, 3Ј-processing operationally marks the transition of the RTC to the pre-integration complex (PIC) (Fig. 1). In the strand transfer step, IN utilizes the 3Ј-oxygen atoms to cut chromosomal DNA in a staggered fashion and simultaneously join the viral DNA ends to the 5Ј-phosphates of the target DNA (4, 6, 7). The resulting DNA recombination intermediate, with unjoined viral DNA 5Ј-ends, is repaired by host cell enzymes to yield the integrated provirus flanked by the duplication of the sequence of the staggered DNA cut (Fig. 1). The spumaviruses, which compose one of seven Retroviridae genera, are an exception to this generalized scheme, as DNA synthesis is largely complete prior to target cell infection (8). Research on the functionality of the active nucleoprotein complexes that mediate HIV-1 DNA integration has led to the development of antiviral inhibitors that target the IN and block integration. IN Domain Structure and Reaction MechanismRetroviral INs belong to a superfamily of proteins known as the retroviral IN superfam...

show abstract

Transcriptional Coactivator LEDGF/p75 Modulates Human Immunodeficiency Virus Type 1 Integrase-Mediated Concerted Integration

Cited by 55 publications

References 50 publications

Integrase, LEDGF/p75 and HIV replication

Integrase, LEDGF/p75 and HIV replication

Integrase: An Important Therapeutic Target in the Fight Against HIV/AIDS Infection

Retroviral Integrase Proteins and HIV-1 DNA Integration

Contact Info

Product

Resources

About