Integrase and integration: biochemical activities of HIV-1 integrase

Delelis, Olivier; Carayon, Kévin; Saı̈b, Ali; Deprez, Eric; Mouscadet, Jean François

doi:10.1186/1742-4690-5-114

Cited by 188 publications

(166 citation statements)

References 134 publications

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“…This protein is encoded by the 3Ј end of the HIV-1 pol gene, which contains 288 amino acids and which functions as a tetramer (11). The integration process consists of multiple steps (3,6,7). First, a stable complex is formed between the IN enzyme and specific viral sequences at the end of the long terminal repeats (LTRs).…”

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confidence: 99%

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Wesenbeeck¹,

Rondelez²,

Feyaerts³

et al. 2011

Antimicrob Agents Chemother

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The integrase inhibitor raltegravir (RAL) is currently used for the treatment of both treatment-naïve and treatment-experienced HIV-1-infected patients. Elvitegravir (EVG) is in late phases of clinical development. Since significant cross-resistance between RAL and EVG is observed, there is a need for second-generation integrase inhibitors (INIs) with a higher genetic barrier and limited cross-resistance to RAL/EVG. A panel of HIV-1 integrase recombinants, derived from plasma samples from raltegravir-treated patients (baseline and follow-up samples), were used to study the cross-resistance profile of two second-generation integrase inhibitors, MK-2048 and compound G. Samples with Q148H/R mutations had elevated fold change values with all compounds tested. Although samples with the Y143R/C mutation had reduced susceptibility to RAL, they remained susceptible to MK-2048 and compound G. Samples with the N155H mutation had no reduced susceptibility to compound G. In conclusion, our results allowed ranking of the INIs on the basis of the antiviral activities using recombinant virus stocks from RAL-treated patient viruses. The order according to decreasing susceptibility is compound G, MK-2048, and EVG.

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mentioning

confidence: 99%

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Wesenbeeck¹,

Rondelez²,

Feyaerts³

et al. 2011

Antimicrob Agents Chemother

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“…This transesterification reaction generates an intermediate in which the 3′ ends of the viral DNA are covalently joined to the host DNA and there are 4-to 6-bp gaps in the host DNA associated with both of the 5′ ends of the viral DNA. Cellular machinery repairs these gaps, creating a 4-to 6-bp duplication (the size of the duplication varies for different retroviruses) of the host DNA flanking the integrated viral DNA (1)(2)(3)(4). HIV-1 integration generates a 5-bp duplication of the host DNA at the integration site (5,6).…”

mentioning

confidence: 99%

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Varadarajan

McWilliams

Hughes

2013

Proc. Natl. Acad. Sci. U.S.A.

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Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3′ processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen.strand transfer inhibitor | chromosomal rearrangements | integrase inhibitors H IV-1 integration is a two-step process: first, in the cytoplasm, an integrase (IN) dimer binds to each end of the newly synthesized linear viral DNA and removes two nucleotides from each of the 3′ ends, exposing the conserved CA dinucleotide. The preintegration complex (PIC) is translocated from the cytoplasm into the nucleus, where the viral DNA is integrated into the host genome. In the strand transfer (ST) reaction, the two exposed 3′ hydroxyl groups on the newly processed viral DNA ends attack phosphodiester bonds on the opposite strands of the target DNA at positions that lie across the major groove, 4-6 bp apart. This reaction is carried out by a tetramer of IN; each of the viral DNA ends is associated with an IN dimer. This transesterification reaction generates an intermediate in which the 3′ ends of the viral DNA are covalently joined to the host DNA and there are 4-to 6-bp gaps in the host DNA associated with both of the 5′ ends of the viral DNA. Cellular machinery repairs these gaps, creating a 4-to 6-bp duplication (the size of the duplication varies for different retroviruses) of the host DNA flanking the integrated viral DNA (1-4). HIV-1 integration generates a 5-bp duplication of the host DNA at the integration site (5, 6).Raltegravir (RAL) and all of the potent IN inhibitors thus far discovered bind to...

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“…It is a complex process catalyzed by the viral integrase (IN) in cooperation with cellular cofactors [1].…”

Section: Introductionmentioning

confidence: 99%

Fueling HIV-1 integrase drug design with structural insights

Demeulemeester

Christ

Maeyer

et al. 2012

Drug Discovery Today: Technologies

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Integrase and integration: biochemical activities of HIV-1 integrase

Cited by 188 publications

References 134 publications

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Cross-Resistance Profile Determination of Two Second-Generation HIV-1 Integrase Inhibitors Using a Panel of Recombinant Viruses Derived from Raltegravir-Treated Clinical Isolates

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Fueling HIV-1 integrase drug design with structural insights

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