HIV‐1 Integrase Inhibitors: Update and Perspectives

Семенова, Е. А.; Marchand, Christophe; Pommier, ﻿Yves

doi:10.1016/s1054-3589(07)56007-2

Cited by 38 publications

(33 citation statements)

References 136 publications

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“…The 50% effective concentration (EC 50 ) values obtained for the IIIB reference strain were 6.1 Ϯ 2.3 nM for raltegravir and 11.6 Ϯ 3.5 nM for elvitegravir. FC values of the recombinant viruses ranged from 0.1 to 2.6 (average, 0.9 Ϯ 0.4) for raltegravir and from 0.1 to 13 (average, 0.9 Ϯ 0.8) for elvitegravir.…”

Section: Resultsmentioning

confidence: 98%

“…It is a 32-kDa protein of 288 amino acids comprising three structural domains: the N-terminal domain (NTD) (amino acids 1 to 49), the central core domain (CCD) (amino acids 50 to 212), and the C-terminal domain (CTD) (amino acids 213 to 288) (45). Based on its essential function for viral replication, IN represents an important target of potential clinical relevance for treating HIV infection and preventing AIDS (45,50).…”

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confidence: 99%

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Secondary Integrase Resistance Mutations Found in HIV-1 Minority Quasispecies in Integrase Therapy-Naive Patients Have Little or No Effect on Susceptibility to Integrase Inhibitors

Ceccherini‐Silberstein

Baelen²,

Armenia

et al. 2010

Antimicrob Agents Chemother

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The goal of this study was to explore the presence of integrase strand transfer inhibitor (InSTI) resistance mutations in HIV-1 quasispecies present in InSTI-naïve patients and to evaluate their in vitro effects on phenotypic susceptibility to InSTIs and their replication capacities. The RT-RNase H-IN region was PCR amplified from plasma viral RNA obtained from 49 HIV-1 subtype B-infected patients (21 drug naïve and 28 failing highly active antiretroviral therapy [HAART] not containing InSTIs) and recombined with an HXB2-based backbone with RT and IN deleted. Recombinant viruses were tested against raltegravir and elvitegravir and for replication capacity. Three-hundred forty-four recombinant viruses from 49 patients were successfully analyzed both phenotypically and genotypically. The majority of clones were not phenotypically resistant to InSTIs: 0/344 clones showed raltegravir resistance, and only 3 (0.87%) showed low-level elvitegravir resistance. No primary resistance mutations for raltegravir and elvitegravir were found as major or minor species. The majority of secondary mutations were also absent or rarely present. Secondary mutations, such as T97A and G140S, found rarely and only as minority quasispecies, were present in the elvitegravir-resistant clones. A novel mutation, E92G, although rarely found in minority quasispecies, showed elvitegravir resistance. Preexisting genotypic and phenotypic raltegravir resistance was extremely rare in InSTI-naïve patients and confined to only a restricted minority of secondary variants. Overall, these results, together with others based on population and ultradeep sequencing, suggest that at this point IN genotyping in all patients before raltegravir treatment may not be cost-effective and should not be recommended until evidence of transmitted drug resistance to InSTIs or the clinical relevance of IN minor variants/polymorphisms is determined.

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Section: Resultsmentioning

confidence: 98%

mentioning

confidence: 99%

Secondary Integrase Resistance Mutations Found in HIV-1 Minority Quasispecies in Integrase Therapy-Naive Patients Have Little or No Effect on Susceptibility to Integrase Inhibitors

Ceccherini‐Silberstein

Baelen²,

Armenia

et al. 2010

Antimicrob Agents Chemother

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“…3Ј-end processing prepares both ends of the proviral DNA for integration, and final strand transfer joins the viral and nicked chromosomal DNAs (12). As this step is crucial for viral replication, IN represents an important target that has clinical relevance for treating HIV infection and preventing AIDS (30,35).…”

mentioning

confidence: 99%

Structure-Analysis of the HIV-1 Integrase Y143C/R Raltegravir Resistance Mutation in Association with the Secondary Mutation T97A

Reigadas

Masquelier

Calmels

et al. 2011

Antimicrob Agents Chemother

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In the strand transfer assay, the IN Y143C or R mutation combined with the secondary mutation T97A severely impaired susceptibility to RAL compared to results with the IN Y143C or R mutation alone. Assays without RAL suggested that the T97A mutation could rescue the catalytic activity which was impaired by the presence of the Y143C/R mutation. The combination of the T97A mutation with the primary RAL resistance mutations Y143C/R strongly reduces the susceptibility to RAL and rescues the catalytic defect due to the Y143C/R mutation. This result indicates that the emergence of the Y143C/R/T97A double-mutation pattern in patients is a signature of a high resistance level.

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“…To counteract this property, the available HIV-1 therapies utilize combinations of drugs targeting the viral RT, protease, and recently also the integrase and viral envelope fusion with the host cell plasma membrane (9,19,33). However, HIV-1 still poses a significant therapeutic problem as it continues to evolve multidrug resistance (20).…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Targets Env for Endoplasmic Reticulum-Associated Protein Degradation and Inhibits Human Immunodeficiency Virus Type 1 Propagation

Jejcic

Daniels

Goobar-Larsson

et al. 2009

J Virol

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Human immunodeficiency virus type 1 (HIV-1) is dependent on its envelope glycoprotein (Env) to bind, fuse, and subsequently infect a cell. We show here that treatment of HIV-1-infected cells with glycyl-prolyl-glycine amide (GPG-NH 2 ), dramatically reduced the infectivity of the released viral particles by decreasing their Env incorporation. The mechanism of GPG-NH 2 was uncovered by examining Env expression and maturation in treated cells. GPG-NH 2 treatment was found to affect Env by significantly decreasing its steady-state levels, its processing into gp120/gp41, and its mass by inducing glycan removal in a manner dependent on its native signal sequence and the proteasome. Therefore, GPG-NH 2 negatively impacts Env maturation, facilitating its targeting for endoplasmic reticulum-associated protein degradation, where Env is deglycosylated en route to its degradation. These findings illustrate that nontoxic drugs such as GPG-NH 2 , which can selectively target glycoproteins to existing cellular degradation pathways, may be useful for pathogen therapy.

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HIV‐1 Integrase Inhibitors: Update and Perspectives

Cited by 38 publications

References 136 publications

Secondary Integrase Resistance Mutations Found in HIV-1 Minority Quasispecies in Integrase Therapy-Naive Patients Have Little or No Effect on Susceptibility to Integrase Inhibitors

Secondary Integrase Resistance Mutations Found in HIV-1 Minority Quasispecies in Integrase Therapy-Naive Patients Have Little or No Effect on Susceptibility to Integrase Inhibitors

Structure-Analysis of the HIV-1 Integrase Y143C/R Raltegravir Resistance Mutation in Association with the Secondary Mutation T97A

Small Molecule Targets Env for Endoplasmic Reticulum-Associated Protein Degradation and Inhibits Human Immunodeficiency Virus Type 1 Propagation

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