Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir

Canducci, Filippo; Marinozzi, Maria Chiara; Sampaolo, Michela; Boeri, Enzo; Spagnuolo, Vincenzo; Gianotti, Nicola; Castagna, Antonella; Paolucci, Stefania; Baldanti, Fausto; Lazzarin, Adriano; Clementi, Massimo

doi:10.1093/jac/dkp477

Cited by 43 publications

(47 citation statements)

References 24 publications

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“…Secondary mutations increasing the fitness of the resistant viruses have been identified and include the T97A mutation for the Y143C/H/R pathway (5,8,26). In vitro, we observed a significant catalytic defect for both 3Ј-P and ST activities of Y143C/R proteins (31) (Fig.…”

Section: Biochemical Activities Of Mutant Inmentioning

confidence: 91%

“…The Y143C/R mutation in patients was found to be accompanied by the T97A mutation, and this double mutation is one of the profiles identified in patients resistant to RAL (5,31). To elucidate whether the combination of the primary RAL resistance mutations, Y143C or Y143R, with the T97A secondary mutation reduces the susceptibility to RAL and rescues the catalytic defect due to the Y143C/R mutation, we generated mutations at amino acids positions 97 and 143.…”

Section: Biochemical Activities Of Mutant Inmentioning

confidence: 99%

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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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Section: Biochemical Activities Of Mutant Inmentioning

confidence: 91%

Section: Biochemical Activities Of Mutant Inmentioning

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

View full text Add to dashboard Cite

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“…Each of these pathways is defined by one or more substitutions at specific amino acid positions within the integrase coding region: Y143C or R (here denoted Y143C,R), Q148H,K,R, and N155H (8,(15)(16)(17)(18)(19). Cross-resistance between RAL and EVG has been described for the viruses containing Q148H,K,R and N155H substitutions (20)(21)(22).…”

mentioning

confidence: 99%

Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

Huang¹,

Frantzell²,

Fransen³

et al. 2013

Antimicrob Agents Chemother

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“…Substitutions at positions Y143, Q148, and N155 in HIV-1 IN confer resistance to RAL (48). Although these mutations affect the fitness of the virus, secondary mutations that improve viral fitness can be selected (10,38). Mutations at Y143 eliminate a -stacking interaction with the oxadiazole ring, which is present in RAL but not in most other INSTIs; this mutant is effectively inhibited by INSTIs whose binding does not rely on contact with Y143 (49).…”

mentioning

confidence: 99%

Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

Johnson

Métifiot

Pommier

et al. 2012

Antimicrob Agents Chemother

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The design of novel integrase (IN) inhibitors has been aided by recent crystal structures revealing the binding mode of these compounds with a full-length prototype foamy virus (PFV) IN and synthetic viral DNA ends. Earlier docking studies relied on incomplete structures and did not include the contribution of the viral DNA to inhibitor binding. Using the structure of PFV IN as the starting point, we generated a model of the corresponding HIV-1 complex and developed a molecular dynamics (MD)-based approach that correlates with the in vitro activities of novel compounds. Four well-characterized compounds (raltegravir, elvitegravir, MK-0536, and dolutegravir) were used as a training set, and the data for their in vitro activity against the Y143R, N155H, and G140S/Q148H mutants were used in addition to the wild-type (WT) IN data. Three additional compounds were docked into the IN-DNA complex model and subjected to MD simulations. All three gave interaction potentials within 1 standard deviation of values estimated from the training set, and the most active compound was identified. Additional MD analysis of the raltegravir-and dolutegravir-bound complexes gave internal and interaction energy values that closely match the experimental binding energy of a compound related to raltegravir that has similar activity. These approaches can be used to gain a deeper understanding of the interactions of the inhibitors with the HIV-1 intasome and to identify promising scaffolds for novel integrase inhibitors, in particular, compounds that retain activity against a range of drug-resistant mutants, making it possible to streamline synthesis and testing. . This leaves a conserved CA sequence with a free hydroxyl on each of the 3= ends of the viral DNA and a 2-nucleotide overhang on each of the 5= ends. In the second reaction, IN uses the newly created 3= hydroxyl to attack the phosphodiester backbone of the host genome (strand transfer [ST]). Depending on the retrovirus, the two viral ends are inserted 4 to 6 bases apart, creating a small duplication in the target DNA flanking the provirus (5 nucleotides in the case of HIV-1 and 4 for prototype foamy virus [PFV]) (50). Cellular enzymes repair the gaps, leaving the double-stranded proviral DNA stably integrated into the genome of the infected cell.Integrases consist of three functionally distinct domains that have been characterized by biochemical and mutational analyses. The N-terminal domain (NTD; residues 1 to 50) contains a zincbinding HHCC motif and contributes to multimer formation (7,8). The C-terminal domain (CTD; identified as residues 212 to 288 in deletion studies) nonspecifically binds DNA (18,20,34,42). The catalytic core domain (CCD; residues 50 to 212) contains the catalytic triad DD35E motif that is well conserved among the retroviral integrase superfamily (7,11,19,32). This active site coordinates two metal ions and binds one viral DNA end. Although IN complexes exist in solution in different multimeric states, recent crystallographic data confirmed that the functi...

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Genotypic/phenotypic patterns of HIV-1 integrase resistance to raltegravir

Cited by 43 publications

References 24 publications

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

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

Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir

Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

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