Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

Vavro, Cindy; Hasan, Samiul; Madsen, Heather M.; Horton, Joseph; Deanda, Felix; Martin-Carpenter, Louise; Sato, Akihiko; Cuffe, Robert; Chen, Shuguang; Underwood, Mark; Nichols, Garrett

doi:10.1128/aac.01791-12

Cited by 18 publications

(7 citation statements)

References 21 publications

(30 reference statements)

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“…DTG (8,(16)(17)(18)(19)(20)(21)(22)(23) also binds to integrase protein with a longer residence time than either RAL and EVG (24) and has yet to select for resistance substitutions in HIV-positive previously antiretroviral (ARV)-naive patients receiving ARVs for the first time, despite having been used over a period of 96 weeks (20,21,25). It is important to better understand the resistance profile of DTG as well as to determine whether differences in HIV subtype might ultimately affect the clinical performance of this drug.…”

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confidence: 99%

Biochemical Analysis of the Role of G118R-Linked Dolutegravir Drug Resistance Substitutions in HIV-1 Integrase

Quashie

Mésplède

Han

et al. 2013

Antimicrob Agents Chemother

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Drug resistance mutations (DRMs) have been reported for all currently approved anti-HIV drugs, including the latest integrase strand transfer inhibitors (INSTIs). We previously used the new INSTI dolutegravir (DTG) to select a G118R integrase resistance substitution in tissue culture and also showed that secondary substitutions emerged at positions H51Y and E138K. Now, we have characterized the impact of the G118R substitution, alone or in combination with either H51Y or E138K, on 3= processing and integrase strand transfer activity. The results show that G118R primarily impacted the strand transfer step of integration by diminishing the ability of integrase-long terminal repeat (LTR) complexes to bind target DNA. The addition of H51Y and E138K to G118R partially restored strand transfer activity by modulating the formation of integrase-LTR complexes through increasing LTR DNA affinity and total DNA binding, respectively. This unique mechanism, in which one function of HIV integrase partially compensates for the defect in another function, has not been previously reported. The G118R substitution resulted in low-level resistance to DTG, raltegravir (RAL), and elvitegravir (EVG). The addition of either of H51Y or E138K to G118R did not enhance resistance to DTG, RAL, or EVG. Homology modeling provided insight into the mechanism of resistance conferred by G118R as well as the effects of H51Y or E138K on enzyme activity. The G118R substitution therefore represents a potential avenue for resistance to DTG, similar to that previously described for the R263K substitution. For both pathways, secondary substitutions can lead to either diminished integrase activity and/or increased INSTI susceptibility. The HIV integrase (IN) enzyme catalyzes the insertion of viral DNA into host DNA, a process known as integration (1). In a reaction termed 3= processing, integrase recognizes and cleaves off a dinucleotide GT downstream of a conserved dinucleotide CA signal, located within the last 15 bp of the long terminal repeats (LTR) that flank the viral DNA, and this effectively creates new 3= hydroxyl ends (2). The second step in integration, termed strand transfer, is the integrase-mediated insertion of the processed viral DNA into host DNA by a 5-bp staggered cleavage of target DNA. The exposed 3= hydroxyl groups on the viral insert interact with exposed 5= phosphates on the host DNA. Integration, which occurs primarily in highly expressed genes (3), causes the host machinery to transcribe viral genes and leads to successful propagation of viral particles. Integration is essential for productive infection and the establishment of viral persistence; therefore, integration was an early choice for the development of inhibitory compounds (4).The development of in vitro microtiter plate-based biochemical assays for the measurement of the various biochemical activities of integrase facilitated compound screening and identification of viable integrase inhibitors (5). The first specific integrase inhibitors, identified in 2000 (5), posses...

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confidence: 99%

Biochemical Analysis of the Role of G118R-Linked Dolutegravir Drug Resistance Substitutions in HIV-1 Integrase

Quashie

Mésplède

Han

et al. 2013

Antimicrob Agents Chemother

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“…In another study, the T124A mutation was highly prevalent in INSTI-naïve and RAL-failed patients, and it was significantly associated with HIV-nonB ( Saladini et al, 2012 ). While the T124A mutation was selected under DTG pressure, it does not significantly affect the efficacy of DTG ( Kobayashi et al, 2011 ; Vavro et al, 2013 ). These results suggest that the T124A mutation affects the binding of RAL more than the binding of DTG.…”

Section: Resultsmentioning

confidence: 99%

Structural Implications of Genotypic Variations in HIV-1 Integrase From Diverse Subtypes

et al. 2018

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Human immunodeficiency virus type 1 (HIV-1) integrase (IN) integrates viral DNA into the host genome using its 3′-end processing and strand-transfer activities. Due to the importance of HIV-1 IN, it is targeted by the newest class of approved drugs known as integrase strand transfer inhibitors (INSTIs). INSTIs are efficient in maintaining low viral load; however, as with other approved antivirals, resistance mutations emerge in patients receiving INSTI-containing therapy. As INSTIs are becoming increasingly accessible worldwide, it is important to understand the mechanism(s) of INSTI susceptibility. There is strong evidence suggesting differences in the patterns and mechanisms of drug resistance between HIV-1 subtype B, which dominates in United States, Western Europe and Australia, and non-B infections that are most prevalent in countries of Africa and Asia. IN polymorphisms and other genetic differences among diverse subtypes are likely responsible for these different patterns, but lack of a full-length high-resolution structure of HIV-1 IN has been a roadblock in understanding the molecular mechanisms of INSTI resistance and the impact of polymorphisms on therapy outcome. A recently reported full-length medium-resolution cryoEM structure of HIV-1 IN provides insights into understanding the mechanism of integrase function and the impact of genetic variation on the effectiveness of INSTIs. Here we use molecular modeling to explore the structural impact of IN polymorphisms on the IN reaction mechanism and INSTI susceptibility.

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“…Because genetic barrier is an important determinant of drug resistance, genetic variability among patients with different HIV-1 subtypes may influence the ease with which an integrase mutation can occur before or during INSTI treatment [ 44 , 52 , 56 , 58 , 60 , 61 , 66 – 70 , 113 ]. Previous studies have indicated that the prevalence of specific integrase polymorphisms, characterized as emergent secondary INSTI RAMs in subtype B, are greater among patients with non-B subtypes [ 56 – 58 , 60 , 61 , 110 ] and therefore may impact the magnitude of INSTI resistance, virologic response, or the propensity to acquire primary INSTI RAMs [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome

et al. 2017

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T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38–44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.

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Prevalent Polymorphisms in Wild-Type HIV-1 Integrase Are Unlikely To Engender Drug Resistance to Dolutegravir (S/GSK1349572)

Cited by 18 publications

References 21 publications

Biochemical Analysis of the Role of G118R-Linked Dolutegravir Drug Resistance Substitutions in HIV-1 Integrase

Biochemical Analysis of the Role of G118R-Linked Dolutegravir Drug Resistance Substitutions in HIV-1 Integrase

Structural Implications of Genotypic Variations in HIV-1 Integrase From Diverse Subtypes

Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome

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