Antiviral activity of HIV‐1 integrase strand‐transfer inhibitors against mutants with integrase resistance‐associated mutations and their frequency in treatment‐naïve individuals

Margot, Nicolas; Ram, Renee; White, Kirsten; Abram, Michael E.; Callebaut, Christian

doi:10.1002/jmv.25564

Cited by 23 publications

(29 citation statements)

References 29 publications

(57 reference statements)

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“…Five highly polymorphic mutations, R20K [ 50 ], I72V [ 9 , 33 , 51 ], L74I [ 7 , 23 , 24 , 25 , 26 ], S119P [ 51 , 52 ], and V201I [ 11 , 26 , 38 , 53 ], were frequently reported in regard to a small reduction in replication capacity relative to the wild type. It has been reported that in the absence of major mutations, all these polymorphic mutations had little, if any, effect on drug susceptibility in vitro, thus suggesting a secondary role for viral fitness rescue and increasing resistance.…”

Section: Resultsmentioning

confidence: 99%

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Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

Kirichenko

Lapovok

Baryshev

et al. 2020

Viruses

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The increasing use of the integrase strand transfer inhibitor (INSTI) class for the treatment of HIV-infection has pointed to the importance of analyzing the features of HIV-1 subtypes for an improved understanding of viral genetic variability in the occurrence of drug resistance (DR). In this study, we have described the prevalence of INSTI DR in a Russian cohort and the genetic features of HIV-1 integrase sub-subtype A6. We included 408 HIV infected patients who were not exposed to INSTI. Drug resistance mutations (DRMs) were detected among 1.3% of ART-naïve patients and among 2.7% of INSTI-naïve patients. The prevalence of 12 polymorphic mutations was significantly different between sub-subtypes A6 and A1. Analysis of the genetic barriers determined two positions in which subtype A (A1 and A6) showed a higher genetic barrier (G140C and V151I) compared with subtype B, and one position in which subtypes A1 and B displayed a higher genetic barrier (L74M and L74I) than sub-subtype A6. Additionally, we confirmed that the L74I mutation was selected at the early stage of the epidemic and subsequently spread as a founder effect in Russia. Our data have added to the overall understanding of the genetic features of sub-subtype A6 in the context of drug resistance.

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Section: Resultsmentioning

confidence: 99%

“…A total of 108 mutations were detected, including 16 highly polymorphic mutations. Five of them (R20K, I72V, L74I, S119P, and V201I) were described as INSTI resistant [7,9,11,[23][24][25][26]33,36,[49][50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

Kirichenko

Lapovok

Baryshev

et al. 2020

Viruses

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“…Ultimately, the amine portion of the scaffold was modified to substitute an oxadiazole group for the oxalamide, producing RAL [53]. As stated above, RAL potently inhibited IN strand transfer in both in vitro assays (IC 50 ) and had antiviral activity against HIV-1 in single round replication assays (EC 50 ) [53,74,75]. RAL was also broadly active against a number of HIV-1 isolates, human immunodeficiency virus type two (HIV-2), and SIV [76].…”

Section: Raltegravir (Ral)mentioning

confidence: 99%

“…When the amino acid substitutions Y143R, N155H, and G140S/Q148H were introduced in HIV-1 pNL4-3 and the EC 50 values of the WT and mutant viruses were determined using single round replication assays, the IN mutants Y143R and N155H caused substantial losses in potency (for Y143R, the fold change (FC), which is the decrease in potency between WT and IN mutant, was 41, and for N155H, the FC was 38). RAL displayed an even larger loss in potency with the IN double mutant G140S/Q148H (the FC was 475) [75]. Mutations in the three amino acid substitution pathways arise at different rates [81,[83][84][85].…”

Section: Raltegravir (Ral)mentioning

confidence: 99%

Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Smith

Zhao

Passos

et al. 2021

Viruses

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Integrase strand transfer inhibitors (INSTIs) are currently recommended for the first line treatment of human immunodeficiency virus type one (HIV-1) infection. The first-generation INSTIs are effective but can select for resistant viruses. Recent advances have led to several potent second-generation INSTIs that are effective against both wild-type (WT) HIV-1 integrase and many of the first-generation INSTI-resistant mutants. The emergence of resistance to these new second-generation INSTIs has been minimal, which has resulted in alternative treatment strategies for HIV-1 patients. Moreover, because of their high antiviral potencies and, in some cases, their bioavailability profiles, INSTIs will probably have prominent roles in pre-exposure prophylaxis (PrEP). Herein, we review the current state of the clinically relevant INSTIs and discuss the future outlook for this class of antiretrovirals.

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“…To gain insight into the mechanisms of drug resistance, we additionally determined the structure of BIC bound to IN mutant Q148H/G140S intasomes. The double mutation, which arose initially in response to RAL treatment [29], was subsequently shown to confer significant (> 150-fold) cross-resistance to EVG, yet overall milder, approximately twofold to 10-fold, resistance to DTG and BIC [7,[30][31][32][33].…”

Section: Insights Into Insti Drug Resistance Mechanismsmentioning

confidence: 99%

Close‐up: HIV/SIV intasome structures shed new light on integrase inhibitor binding and viral escape mechanisms

Engelman

Cherepanov

2020

The FEBS Journal

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Integrase strand transfer inhibitors (INSTIs) are important components of drug formulations that are used to treat people living with HIV, and second-generation INSTIs dolutegravir and bictegravir impart high barriers to the development of drug resistance. Reported 10 years ago, X-ray crystal structures of prototype foamy virus (PFV) intasome complexes explained how INSTIs bind integrase to inhibit strand transfer activity and provided initial glimpses into mechanisms of drug resistance. However, comparatively low sequence identity between PFV and HIV-1 integrases limited the depth of information that could be gleaned from the surrogate model system. Recent high-resolution structures of HIV-1 intasomes as well as intasomes from a closely related strain of simian immunodeficiency virus (SIV), which were determined using single-particle cryogenic electron microscopy, have overcome this limitation. The new structures reveal the binding modes of several advanced INSTI compounds to the HIV/SIV integrase active site and critically inform the structural basis of drug resistance. These findings will help guide the continued development of this important class of antiretroviral therapeutics.

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Antiviral activity of HIV‐1 integrase strand‐transfer inhibitors against mutants with integrase resistance‐associated mutations and their frequency in treatment‐naïve individuals

Cited by 23 publications

References 29 publications

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs

Close‐up: HIV/SIV intasome structures shed new light on integrase inhibitor binding and viral escape mechanisms

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