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

Rogers, Leonard C.; Obasa, Adetayo Emmanuel; Jacobs, Graeme Brendon; Sarafianos, Stefan G.; Sönnerborg, Anders; Neogi, Ujjwal; Singh, Kamalendra

doi:10.3389/fmicb.2018.01754

Cited by 21 publications

(25 citation statements)

References 41 publications

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“…The NOPs that have been identified in subtype C and CRF_02_AG IN have not been previously associated with HIV-1 IN drug resistance, with the exception of the polymorphism M50I. M50I was identified in our subtype C IN sequence and this polymorphism has been reported to reduce DTG susceptibility when found in combination with the mutation R263K in HIV-1 subtype B IN [43,44] However, in our study the mutation R263K was not present. Furthermore, M50I is not able to cause drug resistance on its own, but increases the effect of resistance exhibited by R263K [43] In our study M50I had no effect on INSTI's binding to IN.…”

Section: Discussioncontrasting

confidence: 69%

Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

Isaacs¹,

Mikasi²,

Obasa³

et al. 2020

Preprint

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The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral Integrase (IN) enzyme catalyses integration. IN is an ideal therapeutic enzyme targeted by several drugs; raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG) and bictegravir (BIC) having been approved by the USA Food and Drug Administration (FDA). Due to high HIV-1 diversity, it is not well understood how specific naturally occurring polymorphisms (NOPs) in IN may affect the structure/function and binding affinity of Integrase Strand Transfer Inhibitors (INSTIs). In this study, we applied computational methods of molecular modelling and docking to analyse the effect of NOPs on the full-length IN structure and INSTI binding. We identified 16 NOPs within the Cameroonian derived CRF02_AG IN sequences and further identified 17 NOPs within HIV-1C South African sequences. The NOPs in the IN structures did not show any effect on INSTI binding. INSTIs displayed similar binding affinities to each IN structure. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment naïve populations. This study supports the use of second-generation INSTI DTG as part of first-line combination antiretroviral therapy (cART) regimens, due to DTG possessing a stronger genetic barrier to the emergence of drug resistance.

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Section: Discussioncontrasting

confidence: 69%

Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

Isaacs¹,

Mikasi²,

Obasa³

et al. 2020

Preprint

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“…The 9 amino acid substitutions (V31I [22,35,54], T112V [35,39,54], I113V [26], T125A [24,26,35,54], G134N [35,39,54], K136Q [39,54], D167E [22,35,54], T218I [22,54], and L234I [22,35,54]) were described as polymorphic mutations in non-B clades, none of which were ascribed to INSTI resistance.…”

Section: Prevalence Of Naturally Occurring Integrase Polymorphismsmentioning

confidence: 99%

“…The L74I mutation is located in the catalytic core domain and is part of the hydrophobic cluster including L63, T97, F100/Y100, L101, L113/I113, and F121 near the active site of integrase [22]. In vitro selection experiments indicated that substitutions in the 74 position combined with major mutations (G140A/C/S, Q148 H/K/R) and other accessory mutations (V75I, T97A) can significantly reduce susceptibility to INSTI, whereas this mutation alone has minimal impact on INSTI susceptibility or HIV-1 replication capacity [7,[23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several studies of subtype-specific differences in sensitivity and the impact of naturally occurring polymorphisms were presented. Investigated polymorphic substitutions, especially at the active site of integrase, demonstrated that the natural variability of integrase across HIV-1 genetic variants can significantly affect the genetic barrier to drug resistance (DR) by influencing the selection of resistance mutations, native protein activity, structure, and the function of the drug-mediated inhibition of the enzyme, which may have important implications for INSTI therapy [13,22,[34][35][36][37][38][39][40].…”

Section: Introductionmentioning

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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“…The IN mutations usually associated with reduced INSTIs susceptibility include both polymorphic mutations and non-polymorphic mutations (25,26). Other studies have reported that several NOPs can affect structural stability and exibility of the IN protein structure (27,28). Low rates of IN mutations against INSTIs were reported in Cameroon (21).…”

Section: Discussionmentioning

confidence: 99%

Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations

Mikasi

Isaacs

Chotongo

et al. 2020

Preprint

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Abstract Background The Integrase (IN) strand transfer inhibitor (INSTI), Dolutegravir (DTG), has been given the green light to form part of first-line combination antiretroviral therapy (cART) by the World Health Organization (WHO). DTG is clinically effective against all HIV-1 isolates previously showing resistance to INSTIs.Methods We evaluated the HIV-1 CRF02_AG IN gene sequences from Cameroon for the presence of resistance-associated mutations (RAMs) against INSTIs and naturally occurring polymorphisms (NOPs), using study sequences (n=20) and (n=278) sequences data derived from HIV Los Alamos National Library (LANL) database. The possible impact of NOPs on protein structure caused by HIV-1 CRF02_AG variations was addressed within the context of a 3D model of the HIV-1 IN complex. Results We observed 12.8% (37/287) sequences to contain RAMs, with only 1.0% (3/287) of the sequences having major INSTI RAMs: T66A, Q148H, R263K and N155H. Of these,11.8% (34/287) of the sequences contained five different IN accessory mutations; namely Q95K, T97A, G149A, E157Q and D232N. NOP rates equal or above 50% were found for 66% of central core domain (CCD) positions, 44% C-terminal domain (CTD) positions and 35% of the N-terminal domain (NTD) positions.Conclusions Our analysis indicated that all mutations that resulted in a change in the number of interactions encompassing residues were found within the stable alpha-helix secondary structure element and not in close proximity to the drug active site. Our findings highlight the structural basis for HIV-1 IN interactions and that INSTIs will remain effective against CRF02_AG.

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

Cited by 21 publications

References 41 publications

Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

Structural Comparison of Diverse HIV-1 Subtypes using Molecular Modelling and Docking Analyses of Integrase Inhibitors

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

Interaction Analysis of Statistically Enriched Mutations Identified in Cameroon Recombinant Subtype CRF02_AG that can Influence the Development of Dolutegravir Drug Resistance Mutations

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