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

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

Viruses ◽

10.3390/v12090936 ◽

2020 ◽

Vol 12 (9) ◽

pp. 936

Author(s):

Darren Isaacs ◽

Sello Given Mikasi ◽

Adetayo Emmanuel Obasa ◽

George Mondinde Ikomey ◽

Sergey Shityakov ◽

...

Keyword(s):

South African ◽

Binding Affinity ◽

Molecular Modelling ◽

Linear Regression Analysis ◽

Strand Transfer ◽

Genetic Barrier ◽

Naturally Occurring ◽

Treatment Naïve ◽

The Usa ◽

Hiv 1

The process of viral integration into the host genome is an essential step of the HIV-1 life cycle. The viral integrase (IN) enzyme catalyzes 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). We applied computational methods of molecular modelling and docking to analyze the effect of NOPs on the full-length IN structure and INSTI binding. We identified 13 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 differences in INSTI binding affinity. However, linear regression analysis revealed a positive correlation between the Ki and EC50 values for DTG and BIC as strong inhibitors of HIV-1 IN subtypes. All INSTIs are clinically effective against diverse HIV-1 strains from INSTI treatment-naïve populations. This study supports the use of second-generation INSTIs such as DTG and BIC as part of first-line combination antiretroviral therapy (cART) regimens, due to a stronger genetic barrier to the emergence of drug resistance.

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Primary resistance to integrase strand transfer inhibitors in Spain using ultrasensitive HIV-1 genotyping

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa349 ◽

2020 ◽

Vol 75 (12) ◽

pp. 3517-3524

Author(s):

M Casadellà ◽

J R Santos ◽

M Noguera-Julian ◽

R Micán-Rivera ◽

P Domingo ◽

...

Keyword(s):

Reverse Transcriptase ◽

Low Frequency ◽

Transmitted Drug Resistance ◽

Strand Transfer ◽

Resistance Mutations ◽

First Line ◽

Primary Resistance ◽

Integrase Strand Transfer Inhibitors ◽

Virological Outcomes ◽

Hiv 1

Abstract Background Transmission of resistance mutations to integrase strand transfer inhibitors (INSTIs) in HIV-infected patients may compromise the efficacy of first-line antiretroviral regimens currently recommended worldwide. Continued surveillance of transmitted drug resistance (TDR) is thus warranted. Objectives We evaluated the rates and effects on virological outcomes of TDR in a 96 week prospective multicentre cohort study of ART-naive HIV-1-infected subjects initiating INSTI-based ART in Spain between April 2015 and December 2016. Methods Pre-ART plasma samples were genotyped for integrase, protease and reverse transcriptase resistance using Sanger population sequencing or MiSeq™ using a ≥ 20% mutant sensitivity cut-off. Those present at 1%–19% of the virus population were considered to be low-frequency variants. Results From a total of 214 available samples, 173 (80.8%), 210 (98.1%) and 214 (100.0%) were successfully amplified for integrase, reverse transcriptase and protease genes, respectively. Using a Sanger-like cut-off, the overall prevalence of any TDR, INSTI-, NRTI-, NNRTI- and protease inhibitor (PI)-associated mutations was 13.1%, 1.7%, 3.8%, 7.1% and 0.9%, respectively. Only three (1.7%) subjects had INSTI TDR (R263K, E138K and G163R), while minority variants with integrase TDR were detected in 9.6% of subjects. There were no virological failures during 96 weeks of follow-up in subjects harbouring TDR as majority variants. Conclusions Transmitted INSTI resistance remains rare in Spain and, to date, is not associated with virological failure to first-line INSTI-based regimens.

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Comparable In Vitro Activities of Second-Generation HIV-1 Integrase Strand Transfer Inhibitors (INSTIs) on HIV-1 Clinical Isolates with INSTI Resistance Mutations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01717-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 1

Author(s):

Francesco Saladini ◽

Alessia Giannini ◽

Adele Boccuto ◽

Filippo Dragoni ◽

Alice Appendino ◽

...

Keyword(s):

First Generation ◽

Second Generation ◽

Cross Resistance ◽

Strand Transfer ◽

Resistance Mutations ◽

Genetic Barrier ◽

Integrase Strand Transfer Inhibitors ◽

Comparable Activity ◽

Hiv 1

ABSTRACT Second-generation HIV-1 integrase strand transfer inhibitors (INSTIs) dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) showed a high genetic barrier to resistance and limited cross-resistance with first-generation INSTIs raltegravir (RAL) and elvitegravir (EVG). In this study, DTG, BIC, and CAB demonstrated a comparable activity on a panel of INSTI-resistant strains isolated from patients exposed to RAL, EVG, and/or DTG, with a significantly reduced susceptibility only with the pathway Q148H/K/R plus one to two additional INSTI mutations.

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Incidence of diabetes in HIV-infected patients treated with first-line integrase strand transfer inhibitors: a French multicentre retrospective study

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa330 ◽

2020 ◽

Vol 75 (11) ◽

pp. 3344-3348 ◽

Cited By ~ 2

Author(s):

Axel Ursenbach ◽

Vincent Max ◽

Marine Maurel ◽

Firouzé Bani-Sadr ◽

Amandine Gagneux-Brunon ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glycated Haemoglobin ◽

Incident Diabetes ◽

Strand Transfer ◽

First Line ◽

Genetic Barrier ◽

Onset Diabetes ◽

Integrase Strand Transfer Inhibitors ◽

Long Time ◽

New Onset

Abstract Background Integrase strand transfer inhibitors (INSTIs) are increasingly used in patients living with HIV due to their safety, effectiveness and high genetic barrier. However, an association with weight gain has recently been suggested and several cases of diabetes mellitus have been reported with raltegravir and dolutegravir. The long-time metabolic impact of these recent molecules remains unclear. Objectives To assess if an INSTI as a third agent is statistically associated with new-onset diabetes mellitus compared with an NNRTI or a PI. Patients and methods Patients undergoing first-line combined ART (cART) without diabetes at baseline were retrospectively included from the Dat’AIDS French cohort study (ClinicalTrials.gov NCT02898987). Incident diabetes mellitus was defined as a notification of new diabetes in the medical history, a glycated haemoglobin (HbA1c) level superior to 7.5% or the start of a diabetes therapy following the initiation of ART. Results From 2009 to 2017, 19 462 patients were included, among which 265 cases of diabetes mellitus occurred. Multivariate and survival analyses did not highlight an increase in new-onset diabetes in patients undergoing cART with an INSTI as a third agent compared with an NNRTI or a PI. BMI >30 kg/m2, age >37 years old (in survival analysis), black race or Hispanic ethnicity, arterial hypertension and AIDS were associated with a higher proportion of incident diabetes. Conclusions INSTIs were not statistically associated with new-onset diabetes. However, clinicians should remain aware of this possible metabolic comorbidity, particularly in patients with a high BMI and older patients.

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Structural effects of HIV-1 subtype C integrase mutations on the activity of integrase strand transfer inhibitors in South African patients

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2021.1972840 ◽

2021 ◽

pp. 1-11

Author(s):

Nokuzola Mbhele ◽

Michelle Gordon

Keyword(s):

South African ◽

Strand Transfer ◽

Structural Effects ◽

Subtype C ◽

Integrase Strand Transfer Inhibitors ◽

African Patients ◽

Hiv 1

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Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

Scientific Reports ◽

10.1038/s41598-021-90678-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Prats ◽

Ignacio Martínez-Zalacaín ◽

Beatriz Mothe ◽

Eugènia Negredo ◽

Núria Pérez-Álvarez ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Integrase Inhibitor ◽

Strand Transfer ◽

Cognitive Differences ◽

Integrase Strand Transfer Inhibitors ◽

Initiation Of Therapy ◽

Main Component ◽

Living With Hiv ◽

The Impact ◽

Hiv 1

AbstractIntegrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

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