scholarly journals Variability in HIV-1 Integrase Gene and 3′-Polypurine Tract Sequences in Cameroon Clinical Isolates, and Implications for Integrase Inhibitors Efficacy

2020 ◽  
Vol 21 (5) ◽  
pp. 1553 ◽  
Author(s):  
Arpan Acharya ◽  
Claude T. Tagny ◽  
Dora Mbanya ◽  
Julius Y. Fonsah ◽  
Emilienne Nchindap ◽  
...  
Keyword(s):  
Low Frequency ◽  
Clinical Samples ◽  
Strand Transfer ◽  
African Countries ◽  
High Genetic Diversity ◽  
Integrase Gene ◽  
Infected People ◽  
Polypurine Tract ◽  
Clade B ◽  
Hiv 1

Integrase strand-transfer inhibitors (INSTIs) are now included in preferred first-line antiretroviral therapy (ART) for HIV-infected adults. Studies of Western clade-B HIV-1 show increased resistance to INSTIs following mutations in integrase and nef 3′polypurine tract (3′-PPT). With anticipated shifts in Africa (where 25.6-million HIV-infected people resides) to INSTIs-based ART, it is critical to monitor patients in African countries for resistance-associated mutations (RAMs) affecting INSTIs efficacy. We analyzed HIV-1 integrase and 3′-PPT sequences in 345 clinical samples from INSTIs-naïve HIV-infected Cameroonians for polymorphisms and RAMs that affect INSTIs. Phylogeny showed high genetic diversity, with the predominance of HIV-1 CRF02_AG. Major INSTIs RAMs T66A and N155K were found in two (0.6%) samples. Integrase polymorphic and accessory RAMs found included T97A, E157Q, A128T, M50I, S119R, L74M, L74I, S230N, and E138D (0.3′23.5% of samples). Ten (3.2%) samples had both I72V+L74M, L74M+T97A, or I72V+T97A mutations; thirty-one (9.8%) had 3′-PPT mutations. The low frequency of major INSTIs RAMs shows that INSTIs-based ART can be successfully used in Cameroon. Several samples had ≥1 INSTIs accessory RAMs known to reduce INSTIs efficacy; thus, INSTIs-based ART would require genetic surveillance. The 3′-PPT mutations could also affect INSTIs. For patients failing INSTIs-based ART with no INSTIs RAMs, monitoring 3′-PPT sequences could reveal treatment failure etiology.

scholarly journals INSTIs and NNRTIs Potently Inhibit HIV-1 Polypurine Tract Mutants in a Single Round Infection Assay

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2501
Author(s):  
Steven J. Smith ◽  
Andrea Ferris ◽  
Xuezhi Zhao ◽  
Gary Pauly ◽  
Joel P. Schneider ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Envelope Gene ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Integrase Gene ◽  
Polypurine Tract ◽  
Emergence Of Resistance ◽  
Hiv 1

Integrase strand transfer inhibitors (INSTIs) are a class of antiretroviral compounds that prevent the insertion of a DNA copy of the viral genome into the host genome by targeting the viral enzyme integrase (IN). Dolutegravir (DTG) is a leading INSTI that is given, usually in combination with nucleoside reverse transcriptase inhibitors (NRTIs), to treat HIV-1 infections. The emergence of resistance to DTG and other leading INSTIs is rare. However, there are recent reports suggesting that drug resistance mutations can occur at positions outside the integrase gene either in the HIV-1 polypurine tract (PPT) or in the envelope gene (env). Here, we used single round infectivity assays to measure the antiviral potencies of several FDA-approved INSTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) against a panel of HIV-1 PPT mutants. We also tested several of our promising INSTIs and NNRTIs in these assays. No measurable loss in potency was observed for either INSTIs or NNRTIs against the HIV-1 PPT mutants. This suggests that HIV-1 PPT mutants are not able, by themselves, to confer resistance to INSTIs or NNRTIs.

scholarly journals Mutations in the HIV-1 3’-Polypurine Tract and Integrase Strand-Transfer Inhibitor Resistance

2021 ◽  
Author(s):  
Yuliang Wei ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Strand Transfer ◽  
Integrase Gene ◽  
Polypurine Tract ◽  
Integrase Strand Transfer Inhibitors ◽  
Transfer Inhibitor ◽  
Inhibitor Resistance ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1

Integrase strand-transfer inhibitors (INSTIs), in combination with other antivirals, are widely used for the treatment of HIV-1-infected individuals. HIV-1 resistance to INSTIs is typically associated with mutations in the viral integrase gene [1].…

scholarly journals Characterization of HIV-1 Integrase Gene and Resistance Associated Mutations Prior to Roll out of Integrase Inhibitors by Kenyan National HIV-Treatment Program in Kenya

2020 ◽  
Vol 30 (1) ◽  
Author(s):  
Mabeya Sepha ◽  
Nyamache Anthony ◽  
Ngugi Caroline ◽  
Nyerere Andrew ◽  
Lihana Raphael
Keyword(s):  
Drug Resistance ◽  
Direct Sequencing ◽  
Integrase Inhibitor ◽  
Hiv Treatment ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Resistance Mutations ◽  
Integrase Gene ◽  
Hiv 1

BACKGROUND: Antiretroviral therapy containing an integrase strand transfer inhibitor plus two Nucleoside Reverse Transcriptase inhibitors has now been recommended for treatment of HIV-1-infected patients. This thus determined possible pre-existing integrase resistance associated mutations in the integrase gene prior to introduction of integrase inhibitors combination therapy in Kenya.METHODS: Drug experienced HIV patients were enrolled at Kisii Teaching and Referral in Kenya. Blood specimens from (33) patients were collected for direct sequencing of HIV-1 polintegrase genes. Drug resistance mutations were interpreted according to the Stanford algorithm and phylogenetically analysed using insilico tools.RESULTS: From pooled 188 Kenyan HIV integrase sequences that were analysed for drug resistance, no major mutations conferring resistance to integrase inhibitors were detected. However, polymorphic accessory mutations associated with reduced susceptibility of integrase inhibitors were observed in low frequency; M50I (12.2%), T97A (3.7%), S153YG, E92G (1.6%), G140S/A/C (1.1%) and E157Q (0.5%). Phylogenetic analysis (330 sequences revealed that HIV-1 subtype A1 accounted for majority of the infections, 26 (78.8%), followed by D, 5 (15.2%) and C, 2 (6%).CONCLUSION: The integrase inhibitors will be effective in Kenya where HIV-1 subtype A1 is still the most predominant. However, occurring polymorphisms may warrant further investigation among drug experienced individuals on dolutegravir combination or integrase inhibitor treatment. 

scholarly journals Number of HIV-1 founder variants is determined by the recency of the source partner infection

Science ◽  
2020 ◽  
Vol 369 (6499) ◽  
pp. 103-108 ◽  
Author(s):  
Ch. Julián Villabona-Arenas ◽  
Matthew Hall ◽  
Katrina A. Lythgoe ◽  
Stephen G. Gaffney ◽  
Roland R. Regoes ◽  
...  
Keyword(s):  
Early Stage ◽  
Control Strategies ◽  
Sexual Transmission ◽  
Low Frequency ◽  
Epidemiological Data ◽  
High Genetic Diversity ◽  
Partner Characteristics ◽  
Infection Stage ◽  
Hiv 1 ◽  
Founder Strain

During sexual transmission, the high genetic diversity of HIV-1 within an individual is frequently reduced to one founder variant that initiates infection. Understanding the drivers of this bottleneck is crucial to developing effective infection control strategies. Little is known about the importance of the source partner during this bottleneck. To test the hypothesis that the source partner affects the number of HIV founder variants, we developed a phylodynamic model calibrated using genetic and epidemiological data on all existing transmission pairs for whom the direction of transmission and the infection stage of the source partner are known. Our results suggest that acquiring infection from someone in the acute (early) stage of infection increases the risk of multiple–founder variant transmission compared with acquiring infection from someone in the chronic (later) stage of infection. This study provides the first direct test of source partner characteristics to explain the low frequency of multiple–founder strain infections.

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

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.

scholarly journals Resistance of human immunodeficiency virus type 1 to integrase strand transfer inhibitors in Croatia

2019 ◽  
Vol 2 (1) ◽  
pp. 29-33
Author(s):  
Ana Planinic ◽  
Maja Oroz ◽  
Josip Begovac ◽  
Snjezana Zidovec Lepej
Keyword(s):  
Population Based ◽  
Antiretroviral Drugs ◽  
Protease Gene ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Integrase Gene ◽  
Integrase Strand Transfer Inhibitors ◽  
Clinically Significant ◽  
First Time ◽  
Hiv 1

Integrase strand transfer inhibitors (INSTIs) are the latest class of antiretroviral drugs that prevent the integration of proviral DNA into the host genome. The aim of this study was to describe, for the first time, INSTI resistance mutations observed in Croatian HIV-infected patients. Methods: The study was conducted between March 2016 and September 2018 and included 4 previously untreated patients (antiretroviral, ARV-naive) as well as 18 unsuccessfully treated HIV-infected patients (ARV-experienced) that have been tested for INSTI resistance. The genetic data on INSTI resistance was obtained by population-based sequencing of the integrase gene. Resistance analysis to other classes of antiretroviral drugs has been performed in some patients by sequencing the protease gene and a part of the reverse transcriptase HIV-1 gene. Results: INSTI resistance mutations were not found in ARV-naive patients. Mutations associated with resistance to INSTIs have been observed in 5 of 18 (27.8%) patients failing INSTI-based ARV regiment. Resistance to INSTIs in ARV-experienced patients was attributed to major resistance mutations Q148R, N155H and E92Q that confer resistance to two INSTIs (raltegravir and elvitegravir). Conclusions: The results of this study describe the first 5 cases of ARV-experienced HIV-1 infected patients with clinically significant resistance to INSTIs, and emphasize the need for continuous surveillance of INSTI resistance in patients experiencing virological failure to antiretroviral treatment in Croatia.

scholarly journals Systematic determination of in vitro phenotypic resistance to HIV-1 integrase strand transfer inhibitors from clinical samples

2019 ◽  
Author(s):  
Aniqa Shahid ◽  
Wendy W. Zhang ◽  
Vincent Montoya ◽  
Peter K. Cheung ◽  
Natalia Oliveira ◽  
...  
Keyword(s):  
Site Directed Mutagenesis ◽  
Cross Resistance ◽  
Clinical Samples ◽  
Strand Transfer ◽  
Hiv Integrase ◽  
Phenotypic Resistance ◽  
Integrase Strand Transfer Inhibitors ◽  
Hiv 1

ABSTRACTPhenotypic resistance data is relatively sparse for the newest HIV-1 integrase strand transfer inhibitors (INSTIs), dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB). In this study, we report the phenotypic susceptibility of a large panel of oligo-clonal patient-derived HIV-1 integrase viruses. Representative clinical samples (N=141) were selected from a large database (N=17,197) of clinically-derived HIV integrase sequences, based on the presence of permutations of substitutions at 27 pre-defined positions in integrase (N=288). HIV-1 RNA was extracted from patient samples and diluted to approximately 500 HIV RNA copies/mL. Using an “oligo-clonal” amplification approach to achieve single-copy amplification, these dilutions were subjected to 12 parallel RT-PCR reactions to amplify integrase. Confirmed clonal amplicons were co-transfected with linearized pNL4.3∆int into CEM-GXR cells. In total, 162 HIV-1 viruses that carried no mixtures and had a unique sequence were harvested, and phenotyped in MT4-LTR-EGFP cells subsequently. Variants with the highest fold change (FC) had G140S and Q148R/H and resistant to all five drugs; R263K was the only single variant conferring >3-FC to DTG, BIC and CAB. There was extensive cross-resistance between DTG, BIC, and CAB and phenotypic resistance values for all the three INSTIs were almost collinear. The greatest exceptions were variants with N155H/G163E or L74I/T97M/F121C/V151I/E157Q/G163K, where both had >70-FC for CAB, while <3-FC for DTG and BIC. While site-directed mutagenesis is invaluable; the systematic selection of representative mutational patterns observedin vivoprovides an efficient way to identify clinically relevant drug resistance.

scholarly journals Strand Displacement Synthesis in the Central Polypurine Tract Region of HIV-1 Promotes DNA to DNA Strand Transfer Recombination

1996 ◽  
Vol 271 (47) ◽  
pp. 29605-29611 ◽  
Author(s):  
Gloria M. Fuentes ◽  
Chockalingam Palaniappan ◽  
Philip J. Fay ◽  
Robert A. Bambara
Keyword(s):  
Strand Transfer ◽  
Strand Displacement ◽  
Polypurine Tract ◽  
Central Polypurine Tract ◽  
Dna Strand ◽  
Hiv 1

Variability of the HIV-1 3′ polypurine tract (3′PPT) region and implication in integrase inhibitor resistance

2019 ◽  
Vol 74 (12) ◽  
pp. 3440-3444 ◽  
Author(s):  
Isabelle Malet ◽  
Olivier Delelis ◽  
Thuy Nguyen ◽  
Valentin Leducq ◽  
Besma Abdi ◽  
...  
Keyword(s):  
Rapid Change ◽  
Rare Event ◽  
Integration Step ◽  
Integrase Gene ◽  
Polypurine Tract ◽  
Treatment Naïve ◽  
High Level ◽  
Hiv 1 ◽  
Level Resistance

Abstract Background Integrase strand-transfer inhibitors (INSTIs) are efficient at impairing retroviral integration, which is a critical step in HIV-1 replication. To date, resistance to these compounds has been explained by mutations in the viral protein integrase, which catalyses the integration step. Recently, it has been shown that selected mutations in the 3′ polypurine tract (3′PPT), a sequence involved in the reverse transcription mechanism, result in high-level resistance to these compounds. This observation was reinforced by the description of a patient who failed INSTI treatment by selecting mutations in the 3′PPT sequence. Methods Sequences of the 3′PPT region were analysed in 30706 treatment-naive patients from the public Los Alamos database belonging to six different subtypes and, in parallel, in 107 patients failing INSTI treatment. Results The analysis showed that the sequences of patients failing INSTI treatment, in the same way as those of treatment-naive patients, are very well conserved regardless of the presence or absence of resistance mutations in the integrase gene. Conclusions This study confirms that the selection of a mutation in the 3′PPT region conferring high-level resistance to INSTIs is a rare event. It would require a particular in vivo context and especially a long enough time to be selected, this exposure time being generally reduced by the rapid change of treatment in the case of virological failure. Larger-scale studies in patients with INSTI treatment failure are needed to determine whether the 3′PPT region can play an important role in vivo in INSTI resistance.

scholarly journals Surveillance of HIV-1 transmitted integrase strand transfer inhibitor resistance in the UK

2020 ◽  
Vol 75 (11) ◽  
pp. 3311-3318
Author(s):  
Jean L Mbisa ◽  
Juan Ledesma ◽  
Peter Kirwan ◽  
David F Bibby ◽  
Carmen Manso ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Treatment Guidelines ◽  
Low Frequency ◽  
Strand Transfer ◽  
Recent Infection ◽  
Resistant Variant ◽  
Transfer Inhibitor ◽  
The Uk ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1

Abstract Background HIV treatment guidelines have traditionally recommended that all HIV-positive individuals are tested for evidence of drug resistance prior to starting ART. Testing for resistance to reverse transcriptase inhibitors and PIs is well established in routine care. However, testing for integrase strand transfer inhibitor (InSTI) resistance is less consistent. Objectives To inform treatment guidelines by determining the prevalence of InSTI resistance in a national cohort of recently infected individuals. Patients and methods Recent (within 4 months) HIV-1 infections were identified using a Recent Infection Testing Algorithm of new HIV-1 diagnoses in the UK. Resistance-associated mutations (RAMs) in integrase, protease and reverse transcriptase were detected by ultradeep sequencing, which allows for the sensitive estimation of the frequency of each resistant variant in a sample. Results The analysis included 655 randomly selected individuals (median age = 33 years, 95% male, 83% MSM, 78% white) sampled in the period 2014 to 2016 and determined to have a recent infection. These comprised 320, 138 and 197 samples from 2014, 2015 and 2016, respectively. None of the samples had major InSTI RAMs occurring at high variant frequency (≥20%). A subset (25/640, 3.9%) had major InSTI RAMs occurring only as low-frequency variants (2%–20%). In contrast, 47/588 (8.0%) had major reverse transcriptase inhibitor and PI RAMs at high frequency. Conclusions Between 2014 and 2016, major InSTI RAMs were uncommon in adults with recent HIV-1 infection, only occurring as low-frequency variants of doubtful clinical significance. Continued surveillance of newly diagnosed patients for evidence of transmitted InSTI resistance is recommended to inform clinical practice.

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