Additional HIV-1 mutation patterns associated with reduced phenotypic susceptibility to etravirine in clinical samples

AbstractIn a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter-variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but not significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a co-infection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time-points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.Significance StatementA unique conglomeration of TFBS enables the HIV-1 promoter to accomplish two diametrically opposite functions – transcriptional activation and transcriptional silencing. The various phases of viral latency - establishment, maintenance, and reversal - collectively determine the replication fitness of individual viral strains. A profound variation in the TFBS composition of the viral promoter may significantly alter the viral latency properties and the latent reservoir characteristics. Although the duplication of certain TFBS remains a quality unique to HIV-1C, the high-level genetic recombination of HIV-1 may promote the transfer of such molecular properties to the other HIV-1 subtypes. The emergence of several promoter-variant viral strains may make the task of a ‘functional cure’ more challenging in HIV-1C.

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Comparison of the Abbott Alinity m and m2000 assays for the quantification of HIV-1, HCV and HBV in clinical samples

Journal of Clinical Virology ◽

10.1016/j.jcv.2020.104331 ◽

2020 ◽

Vol 126 ◽

pp. 104331

Author(s):

Lina Mouna ◽

Coralie Pallier ◽

Stéphanie Proust ◽

Corinne Prégermain ◽

Anne-Marie Roque-Afonso

Keyword(s):

Clinical Samples ◽

Hiv 1

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2509. Pooled Resistance Analyses of Darunavir (DRV) Once Daily (QD) Regimens and Formulations Across 10 Clinical Studies of Treatment-Naïve (TN) and Treatment-Experienced (TE) Patients with Human Immunodeficiency Virus (HIV)-1 Infection

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2187 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S870-S871 ◽

Cited By ~ 1

Author(s):

Erkki Lathouwers ◽

Sareh Seyedkazemi ◽

Donghan Luo ◽

Kimberley Brown ◽

Sandra De Meyer ◽

...

Keyword(s):

Clinical Studies ◽

Virologic Failure ◽

Transcriptase Inhibitor ◽

Resistance Testing ◽

Resistance Development ◽

Single Tablet Regimen ◽

Treatment Naïve ◽

Tenofovir Alafenamide ◽

Hiv 1 ◽

Phenotypic Susceptibility

Abstract Background DRV has demonstrated high efficacy and barrier to resistance development across diverse populations, from TN to heavily TE patients. We evaluated resistance data from 10 clinical studies of different DRV 800 mg QD–based antiretroviral regimens and formulations. Methods The analysis included patients from 10 phase 2/3 studies (48–192 weeks in duration) of ritonavir- and cobicistat-boosted DRV 800 mg QD–based regimens in TN and virologically failing or suppressed TE patients with HIV-1 (table). Three were phase 3 studies of the DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen (STR). Post-baseline resistance was evaluated in patients experiencing protocol-defined virologic failure (PDVF); definitions and criteria for resistance testing varied slightly among studies. Resistance-associated mutations (RAMs) were based on respective International Antiviral Society–USA mutation lists over time. Results Of the 3,635 patients evaluated, 250 met PDVF criteria and 205 had post-baseline genotypes/phenotypes. Overall, 4 (0.1%) patients developed (or had identified [switch studies]) ≥1 DRV and/or primary protease inhibitor (PI) RAM (table), and only 1 (< 0.1%, ODIN) patient lost DRV phenotypic susceptibility; this TE patient had prior VF with lopinavir. Among those who used a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone (mostly emtricitabine [FTC] + tenofovir [TFV]), 12 (0.4%) patients had ≥1 NRTI RAM, including 10 with M184I/V associated with FTC resistance. No TFV RAMs were observed. Among patients receiving D/C/F/TAF (n = 1,949), none had post-baseline DRV, primary PI, or TFV RAMs; only 2 (0.1%) patients developed an FTC RAM. Conclusion Across a large, diverse population using DRV 800 mg QD–based regimens and formulations, resistance development remains rare; 0.1% of patients had ≥1 DRV and/or primary PI RAM post-baseline. Among 3 trials of the D/C/F/TAF STR, no patients developed a DRV or primary PI RAM. After > 10 years of investigating DRV 800 mg QD–based regimens in clinical trials, loss of phenotypic susceptibility to DRV has never been observed in TN or TE virologically suppressed patients and was only once observed in a TE patient with prior VF on multiple antiretrovirals, including a PI. Disclosures All authors: No reported disclosures.

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Reliability at the Lower Limits of HIV-1 RNA Quantification in Clinical Samples: A Comparison of RT-PCR versus bDNA Assays

PLoS ONE ◽

10.1371/journal.pone.0006008 ◽

2009 ◽

Vol 4 (6) ◽

pp. e6008 ◽

Cited By ~ 9

Author(s):

Ronald J. Lubelchek ◽

Blake Max ◽

Caroline J. Sandusky ◽

Bala Hota ◽

David E. Barker

Keyword(s):

Clinical Samples ◽

Rt Pcr ◽

Rna Quantification ◽

Lower Limits ◽

Hiv 1

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In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01284-07 ◽

2008 ◽

Vol 52 (4) ◽

pp. 1545-1548 ◽

Cited By ~ 91

Author(s):

Delphine Desbois ◽

Bénédicte Roquebert ◽

Gilles Peytavin ◽

Florence Damond ◽

Gilles Collin ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Wild Type ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Phenotypic Susceptibility

ABSTRACT We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.

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World-wide variation in HIV-1 phenotypic susceptibility in untreated individuals: biologically relevant values for resistance testing

AIDS ◽

10.1097/00002030-200109070-00010 ◽

2001 ◽

Vol 15 (13) ◽

pp. 1671-1677 ◽

Cited By ~ 81

Author(s):

P. Richard Harrigan ◽

Julio S. G. Montaner ◽

Scott A. Wegner ◽

Werner Verbiest ◽

Veronica Miller ◽

...

Keyword(s):

World Wide ◽

Resistance Testing ◽

Biologically Relevant ◽

Untreated Individuals ◽

Hiv 1 ◽

Phenotypic Susceptibility

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Analytical Performances of Human Immunodeficiency Virus Type 1 RNA-Based Amplix® Real-Time PCR Platform for HIV-1 RNA Quantification

AIDS Research and Treatment ◽

10.1155/2016/7954810 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12

Author(s):

Christian Diamant Mossoro-Kpinde ◽

Ralph-Sydney Mboumba Bouassa ◽

Mohammad-Ali Jenabian ◽

Serge Tonen Wolyec ◽

Leman Robin ◽

...

Keyword(s):

Real Time ◽

Real Time Pcr ◽

Dynamic Range ◽

Limit Of Detection ◽

Central Africa ◽

Sub Saharan Africa ◽

Clinical Samples ◽

Absolute Bias ◽

Sub Saharan ◽

Hiv 1

Objectives. We evaluated the performances of Amplix real-time PCR platform developed by Biosynex (Strasbourg, France), combining automated station extraction (Amplix station 16 Dx) and real-time PCR (Amplix NG), for quantifying plasma HIV-1 RNA by lyophilized HIV-1 RNA-based Amplix reagents targeting gag and LTR, using samples from HIV-1-infected adults from Central African Republic. Results. Amplix real-time PCR assay showed low limit of detection (28 copies/mL), across wide dynamic range (1.4–10 log copies/mL), 100% sensitivity and 99% specificity, high reproducibility, and accuracy with mean bias < 5%. The assay showed excellent correlations and concordance of 95.3% with the reference HIV-1 RNA load assay (Roche), with mean absolute bias of +0.097 log copies/mL by Bland-Altman analysis. The assay was able to detect and quantify the most prevalent HIV-1 subtype strains and the majority of non-B subtypes, CRFs of HIV-1 group M, and HIV-1 groups N and O circulating in Central Africa. The Amplix assay showed 100% sensitivity and 99.6% specificity to diagnose virological failure in clinical samples from antiretroviral drug-experienced patients. Conclusions. The HIV-1 RNA-based Amplix real-time PCR platform constitutes sensitive and reliable system for clinical monitoring of HIV-1 RNA load in HIV-1-infected children and adults, particularly adapted to intermediate laboratory facilities in sub-Saharan Africa.

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Prevalence in the USA of rilpivirine resistance-associated mutations in clinical samples and effects on phenotypic susceptibility to rilpivirine and etravirine

Antiviral Therapy ◽

10.3851/imp2771 ◽

2014 ◽

Vol 19 (8) ◽

pp. 819-823 ◽

Cited By ~ 16

Author(s):

Gaston R Picchio ◽

Laurence T Rimsky ◽

Veerle Van Eygen ◽

Mojgan Haddad ◽

Laura A Napolitano ◽

...

Keyword(s):

Clinical Samples ◽

The Usa ◽

Phenotypic Susceptibility

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The Evolution of Regulatory Elements in the Emerging Promoter-Variant Strains of HIV-1 Subtype C

Frontiers in Microbiology ◽

10.3389/fmicb.2021.779472 ◽

2021 ◽

Vol 12 ◽

Author(s):

Disha Bhange ◽

Nityanand Prasad ◽

Swati Singh ◽

Harshit Kumar Prajapati ◽

Shesh Prakash Maurya ◽

...

Keyword(s):

Viral Gene Expression ◽

Regulatory Elements ◽

Clinical Samples ◽

Latent Reservoir ◽

Viral Gene ◽

Subtype C ◽

Regulatory Circuit ◽

First Time ◽

Hiv 1

In a multicentric, observational, investigator-blinded, and longitudinal clinical study of 764 ART-naïve subjects, we identified nine different promoter variant strains of HIV-1 subtype C (HIV-1C) emerging in the Indian population, with some of these variants being reported for the first time. Unlike several previous studies, our work here focuses on the evolving viral regulatory elements, not the coding sequences. The emerging viral strains contain additional copies of the existing transcription factor binding sites (TFBS), including TCF-1α/LEF-1, RBEIII, AP-1, and NF-κB, created by sequence duplication. The additional TFBS are genetically diverse and may blur the distinction between the modulatory region of the promoter and the viral enhancer. In a follow-up analysis, we found trends, but no significant associations between any specific variant promoter and prognostic markers, probably because the emerging viral strains might not have established mono infections yet. Illumina sequencing of four clinical samples containing a coinfection indicated the domination of one strain over the other and establishing a stable ratio with the second strain at the follow-up time points. Since a single promoter regulates viral gene expression and constitutes the master regulatory circuit with Tat, the acquisition of additional and variant copies of the TFBS may significantly impact viral latency and latent reservoir characteristics. Further studies are urgently warranted to understand how the diverse TFBS profiles of the viral promoter may modulate the characteristics of the latent reservoir, especially following the initiation of antiretroviral therapy.

Download Full-text