scholarly journals Replicative Fitness Costs of Nonnucleoside Reverse Transcriptase Inhibitor Drug Resistance Mutations on HIV Subtype C

2011 ◽  
Vol 55 (5) ◽  
pp. 2146-2153 ◽  
Author(s):  
Kimberly L. Armstrong ◽  
Tun-Hou Lee ◽  
M. Essex
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Subtype C ◽  
Replicative Fitness ◽  
Drug Resistance Mutations ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Subtype B ◽  
Reverse Transcriptase Inhibitor

ABSTRACTSingle-dose nevirapine (NVP) is quite effective in preventing transmission of the human immunodeficiency virus (HIV) from mother to child; however, many women develop resistance to NVP in this setting. Comparing outcomes of clinical studies reveals an increased amount of resistance in subtype C relative to that in other subtypes. This study investigates how nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations of subtype C affect replication capacity. The 103N, 106A, 106M, 181C, 188C, 188L, and 190A drug resistance mutations were placed in a reverse transcriptase (RT) that matches the consensus subtype C sequence as well as the HXB2 RT, as a subtype B reference. The replicative fitness of each mutant was compared with that of the wild type in a head-to-head competition assay. The 106A mutant of subtype C would not grow in the competition assay, making it the weakest virus tested. The effect of the 106M mutation was weaker than those of the 181C and 188C mutations in the consensus C RT, but in subtype B, this difference was not seen. To see if the 106A mutation in a different subtype C background would have a different replicative profile, the same NNRTI resistance mutations were added to the MJ4 RT, a reference subtype C molecular clone. In the context of MJ4 RT, the 106A mutant was not the only mutant that showed poor replicative fitness; the 106M, 188C, and 190A mutants also failed to replicate. These results suggest that NNRTIs may be a cost-effective alternative for salvage therapy if deleterious mutations are present in a subtype C setting.

Diversity of HIV-1 subtypes and transmitted drug-resistance mutations among minority HIV-1 variants in a Turkish cohort

2021 ◽  
Vol 19 ◽  
Author(s):  
Rabia Can Sarinoglu ◽  
Uluhan Sili ◽  
Ufuk Hasdemir ◽  
Burak Aksu ◽  
Guner Soyletir ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Transmitted Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Treatment Naïve ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

Background: The World Health Organization (WHO) recommends the surveillance of transmitted drug resistance mutations (TDRMs) to ensure the effectiveness and sustainability of HIV treatment programs. Objective: Our aim was to determine the TDRMs and evaluate the distribution of HIV-1 subtypes using and compared next-generation sequencing (NGS) and Sanger-based sequencing (SBS) in a cohort of 44 antiretroviral treatment-naïve patients. Methods: All samples that were referred to the microbiology laboratory for HIV drug resistance analysis between December 2016 and February 2018 were included in the study. After exclusions, 44 treatment-naive adult patients with a viral load of >1000 copies/mL were analyzed. DNA sequencing for reverse transcriptase and protease regions was performed using both DeepChek ABL single round kit and Sanger-based ViroSeq HIV-1 Genotyping System. The mutations and HIV-1 subtypes were analyzed using the Stanford HIVdb version 8.6.1 Genotypic Resistance software, and TDRMs were assessed using the WHO surveillance drug-resistance mutation database. HIV-1 subtypes were confirmed by constructing a maximum-likelihood phylogenetic tree using Los Alamos IQ-Tree software. Results: NGS identified nucleos(t)ide reverse transcriptase inhibitor (NRTI)-TDRMs in 9.1% of the patients, non-nucleos(t)ide reverse transcriptase inhibitor (NNRTI)-TDRMs in 6.8% of the patients, and protease inhibitor (PI)-TDRMs in 18.2% of the patients at a detection threshold of ≥1%. Using SBS, 2.3% and 6.8% of the patients were found to have NRTI- and NNRTI-TDRMs, respectively, but no major PI mutations were detected. M41L, L74I, K65R, M184V, and M184I related to NRTI, K103N to NNRTI, and N83D, M46I, I84V, V82A, L24I, L90M, I54V to the PI sites were identified using NGS. Most mutations were found in low-abundance (frequency range: 1.0% - 4.7%) HIV-1 variants, except M41L and K103N. The subtypes of the isolates were found as follows; 61.4% subtype B, 18.2% subtype B/CRF02_AG recombinant, 13.6% subtype A, 4.5% CRF43_02G, and 2.3% CRF02_AG. All TDRMs, except K65R, were detected in HIV-1 subtype B isolates.. Conclusion: The high diversity of protease site TDRMs in the minority HIV-1 variants and prevalence of CRFs were remarkable in this study. All minority HIV-1 variants were missed by conventional sequencing. TDRM prevalence among minority variants appears to be decreasing over time at our center.

scholarly journals Antiviral Activity andIn VitroMutation Development Pathways of MK-6186, a Novel Nonnucleoside Reverse Transcriptase Inhibitor

2012 ◽  
Vol 56 (6) ◽  
pp. 3324-3335 ◽  
Author(s):  
Meiqing Lu ◽  
Peter J. Felock ◽  
Vandna Munshi ◽  
Renee C. Hrin ◽  
Ying-Jie Wang ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Nnrti Resistance ◽  
Resistance Selection ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Subtype B ◽  
Biochemical Assays ◽  
Reverse Transcriptase Inhibitor

ABSTRACTMK-6186 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) which displays subnanomolar potency against wild-type (WT) virus and the two most prevalent NNRTI-resistant RT mutants (K103N and Y181C) in biochemical assays. In addition, it showed excellent antiviral potency against K103N and Y181C mutant viruses, with fold changes (FCs) of less than 2 and 5, respectively. When a panel of 12 common NNRTI-associated mutant viruses was tested with MK-6186, only 2 relatively rare mutants (Y188L and V106I/Y188L) were highly resistant, with FCs of >100, and the remaining viruses showed FCs of <10. Furthermore, a panel of 96 clinical virus isolates with NNRTI resistance mutations was evaluated for susceptibility to NNRTIs. The majority (70%) of viruses tested displayed resistance to efavirenz (EFV), with FCs of >10, whereas only 29% of the mutant viruses displayed greater than 10-fold resistance to MK-6186. To determine whether MK-6186 selects for novel resistance mutations,in vitroresistance selections were conducted with one isolate each from subtypes A, B, and C under low-multiplicity-of-infection (MOI) conditions. The results showed a unique mutation development pattern in which L234I was the first mutation to emerge in the majority of the experiments. In resistance selection under high-MOI conditions with subtype B virus, V106A was the dominant mutation detected in the breakthrough viruses. More importantly, mutant viruses selected by MK-6186 showed FCs of <10 against EFV or etravirine (ETR), and the mutant viruses containing mutations selected by EFV or ETR were sensitive to MK-6186 (FCs of <10).

scholarly journals Global Comparison of Drug Resistance Mutations After First-Line Antiretroviral Therapy Across Human Immunodeficiency Virus-1 Subtypes

2015 ◽  
Vol 3 (2) ◽  
Author(s):  
Austin Huang ◽  
Joseph W. Hogan ◽  
Xi Luo ◽  
Allison DeLong ◽  
Shanmugam Saravanan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Resistance Mutations ◽  
Subtype C ◽  
First Line ◽  
Drug Resistance Mutations ◽  
Global Comparison ◽  
Subtype B ◽  
Immunodeficiency Virus

Abstract Background.  Human immunodeficiency virus (HIV)-1 drug resistance mutations (DRMs) often accompany treatment failure. Although subtype differences are widely studied, DRM comparisons between subtypes either focus on specific geographic regions or include populations with heterogeneous treatments. Methods.  We characterized DRM patterns following first-line failure and their impact on future treatment in a global, multi-subtype reverse-transcriptase sequence dataset. We developed a hierarchical modeling approach to address the high-dimensional challenge of modeling and comparing frequencies of multiple DRMs in varying first-line regimens, durations, and subtypes. Drug resistance mutation co-occurrence was characterized using a novel application of a statistical network model. Results.  In 1425 sequences, 202 subtype B, 696 C, 44 G, 351 circulating recombinant forms (CRF)01_AE, 58 CRF02_AG, and 74 from other subtypes mutation frequencies were higher in subtypes C and CRF01_AE compared with B overall. Mutation frequency increased by 9%–20% at reverse transcriptase positions 41, 67, 70, 184, 215, and 219 in subtype C and CRF01_AE vs B. Subtype C and CRF01_AE exhibited higher predicted cross-resistance (+12%–18%) to future therapy options compared with subtype B. Topologies of subtype mutation networks were mostly similar. Conclusions.  We find clear differences in DRM outcomes following first-line failure, suggesting subtype-specific ecological or biological factors that determine DRM patterns.

scholarly journals Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil

2021 ◽  
Vol 22 (10) ◽  
pp. 5304
Author(s):  
Ana Santos-Pereira ◽  
Vera Triunfante ◽  
Pedro M. M. Araújo ◽  
Joana Martins ◽  
Helena Soares ◽  
...  
Keyword(s):  
Drug Resistance ◽  
People Living With Hiv ◽  
Resistance Mutations ◽  
Subtype C ◽  
Viral Loads ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Low Prevalence ◽  
Living With Hiv ◽  
Hiv 1

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008–2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.

scholarly journals Clinical Impact of Pretreatment Human Immunodeficiency Virus Drug Resistance in People Initiating Nonnucleoside Reverse Transcriptase Inhibitor–Containing Antiretroviral Therapy: A Systematic Review and Meta-analysis

2020 ◽  
Author(s):  
Silvia Bertagnolio ◽  
Lucas Hermans ◽  
Michael R Jordan ◽  
Santiago Avila-Rios ◽  
Collins Iwuji ◽  
...  
Keyword(s):  
Systematic Review ◽  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Treatment Outcomes ◽  
Meta Analysis ◽  
Transcriptase Inhibitor ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

Abstract Background Increased access to antiretroviral therapy (ART) has resulted in rising levels of pretreatment human immunodeficiency virus drug resistance (PDR). This is the first systematic review and meta-analysis to assess the impact of PDR on treatment outcomes among people initiating nonnucleoside reverse transcriptase inhibitor (NNRTI)–based ART, including the combination of efavirenz (EFV), tenofovir (TDF), and lamivudine or emtricitabine (XTC). Methods We systematically reviewed studies and conference proceedings comparing treatment outcomes in populations initiating NNRTI-based ART with and without PDR. We conducted subgroup analyses by regimen: (1) NNRTIs + 2 nucleoside reverse transcriptase inhibitors (NRTIs), (2) EFV + 2 NRTIs, or (3) EFV/TDF/XTC; by population (children vs adults); and by definition of resistance (PDR vs NNRTI PDR). Results Among 6197 studies screened, 32 were analyzed (31 441 patients). We found that individuals with PDR initiating NNRTIs across all the subgroups had increased risk of virological failure compared to those without PDR. Risk of acquisition of new resistance mutations and ART switch was also higher in people with PDR. Conclusions This review shows poorer treatment outcomes in the presence of PDR, supporting the World Health Organization’s recommendation to avoid using NNRTIs in countries where levels of PDR are high.

scholarly journals Silent mutations at codons 65 and 66 in reverse transcriptase alleviate indel formation and restore fitness in subtype B HIV-1 containing D67N and K70R drug resistance mutations

2015 ◽  
Vol 43 (6) ◽  
pp. 3256-3271 ◽  
Author(s):  
Sushama Telwatte ◽  
Anna C. Hearps ◽  
Adam Johnson ◽  
Catherine F. Latham ◽  
Katie Moore ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Hiv 1
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