scholarly journals Drug resistance evolution in HIV in the late 1990s: hard sweeps, soft sweeps, clonal interference and the accumulation of drug resistance mutations

2019 ◽  
Author(s):  
Kadie-Ann Williams ◽  
Pleuni Pennings
Keyword(s):  
Drug Resistance ◽  
Population Genetics ◽  
Evolutionary Dynamics ◽  
Resistance Mutations ◽  
Clonal Interference ◽  
Resistance Evolution ◽  
Drug Resistance Mutations

1AbstractThe goal of this paper is to provide examples of evolutionary dynamics of HIV within patients who are treated with antiretrovirals. We hope that the figures in this paper will be used in evolution and population genetics classes. We show a wide variety of patterns, specifically: soft sweeps, hard sweeps, softening sweeps and hardening sweeps, simultaneous sweeps, accumulation of mutations and clonal interference.

scholarly journals The clarifying role of time series data in the population genetics of HIV

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1009050
Author(s):  
Alison F. Feder ◽  
Pleuni S. Pennings ◽  
Dmitri A. Petrov
Keyword(s):  
Time Series ◽  
Drug Resistance ◽  
Population Genetics ◽  
Time Series Data ◽  
Series Data ◽  
Selective Sweeps ◽  
Resistance Mutations ◽  
Resistance Evolution ◽  
Drug Resistance Mutations ◽  
Traditional Population

HIV can evolve remarkably quickly in response to antiretroviral therapies and the immune system. This evolution stymies treatment effectiveness and prevents the development of an HIV vaccine. Consequently, there has been a great interest in using population genetics to disentangle the forces that govern the HIV adaptive landscape (selection, drift, mutation, and recombination). Traditional population genetics approaches look at the current state of genetic variation and infer the processes that can generate it. However, because HIV evolves rapidly, we can also sample populations repeatedly over time and watch evolution in action. In this paper, we demonstrate how time series data can bound evolutionary parameters in a way that complements and informs traditional population genetic approaches. Specifically, we focus on our recent paper (Feder et al., 2016, eLife), in which we show that, as improved HIV drugs have led to fewer patients failing therapy due to resistance evolution, less genetic diversity has been maintained following the fixation of drug resistance mutations. Because soft sweeps of multiple drug resistance mutations spreading simultaneously have been previously documented in response to the less effective HIV therapies used early in the epidemic, we interpret the maintenance of post-sweep diversity in response to poor therapies as further evidence of soft sweeps and therefore a high population mutation rate (θ) in these intra-patient HIV populations. Because improved drugs resulted in rarer resistance evolution accompanied by lower post-sweep diversity, we suggest that both observations can be explained by decreased population mutation rates and a resultant transition to hard selective sweeps. A recent paper (Harris et al., 2018, PLOS Genetics) proposed an alternative interpretation: Diversity maintenance following drug resistance evolution in response to poor therapies may have been driven by recombination during slow, hard selective sweeps of single mutations. Then, if better drugs have led to faster hard selective sweeps of resistance, recombination will have less time to rescue diversity during the sweep, recapitulating the decrease in post-sweep diversity as drugs have improved. In this paper, we use time series data to show that drug resistance evolution during ineffective treatment is very fast, providing new evidence that soft sweeps drove early HIV treatment failure.

scholarly journals Drug Resistance Evolution in HIV in the Late 1990s: Hard Sweeps, Soft Sweeps, Clonal Interference and the Accumulation of Drug Resistance Mutations

2020 ◽  
Vol 10 (4) ◽  
pp. 1213-1223
Author(s):  
Kadie-Ann Williams ◽  
Pleuni Pennings
Keyword(s):  
Drug Resistance ◽  
Evolutionary Dynamics ◽  
Evolutionary Medicine ◽  
Multiple Time ◽  
Resistance Mutations ◽  
Clonal Interference ◽  
Data Set ◽  
Resistance Evolution ◽  
Multiple Time Points ◽  
Viral Sequences

The evolution of drug resistance in pathogens such as HIV is an important and widely known example in the field of evolutionary medicine. Here, we focus on a unique data set from the late 1990s with multiple viral sequences from multiple time points in 118 patients. We study patterns of evolutionary dynamics in the viral populations in these patients who were treated with Reverse Transcriptase Inhibitors and Protease Inhibitors in the late 1990s. Specifically, we aim to visualize and analyze examples of population genetic processes such as selective sweeps and clonal interference. The figures and descriptions in this paper can be used in evolution and population genetics classes. We show and analyze a wide variety of patterns, specifically: soft sweeps, hard sweeps, softening sweeps and hardening sweeps, simultaneous sweeps, accumulation of mutations and clonal interference.

scholarly journals Natural polymorphisms in HIV-1 CRF01_AE strain and profile of acquired drug resistance mutations in a long-term combination treatment cohort in northeastern China

2019 ◽  
Author(s):  
Zesong Sun ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Deep Sequencing ◽  
Evolutionary Dynamics ◽  
Northeastern China ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Z Value ◽  
Hiv 1

Abstract Background The impacts of genetic polymorphisms on drug resistance mutations (DRMs) among various HIV-1 subtypes have long been debated. In this study, we aimed to analyze the natural polymorphisms and acquired DRM profile in HIV-1 CRF01_AE-infected patients in a large Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV) first-line antiretroviral therapy (ART) cohort in northeastern China.Methods The natural polymorphisms of CRF01_AE were analyzed in 2034 patients from a long-term ART cohort in northeastern China. The polymorphisms in 105 treatment failure (TF) patients were compared with those in 1148 treatment success (TS) patients. The acquired DRM profile of 42 patients who experienced TF with TDF/3TC/EFV treatment was analyzed by comparing the mutations at TF to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, and CorMut package were used to analyze the mutation rates and co-variation. Deep sequencing was used to analyze the evolutionary dynamics of co-variation.Results Before ART, the natural polymorphisms of 31 sites on reverse transcriptase (RT) were significantly higher in CRF01_AE than subtype B HIV-1 (|Z value|≥3), including five known drug resistance-associated sites (238, 118, 179, 103, and 40). However, only the polymorphism at site 75 was associated with TF (|Z value|≥3). The mutation rate at 14 sites increased significantly at TF compared to baseline, with the most common DRMs comprising G190S/C, K65R, K101E/N/Q, M184V/I, and V179D/I/A/T/E, ranging from 66.7% to 45.2%. Moreover, two unknown mutations (V75L and L228R) increased by 19.0% and 11.9% respectively, and they were under positive selection (Ka/Ks>1, log odds ratio [LOD]>2) and were associated with several other DRMs (cKa/Ks>1, LOD>2). Deep sequencing of longitudinal plasma samples showed that L228R occurred simultaneously or followed the appearance of Y181C.Conclusion The high levels of polymorphisms in CRF01_AE had little impact on treatment outcomes. The findings regarding potential new CRF01_AE-specific minor DRMs indicate the need for more studies on the drug resistance phenotype of CRF01_AE.

scholarly journals HIV Drug Resistance Mutations Detection by Next-Generation Sequencing during Antiretroviral Therapy Interruption in China

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 264
Author(s):  
Miaomiao Li ◽  
Shujia Liang ◽  
Chao Zhou ◽  
Min Chen ◽  
Shu Liang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Next Generation Sequencing ◽  
Antiretroviral Therapy ◽  
Detection Threshold ◽  
Next Generation ◽  
Resistance Mutations ◽  
Hiv Drug Resistance ◽  
Drug Resistance Mutations ◽  
Therapy Interruption ◽  
Generation Sequencing

Patients with antiretroviral therapy interruption have a high risk of virological failure when re-initiating antiretroviral therapy (ART), especially those with HIV drug resistance. Next-generation sequencing may provide close scrutiny on their minority drug resistance variant. A cross-sectional study was conducted in patients with ART interruption in five regions in China in 2016. Through Sanger and next-generation sequencing in parallel, HIV drug resistance was genotyped on their plasma samples. Rates of HIV drug resistance were compared by the McNemar tests. In total, 174 patients were included in this study, with a median 12 (interquartile range (IQR), 6–24) months of ART interruption. Most (86.2%) of them had received efavirenz (EFV)/nevirapine (NVP)-based first-line therapy for a median 16 (IQR, 7–26) months before ART interruption. Sixty-one (35.1%) patients had CRF07_BC HIV-1 strains, 58 (33.3%) CRF08_BC and 35 (20.1%) CRF01_AE. Thirty-four (19.5%) of the 174 patients were detected to harbor HIV drug-resistant variants on Sanger sequencing. Thirty-six (20.7%), 37 (21.3%), 42 (24.1%), 79 (45.4%) and 139 (79.9) patients were identified to have HIV drug resistance by next-generation sequencing at 20% (v.s. Sanger, p = 0.317), 10% (v.s. Sanger, p = 0.180), 5% (v.s. Sanger, p = 0.011), 2% (v.s. Sanger, p < 0.001) and 1% (v.s. Sanger, p < 0.001) of detection thresholds, respectively. K65R was the most common minority mutation, of 95.1% (58/61) and 93.1% (54/58) in CRF07_BC and CRF08_BC, respectively, when compared with 5.7% (2/35) in CRF01_AE (p < 0.001). In 49 patients that followed-up a median 10 months later, HIV drug resistance mutations at >20% frequency such as K103N, M184VI and P225H still existed, but with decreased frequencies. The prevalence of HIV drug resistance in ART interruption was higher than 15% in the survey. Next-generation sequencing was able to detect more minority drug resistance variants than Sanger. There was a sharp increase in minority drug resistance variants when the detection threshold was below 5%.

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 Major drug resistance mutations to HIV-1 protease inhibitors (PI) among patients exposed to PI class failing antiretroviral therapy in São Paulo State, Brazil

PLoS ONE ◽  
2019 ◽  
Vol 14 (10) ◽  
pp. e0223210
Author(s):  
Giselle de Faria Romero Soldi ◽  
Isadora Coutinho Ribeiro ◽  
Cintia Mayumi Ahagon ◽  
Luana Portes Ozório Coelho ◽  
Gabriela Bastos Cabral ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Protease Inhibitors ◽  
Sao Paulo ◽  
Resistance Mutations ◽  
Paulo State ◽  
Drug Resistance Mutations ◽  
São Paulo State ◽  
Major Drug ◽  
Hiv 1

scholarly journals HIV-1 transmitted drug resistance mutations among antiretroviral therapy-Naïve individuals in Surabaya, Indonesia

2015 ◽  
Vol 12 (1) ◽  
Author(s):  
Tomohiro Kotaki ◽  
Siti Qamariyah Khairunisa ◽  
Adiana Mutamsari Witaningrum ◽  
Muhammad Qushai Yunifiar M ◽  
Septhia Dwi Sukartiningrum ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Transmitted Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv 1
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