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 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 ◽  
Northeastern China ◽  
Wilcoxon Test ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Z Value ◽  
Hiv 1 ◽  
Time Point

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 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 tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) treatment was analyzed by comparing the mutations at TF time point to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, Wilcoxon 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, there were significantly more natural polymorphisms of 31 sites on reverse transcriptase (RT) 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 time point 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 natural 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 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 Pairwise and higher-order correlations among drug-resistance mutations in HIV-1 subtype B protease

2009 ◽  
Vol 10 (Suppl 8) ◽  
pp. S10 ◽  
Author(s):  
Omar Haq ◽  
Ronald M Levy ◽  
Alexandre V Morozov ◽  
Michael Andrec
Keyword(s):  
Drug Resistance ◽  
Higher Order ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Hiv 1

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 Transmitted drug resistance mutations and subtype diversity among HIV-1 sero-positive voluntary blood donors in Accra, Ghana

2020 ◽  
Author(s):  
Billal Musah Obeng ◽  
Evelyn Yayra Bonney ◽  
Lucy Asamoah-Akuoko ◽  
Nicholas Israel Nii-Trebi ◽  
Gifty Mawuli ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Blood Donors ◽  
Transmitted Drug Resistance ◽  
Nucleotide Sequencing ◽  
Plasma Samples ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Major Drug ◽  
Hiv 1

Abstract Background: Detection of HIV-1 transmitted drug resistance (TDR) and subtype diversity (SD) are public health strategies to assess current HIV-1 regimen and ensure effective therapeutic outcomes of ART among HIV-1 patients. Globally, limited data exist on TDR and SD among blood donors. In this study, drug resistance mutations and subtype diversity among HIV-1 sero-positive blood donors in Accra, Ghana was characterized.Methods: Purposive sampling method was used to collect 81 HIV sero-positive blood samples from the Southern Area Blood Center and confirmed by serology as HIV-1 and/or HIV-2. Viral RNA was only extracted from plasma samples confirmed as HIV-1 positive. Complementary DNA (cDNA) was synthesized using the RNA as a template and subsequently amplified by nested PCR with specific primers. The expected products were verified, purified and sequenced. Neighbor-joining tree with the Kimura’s 2-parameter distances was generated with the RT sequences using Molecular Evolutionary Genetic Analysis version 6.0 (MEGA 6.0).Results: Out of the 81 plasma samples, 60 (74%) were confirmed as HIV-1 sero-positive by INNO-LIA HIVI/II Score kit with no HIV-2 and dual HIV-1/2 infections. The remaining samples, 21 (26%) were confirmed as HIV sero-negative. Of the 60 confirmed positive samples, (32) 53% and (28) 50% were successfully amplified in the RT and PR genes respectively. Nucleotide sequencing of amplified samples revealed the presence of major drug resistance mutations in two (2) samples; E138A in one sample and another with K65R. HIV-1 Subtypes including subtypes A, B, CRF02_AG and CRF09_cpx were found. Conclusion: This study found major drug resistance mutations, E138A and K65R in the RT gene that confer high level resistance to most NNRTIs and NRTI respectively. CRF02_AG was most predominant, the recorded percentage of subtype B and the evolutionary relationship inferred by phylogenetic analysis suggest possible subtype importation. The data obtained would inform the selection of drugs for ART initiation to maximize therapeutic options in drug-naïve HIV-1 patients in Ghana.

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

scholarly journals MOLECULAR-EPIDEMIOLOGICAL CHARACTERISTICS OF HIV1 VARIANTS CIRCULATING IN THE JEWISH AUTONOMOUS REGION TERRITORY

2019 ◽  
Vol 10 (4) ◽  
pp. 90-99 ◽  
Author(s):  
V. O. Kotova ◽  
O. E. Trotsenko ◽  
L. A. Balakhontseva ◽  
E. A. Bazykina ◽  
O. A. Yanovich ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mutations ◽  
Prevalence Index ◽  
Epidemiological Analysis ◽  
Autonomous Region ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Primary Drug Resistance ◽  
Epidemiological Characteristics ◽  
Hiv 1

Objective: to perform a molecular-epidemiological analysis of HIV-1 variants circulating in the Jewish autonomous region territory. Materials and methods. The research included 58 patients with HIV-infection. Amplified pol-gene fragments were used as a template to detect drug resistance mutations by Sanger sequencing (AmpliSens® HIV-Resist-Seq). Pol-gene is coding protease and a part of reverse transcriptase of HIV-1. Phylogenetic analysis was performed using MEGA version 6.0 program. Results: the research revealed an insignificant prevalence of HIV-1 СRF63_02A1 recombinant form. It was registered in 25 patients (44,6%). Sub-subtype A6 was identified in 23 HIV-positive people (41,1%). Subtype B was revealed in 6 cases (10,7%), subtype С — in two cases (3,6%). Primary drug resistance mutations were identified in 9 patients that were undergoing antiretroviral treatment. This dictates the necessity to change the treatment regimen in the specified patients. The prevalence index of drug resistance mutations in naïve patients equaled to 3,8%.

scholarly journals Transmitted drug resistance mutations and subtype diversity amongst HIV-1 sero-positive voluntary blood donors in Accra, Ghana

2020 ◽  
Author(s):  
Billal Musah Obeng ◽  
Evelyn Yayra Bonney ◽  
Lucy Asamoah-Akuoko ◽  
Nicholas Israel Nii-Trebi ◽  
Gifty Mawuli ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Blood Donors ◽  
Transmitted Drug Resistance ◽  
Nucleotide Sequencing ◽  
Plasma Samples ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Major Drug ◽  
Hiv 1

Abstract Background: Detection of HIV-1 transmitted drug resistance (TDR) and subtype diversity (SD) are public health strategies to assess current HIV-1 regimen and ensure effective therapeutic outcomes of antiretroviral therapy (ART) among HIV-1 patients. Globally, limited data exist on TDR and SD among blood donors. In this study, drug resistance mutations (DRMs) and SD amongst HIV-1 sero-positive blood donors in Accra, Ghana were characterized.Methods: Purposive sampling method was used to collect 81 HIV sero-positive blood samples from the Southern Area Blood Center and confirmed by INNO-LIA as HIV-1 and/or HIV-2. Viral RNA was only extracted from plasma samples confirmed as HIV-1 positive. Complementary DNA (cDNA) was synthesized using the RNA as a template and subsequently amplified by nested PCR with specific primers. The expected products were verified, purified and sequenced. Neighbour-joining tree with the Kimura’s 2-parameter distances was generated with the RT sequences using Molecular Evolutionary Genetic Analysis version 6.0 (MEGA 6.0).Results: Out of the 81 plasma samples, 60 (74%) were confirmed as HIV-1 sero-positive by INNO-LIA HIVI/II Score kit with no HIV-2 and dual HIV-1/2 infections. The remaining samples, 21 (26%) were confirmed as HIV sero-negative. Of the 60 confirmed positive samples, (32) 53% and (28) 47% were successfully amplified in the RT and PR genes respectively. Nucleotide sequencing of amplified samples revealed the presence of major drug resistance mutations in two (2) samples; E138A in one sample and another with K65R. HIV-1 Subtypes including subtypes A, B, CRF02_AG and CRF09_cpx were found. Conclusion: This study found major drug resistance mutations, E138A and K65R in the RT gene that confer high level resistance to most NNRTIs and NRTI respectively. CRF02_AG was most predominant, the recorded percentage of subtype B and the evolutionary relationship inferred by phylogenetic analysis may suggest possible subtype importation. However, a more prospective and detailed analysis is needed to establish this phenomenon. The data obtained would inform the selection of drugs for ART initiation to maximize therapeutic options in drug-naïve HIV-1 patients in Ghana.

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