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1.
BMC Infect Dis ; 20(1): 660, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894102

RESUMO

INTRODUCTION: Although women comprise 33% of the HIV-1-carriers in Israel, they have not previously been considered a risk group requiring special attention. Immigration waves from countries in Africa and in East Europe may have changed the local landscape of women diagnosed with HIV-1. Here, we aimed to assess viral and demographic characteristics of HIV-1-positive women identified in Israel between 2010 and 2018. METHODS: All > 16 year-old, HIV-1-infected women, diagnosed in Israel in 2010-2018, (n = 763) registered in the National HIV reference laboratory were included in this cross-sectional study. Demographic and clinical characteristics were extracted from the database. Viral subtypes and transmitted drug resistance mutations (TDRM) were determined in 337 (44.2%) randomly selected samples collected from treatment-naive women. RESULTS: Median age at diagnosis was 38 years. Most (73.3%) women were immigrants from the former Soviet Union (FSU) (41.2%, 314) or sub-Saharan Africa (SSA) (32.2%, 246) and carried subtype A (79.7%) or C (90.3%), respectively. Only 11.4% (87) were Israeli-born women. Over the years, the prevalence of women from SSA decreased while that of women from FSU increased significantly (p < 0.001). The median CD4+ cell count was 263 cells/mm3, and higher (391 cells/mm3) in Israeli-born women. TDRM were identified in 10.4% of the tested samples; 1.8, 3 and 7.1% had protease inhibitors (PI), nucleotide reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) TDRM, respectively. The prevalence of women with NNRTI TDRM significantly increased from 4.9% in 2010-2012 to 13.3% in 2016-2018. Israeli-born women had the highest prevalence (16.3%) of NNRTI TDRM (p = 0.014). NRTI A62 (5.6%), NNRTI E138 and K103 (5.6 and 4.2%, respectively) were the most prominent mutated sites. CONCLUSIONS: Most HIV-1-positive women diagnosed in Israel in 2010-2018 were immigrants, with the relative ratio of FSU immigrants increasing in recent years. The high proportion of women diagnosed with resistance mutations, particularly, the yearly increase in the frequency of NNRTI mutations, support the national policy of resistance testing at baseline.


Assuntos
Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , HIV-1/genética , Adulto , Antivirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Estudos Transversais , Farmacorresistência Viral/genética , Emigrantes e Imigrantes , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Israel/epidemiologia , Pessoa de Meia-Idade , Mutação , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico
2.
Zhonghua Liu Xing Bing Xue Za Zhi ; 41(8): 1335-1340, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32867446

RESUMO

Objective: To understand the characteristics of HIV-1 genotypes and drug resistance among men who have sex with men in Kunming in 2018. Methods: A total of 193 plasma samples were collected from the newly reported HIV-1 infected MSM in Kunming from January to December 2018. Viral RNA was extracted, and the gag, pol, env gene segments were amplified by nested PCR. HIV-1 genotypes and drug resistance were also analyzed. Subsequently, the evolutionary characteristics of CRF55_01B and CRF68_01B among MSM in Kunming were analyzed by Bayesian Markov Chain Monte Carlo method. Results: Multiple HIV-1 genotypes were identified among these 193 samples, including CRF07_BC (39.4%, 76/193), CRF01_AE (34.2%, 66/193), unique recombinant forms (URFs) (20.2%, 39/193), CRF08_BC (3.1%, 6/193), CRF55_01B (1.6%, 3/193), subtype B (1.0%, 2/193) and CRF68_01B (0.5%, 1/193). Results from the Bayesian evolutionary analysis showed that CRF55_01B started to spread locally after being imported from other provinces, while CRF68_01B was likely to have been brought in from the eastern provinces of China. Prevalence of HIV-1 drug resistant strains was 2.6%(5/190) before antiviral treatment, with mutation rates resistant to non-nucleoside reverse transcriptase inhibitors being the highest (2.1%, 4/190) among MSM in Kunming, 2018. Conclusion: The diversity of HIV-1 was increasing among MSM in Kunming. Although the resistance rate on pretreatment drug was relatively low, the emergence of multiple resistant strains to first-line antiviral drugs posed a challenge to antiretroviral therapy, in Kunming.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , Homossexualidade Masculina , Teorema de Bayes , China/epidemiologia , Genótipo , Infecções por HIV/epidemiologia , Humanos , Masculino
3.
PLoS One ; 15(8): e0236156, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32804970

RESUMO

BACKGROUND: HIV drug resistance (HIVDR) poses a threat to the HIV epidemic control in Zambia especially in sub-populations such as the 15-24 years where there is poor virological suppression. Understanding the prevalence and patterns of HIVDR in this population (15-24 years) will contribute to defining effective antiretroviral therapy (ART) regimens, improving clinical decision making, and supporting behavioral change interventions needed to achieve HIV epidemic control. METHODS: A cross-sectional analysis of study enrollment data from the Project YES! Youth Engaging for Success randomized controlled trial was conducted. Participants were 15 to 24 years old, who knew their HIV status, and had been on ART for at least 6 months. All participants completed a survey and underwent viral load (VL) testing. Participants with viral failure (VL ≥1,000 copies/mL) underwent HIVDR testing which included analysis of mutations in the protease and reverse transcriptase genes. RESULTS: A total of 99 out of 273 analyzed participants receiving ART had VL failure, of whom 77 had successful HIVDR amplification and analysis. Out of the 77, 75% (58) had at least one drug resistant mutation, among which 83% (48/58) required a drug change. Among the 58 with HIVDR mutations, the prevalence of at least one HIVDR mutation to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 81%, 65.5% and 1.7%. The mutation M184V which confers resistance to NRTI drugs of lamivudine (3TC) and emtricitabine (FTC) was the most common (81%) among NRTI associated mutations followed by K65R (34.5%) which is associated with both tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) resistance. Thymidine analogue mutations (TAMs) which confer resistance primarily to zidovudine (AZT), stavudine (d4T) and other NRTIs were observed at 32.8%. Common TAMs were K70RTQNE (32.8%), K219QE (22.4%), D67N (17.2%) and T215IT (15.5%). The most common NNRTI associated mutation was the K103N (65.5%) which confers resistance to both efavirenz (EFV) and nevirapine (NVP). There was a relatively high occurrence of other NNRTI mutations V106A (36.2%), as well as Y188C (36.2%) and Y181C (36.2%) which confer resistance to etravirine. CONCLUSIONS: There is a high prevalence of HIVDR including TAMs despite majority of these patients (90.48%) being on AZT or d4T sparing first line ART among the youth. Emergence of these mutations including the NNRTI associated mutations (Y181C and Y188C) may compromise future second- and third-line regimens in the absence of routine HIVDR testing. HIVDR monitoring at start of ART or at first-line failure can better inform clinical decision making and ART programing.


Assuntos
Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Adolescente , Fármacos Anti-HIV/uso terapêutico , Tomada de Decisão Clínica , Estudos Transversais , Feminino , Infecções por HIV/epidemiologia , HIV-1/genética , Humanos , Masculino , Mutação , Prevalência , RNA Viral/genética , RNA Viral/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Timidina/genética , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zâmbia
4.
BMC Infect Dis ; 20(1): 631, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32842977

RESUMO

BACKGROUND: The drug resistance and the virologic failure of antiretroviral therapy (ART) are quite severe in Liangshan. A better understanding of the virologic failure of ART and the HIV-1 transmission network dynamics is essential for the surveillance and prevention of HIV. Here, we analyzed the HIV-1 CRF07_BC strain genetic transmission networks and their associated factors among people living with HIV-1 (PLWH) who had virologic failure of ART by using close genetic links. METHODS: The drug-resistant mutations were determined using the Stanford University HIV Drug Resistance Database. HIV-1 pol genes sequences were used for phylogenetic and genotypic drug resistance analysis. The genetic transmission networks were performed by comparing sequences, constructing the phylogenetic tree, calculating the pairwise distance, and visualizing the network. RESULTS: A total of 1050 PLWH with CRF07_BC pol sequences were finally identified and included in the genetic transmission network analysis from 2016 to 2017. Of the 1050 CRF07_BC pol sequences, 346 (32.95%) fell into clusters at a genetic distance of 0.006, resulting in 137 clusters ranging in size from 2 to 40 individuals. Subjects who were widowed or divorced were less likely to form a genetic transmission network (adjusted OR: 0.50), while subjects who had shared a needle ≥ five times were more likely to form a network (adjusted OR: 1.88). CONCLUSIONS: The genetic transmission networks revealed the complex transmission pattern, highlighting the urgent need for transmission monitoring of virologic failure of ART and selection of more effective therapeutic regimens to promote viral suppression.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , HIV-1/genética , Grupos Minoritários , Adolescente , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Genes pol , Infecções por HIV/virologia , Humanos , Masculino , Mutação , Filogenia , Falha de Tratamento , Adulto Jovem
5.
PLoS One ; 15(8): e0236642, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756581

RESUMO

INTRODUCTION: The long-term prognosis of HIV-2-infected patients receiving antiretroviral therapy (ART) is still challenging, due to the intrinsic resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the suboptimal response to some protease inhibitors (PI). The objective was to describe the 5-years outcomes among HIV-2 patients harboring drug-resistant viruses. METHODS: A clinic-based cohort of HIV-2-patients experiencing virologic failure, with at least one drug resistance mutation was followed from January 2012 to August 2017 in Côte d'Ivoire. Follow-up data included death, lost to follow-up (LTFU), immuno-virological responses. The Kaplan-Meier curve was used to estimate survival rates. RESULTS: A total of 31 HIV-2 patients with virologic failure and with at least one drug resistance mutation were included. Two-third of them were men, 28(90.3%) were on PI-based ART-regimen at enrolment and the median age was 50 years (IQR = 46-54). The median baseline CD4 count and viral load were 456 cells/mm3 and 3.7 log10 c/mL respectively, and the participants have been followed-up in median 57 months (IQR = 24-60). During this period, 21 (67.7%) patients switched at least one antiretroviral drug, including two (6.5%) and three (9.7%) who switched to a PI-based and an integrase inhibitor-based regimen respectively. A total of 10(32.3%) patients died and 4(12.9%) were LTFU. The 36 and 60-months survival rates were 68.5% and 64.9%, respectively. Among the 17 patients remaining in care, six(35.3%) had an undetectable viral load (<50 c/mL) and for the 11 others, the viral load ranged from 2.8 to 5.6 log10 c/mL. Twelve patients were receiving lopinavir at the time of first genotype, five(42%) had a genotypic susceptibility score (GSS) ≤1 and 4(33%) a GSS >2. CONCLUSIONS: The 36-months survival rate among ART-experienced HIV-2 patients with drug-resistant viruses is below 70%,lower than in HIV-1. There is urgent need to improve access to second-line ART for patients living with HIV-2 in West Africa.


Assuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-2/genética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , Costa do Marfim/epidemiologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , HIV-2/efeitos dos fármacos , HIV-2/patogenicidade , Humanos , Lopinavir/administração & dosagem , Pessoa de Meia-Idade , Mutação , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Carga Viral/efeitos dos fármacos , Carga Viral/genética
6.
PLoS One ; 15(8): e0237162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32750098

RESUMO

Viral diversity is an important feature of hepatitis C virus (HCV) infection and an important predictor of disease progression and treatment response. HIV/HCV co-infection is associated with enhanced HCV replication, increased fibrosis, and the development of liver disease. HIV also increases quasispecies diversity of HCV structural genes, although limited data are available regarding the impact of HIV on non-structural genes of HCV, particularly in the absence of direct-acting therapies. The genetic diversity and presence of drug resistance mutations within the RNA-dependent RNA polymerase (NS5B) gene were examined in 3 groups of women with HCV genotype 1a infection, including those with HCV mono-infection, antiretroviral (ART)-naïve women with HIV/HCV co-infection and CD4 cell count <350 cells/mm3, and ART-naïve women with HIV/HCV co-infection and CD4 cell count ≥350 cells/mm3. None had ever been treated for HCV infection. There was evidence of significant diversity across the entire NS5B gene in all women. There were several nucleotides and amino acids with distinct distributions across the three study groups, although no obvious clustering of NS5B sequences was observed based on HIV co-infection or CD4 cell count. Polymorphisms at amino acid positions associated with resistance to dasabuvir and sofosbuvir were limited, although the Q309R variant associated with ribavirin resistance was present in 12 individuals with HCV mono-infection, 8 HIV/HCV co-infected individuals with CD4 <350 cells/mm3, and 12 HIV/HCV co-infected individuals with CD4 ≥350 cells/mm3. Previously reported fitness altering mutations were rare. CD8+ T cell responses against the human leukocyte antigen (HLA) B57-restricted epitopes NS5B2629-2637 and NS5B2936-2944 are critical for HCV control and were completely conserved in 44 (51.8%) and 70 (82.4%) study participants. These data demonstrate extensive variation across the NS5B gene. Genotypic variation may have a profound impact on HCV replication and pathogenesis and deserves careful evaluation.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/genética , Coinfecção/genética , Variação Genética , HIV , Hepacivirus/genética , Hepatite C/genética , Proteínas não Estruturais Virais/genética , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/virologia , Adulto , Sequência de Aminoácidos , Antivirais/uso terapêutico , Contagem de Linfócito CD4 , Estudos de Coortes , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Filogenia , RNA Replicase/genética , RNA Viral/genética , RNA Viral/isolamento & purificação , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Uracila/análogos & derivados , Uracila/uso terapêutico
7.
BMC Infect Dis ; 20(1): 524, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32689975

RESUMO

BACKGROUND: Currently recommended boosted protease-inhibitor (bPI) regimens may be associated with increased risk of cardiovascular or chronic kidney diseases; in addition, boosted regimens are particularly associated with drug-drug interactions. Since both cardiovascular and renal disease, and polypharmacy, are common in ageing people with HIV, there is a need for alternative efficacious regimens. bPI-based regimens are often the treatment of choice for individuals with pre-treatment or treatment-acquired resistance but it is plausible that carefully selected HIV-positive individuals with drug resistance, who are virologically suppressed on their current bPI regimen, could maintain virological efficacy when switched to bictegravir, emtricitabine and tenofovir alafenamide (B/F/TAF) fixed dose combination (FDC). METHODS/DESIGN: A phase IV, investigator-initiated, multicentre, open label pilot, randomised two-arm study to assess the safety and efficacy of switching from bPI regimen to B/F/TAF single tablet regimen in integrase inhibitor-naïve, virologically suppressed adults with HIV-1 infection harbouring drug resistance mutations. Eligible individuals will either continue on their bPI regimen or switch to B/F/TAF FDC. After 24 weeks, all participants in the bPI arm will be switched to B/F/TAF and followed for a further 24 weeks and all participants will be followed for 48 weeks. The primary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24 using pure virologic response whilst the secondary efficacy endpoint is the proportion of participants with HIV-1 RNA < 50 copies/mL at Week 48. Other secondary outcome measures include between arm comparisons of drug resistance at virological failure, safety and tolerability and patient-reported outcome measures. DISCUSSION: We aim to provide preliminary evidence of the efficacy of switching to B/F/TAF in patients with virological suppression on a bPI-based regimen who harbour select drug resistance mutations. TRIAL REGISTRATION: ISRCTN 44453201 , registered 19 June 2019 and EudraCT 2018-004732-30.


Assuntos
Adenina/análogos & derivados , Farmacorresistência Viral/genética , Emtricitabina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêutico , Adenina/uso terapêutico , Adulto , Combinação de Medicamentos , Emtricitabina/efeitos adversos , Feminino , Infecções por HIV/genética , Infecções por HIV/virologia , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Mutação , Projetos Piloto , Estudos Prospectivos , Inibidores de Proteases/efeitos adversos , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento
8.
BMC Infect Dis ; 20(1): 478, 2020 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-32631240

RESUMO

BACKGROUND: Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir. CASE PRESENTATION: A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/µL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2. CONCLUSIONS: In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.


Assuntos
Antivirais/uso terapêutico , Ciclopentanos/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/tratamento farmacológico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/uso terapêutico , Triazinas/uso terapêutico , Ciclopentanos/efeitos adversos , Ciclopentanos/farmacologia , Farmacorresistência Viral/genética , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Guanidinas/efeitos adversos , Guanidinas/farmacologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Hospedeiro Imunocomprometido , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Mutação , Neuraminidase/antagonistas & inibidores , Neuraminidase/genética , Oseltamivir/uso terapêutico , Transplante Homólogo/métodos , Resultado do Tratamento , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/genética
9.
BMC Infect Dis ; 20(1): 532, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698772

RESUMO

BACKGROUND: The World Health Organisation recommends the use of tenofovir-containing pre-exposure prophylaxis (PrEP) as an additional Human Immunodeficiency Virus (HIV) prevention choice for men and women at substantial risk of HIV infection. PrEP could fill an important HIV prevention gap, especially for sexually active young women who are limited in their ability to negotiate mutual monogamy or condom use. As PrEP is scaled up in high HIV incidence settings, it is crucial to consider the importance of early identification of HIV infection during PrEP use, to allow for rapid discontinuation of PrEP to reduce the risk of antiretroviral (ARV) resistance. The purpose of this case study is to provide this critical evidence. CASE PRESENTATION: This report describes a 20-year-old woman in a HIV sero-discordant relationship who initiated oral PrEP (tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC)) through a demonstration project (CAPRISA 084) in October 2017. Despite good adherence throughout her PrEP use, she tested HIV antibody positive at month nine of study participation. Retrospective testing showed increasing HIV viral load over time, and retrospective use of fourth-generation rapid HIV tests showed HIV detection (positive antigen/antibody) at month one. Sequencing confirmed a dominant wild type at month one with dual therapy resistance patterns emerging by month three (M184V and K65R mutations), which is suggestive of protracted PrEP use during an undetected HIV infection. The participant was referred to infectious diseases for further management of her HIV infection and was initiated on a first line, tenofovir-sparing regimen. At the time of this report (January 2020), the participant had been on ARV- therapy (ART) for 13 months and had no signs of either clinical, immunologic or virologic failure. CONCLUSIONS: This case report highlights the importance of appropriate HIV screening during wider oral PrEP scale-up in high HIV incidence settings to circumvent the consequences of prolonged dual therapy in an undiagnosed HIV infection and in turn prevent ARV resistance.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/uso terapêutico , Epidemias/prevenção & controle , Soropositividade para HIV/tratamento farmacológico , HIV-1/imunologia , Profilaxia Pré-Exposição/métodos , Administração Oral , Benzoxazinas/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/administração & dosagem , Combinação Emtricitabina e Fumarato de Tenofovir Desoproxila/efeitos adversos , Feminino , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Estudos Retrospectivos , África do Sul , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem , Zidovudina/uso terapêutico
10.
Arch Virol ; 165(10): 2193-2203, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32638116

RESUMO

Patients with thalassemia major are at high risk of hepatitis C through blood transfusion from donors infected by hepatitis C virus (HCV). The use of direct-acting antiviral (DAA) therapy against such HCV infections has increased in different populations. However, resistant viral variants can affect treatment outcomes, and therefore improved surveillance strategies are needed. Accordingly, we aimed to evaluate resistance-associated substitutions (RASs) to HCV DAAs at the baseline of treatment in thalassemia patients in a referral center. Out of 89 thalassemia patients who suffered from HCV infection and were referred to our center between 2016 and 2017, 43 underwent further analysis of the HCV nonstructural proteins NS5A and NS5B using polymerase chain reaction (PCR) sequencing methods. Unique primers were designed using bioinformatics software for separate detection of HCV subtypes 1a, 3a, and 1b. Detection of RASs was performed based on previously published literature. Statistical analysis was carried out using SPSS version 19. The participants, 60.4% (26/43) of whom were male, had a mean age ± standard deviation (SD) of 33.0 ± 5.0 years. HCV subtype 1a was found in 27 cases, 3a in 13, and 1b in three. In HCV subtype 1a there were 163 mutations in NS5A and 212 mutations in NS5B. The frequency of RASs was 20.9% (8 RASs in 9 patients), including M28V and H58P in subtype 1a, L28M, R30Q, C316N, and C316S in subtype 1b, and S24F in subtype 3a. Statistically, the subtype 1b and a higher mutation rate in NS5A were associated with RASs (p-value < 0.05). The emergence of natural RASs to HCV DAAs serves as a warning of the risk of drug resistance in response to the broad usage of antivirals. However, relapses in these DAA-treated HCV-infected thalassemia patients are rarely reported. Our findings indicate that the prevalence of RASs prevalence at baseline was 20.9% in these patients, and this calls for extrapolation to a larger population study, as highlighted in other studies, with larger sample sizes, high-throughput methods, and follow-up in order to fully evaluate treatment outcomes in RASs-detected individuals. Optimized therapeutic strategies, particularly in complex, difficult-to-cure patients, can effectively prevent DAA treatment failure as a result of selection for RASs.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Talassemia/virologia , Adulto , Farmacorresistência Viral/genética , Feminino , Genótipo , Hepacivirus/genética , Humanos , Masculino , Mutação/genética , Encaminhamento e Consulta , Proteínas não Estruturais Virais/genética
11.
PLoS One ; 15(7): e0235958, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32692778

RESUMO

BACKGROUND: With the scale-up of antiretroviral therapy (ART), pre-treatment drug resistance (PDR) appears ≥10% amongst ART-initiators in many developing countries, including Cameroon. Northwest region-Cameroon having the second epidemiological burden of HIV infection, generating data on PDR in these geographical settings, will enhance evidence-based decision-making. OBJECTIVES: We sought to ascertain levels of PDR and HIV-1 clade dispersal in rural and urban settings, and their potential association with subtype distribution and CD4-staging. METHODS: A cross-sectional study was conducted from February to May 2017 among patients recently diagnosed with HIV-infection and initiating ART at the Bamenda regional Hospital (urban setting) and the Mbingo Baptist hospital (rural setting). Protease and reverse transcriptase sequencing was performed using an in-house protocol and pre-treatment drug resistance mutations were interpreted using Stanford HIVdb.v8.3. Phylogeny was performed for subtype assignation. RESULTS: A total of 61 patient sequences were generated from ART initiators (median age: 37 years old; 57.4% female; median CD4 cell count: 184 [IQR: 35-387] in urban vs. 161 [IQR: 96-322] cells/mm3 in rural). Overall, the level of PDR was 9.8% (6/61). Of note, burden of PDR was almost doubled in urban (12.9% [4/31]) compared to rural setting 6.7% (2/30), p = 0.352). Fifteen (15) PDR mutations were found among four patients the urban settings [6 resistance mutations to NRTIs:[M41L (2), E44D (1), K65R (1), K70E (1), M184V/I (2), K219R (1)] and 6 resistance mutations to NNRTIs: K103N (1), E138A/G (2), V179E (1), M230L (1), K238T (1), P225H (1)] against two (02) mutations found in two patients in the rural setting[2 resistant mutations to NNRTIs: E138A (1) and Y188H (1)]. The rural setting showed more genetic diversity (8 subtypes) than the urban setting (5 subtypes), with CRF02_AG being the most prevalent clade (72.1% [44/61]). Of note, level of PDR was similar between patients infected with CRF02_AG and non-CRF02_AG infected (9.1% [4/44]) vs. 11.8% [2/17]), p = 1.000). Moreover, PDR appeared higher in patients with CD4 cell count <200 cells/mm3 compared to those with CD4 cell count ≥200 cells/mm3 (14.7% [5/34]) vs. 3.7% [1/27]), p = 0.214). CONCLUSIONS: PDR is at a moderate rate in the Northwest region of Cameroon, with higher burden within urban populations. CRF02_AG is the most predominant clade in both urban and rural settings. No effect of HIV molecular epidemiology and CD4-staging on the presence of PDR in patients living in these settings was found. Our findings suggest close monitoring, NNRTI-sparing regimens or sequencing for patients initiating ART, especially in urban settings.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Variação Genética/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Carga Viral/efeitos dos fármacos , Adulto , Camarões/epidemiologia , Estudos Transversais , Feminino , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1/isolamento & purificação , Humanos , Masculino , População Rural , População Urbana , Carga Viral/genética
12.
Comput Biol Med ; 121: 103749, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32568687

RESUMO

This paper continues a recent study of the spike protein sequence of the COVID-19 virus (SARS-CoV-2). It is also in part an introductory review to relevant computational techniques for tackling viral threats, using COVID-19 as an example. Q-UEL tools for facilitating access to knowledge and bioinformatics tools were again used for efficiency, but the focus in this paper is even more on the virus. Subsequence KRSFIEDLLFNKV of the S2' spike glycoprotein proteolytic cleavage site continues to appear important. Here it is shown to be recognizable in the common cold coronaviruses, avian coronaviruses and possibly as traces in the nidoviruses of reptiles and fish. Its function or functions thus seem important to the coronaviruses. It might represent SARS-CoV-2 Achilles' heel, less likely to acquire resistance by mutation, as has happened in some early SARS vaccine studies discussed in the previous paper. Preliminary conformational analysis of the receptor (ACE2) binding site of the spike protein is carried out suggesting that while it is somewhat conserved, it appears to be more variable than KRSFIEDLLFNKV. However compounds like emodin that inhibit SARS entry, apparently by binding ACE2, might also have functions at several different human protein binding sites. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 is again argued to be a convenient model pharmacophore perhaps representing an ensemble of targets, and it is noted that it occurs both in lung and alimentary tract. Perhaps it benefits the virus to block an inflammatory response by inhibiting the dehydrogenase, but a fairly complex web involves several possible targets.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Glicoproteína da Espícula de Coronavírus/química , Vacinas Virais/imunologia , Sequência de Aminoácidos , Animais , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/genética , Betacoronavirus/imunologia , Sítios de Ligação , Biologia Computacional , Coronavirus/química , Coronavirus/genética , Coronavirus/imunologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Desenho de Fármacos , Farmacorresistência Viral/genética , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Modelos Moleculares , Mutação , Peptidomiméticos/farmacologia , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Homologia de Sequência de Aminoácidos , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Virais/genética
13.
PLoS One ; 15(6): e0234133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525892

RESUMO

BACKGROUND: The first case of HIV infection in Sri Lanka was reported in 1987 and at the end of 2018 there were 3500 people living with HIV. There have been commendable efforts made towards the detection, treatment, and prevention of HIV in the country. Even though the genetic diversity of HIV has been shown to affect the parameters ranging from detection to vaccine development, there is no data available with respect to the molecular epidemiology of HIV-1 in Sri Lanka. METHODS: In this report we have performed the ancillary analysis of pol gene region sequences (n = 85) obtained primarily for the purpose of HIV-1 drug resistance genotyping. Briefly, dried blood spot specimens (DBS) collected from HIV-1 infected individuals between December 2015 and August 2018 were subjected to pol gene amplification and sequencing. These pol gene sequences were used to interpret the drug resistance mutation profiles. Further, sequences were subjected to HIV-1 subtyping using REGA 3.0, COMET, jPHMM and, RIP online subtyping tools. Moreover, Bayesian phylogenetic analysis was employed to estimate the evolutionary history of HIV-1 subtype C in Sri Lanka. RESULTS: Our analysis revealed that the majority (51.8%) of pol gene sequences were subtype C. Other than subtype C, there were sequences categorized as subtypes A1, B, D and G. In addition to pure subtypes there were sequences which were observed to be circulating recombinant forms (CRFs) and a few of the recombinants were identified as potential unique recombinants (URFs). We also observed the presence of drug resistance mutations in 56 (65.9%) out of 85 sequences. Estimates of the Bayesian evolutionary analysis suggested that the HIV-1 subtype C was introduced to Sri Lanka during the early 1970s (1972.8). CONCLUSION: The findings presented here indicate the presence of multiple HIV-1 subtypes and the prevalence of drug resistance mutations in Sri Lanka. The majority of the sequences were subtype C, having their most recent common ancestor traced back to the early 1970s. Continuous molecular surveillance of HIV-1 molecular epidemiology will be crucial to keep track of drug resistance, genetic diversity, and evolutionary history of HIV-1 in Sri Lanka.


Assuntos
Variação Genética , HIV-1/metabolismo , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Adolescente , Adulto , Idoso , Antirretrovirais/uso terapêutico , Teorema de Bayes , Criança , Pré-Escolar , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Filogenia , Sri Lanka/epidemiologia , Adulto Jovem , Produtos do Gene pol do Vírus da Imunodeficiência Humana/química , Produtos do Gene pol do Vírus da Imunodeficiência Humana/classificação
14.
BMC Infect Dis ; 20(1): 443, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32576136

RESUMO

BACKGROUND: Liangshan Yi Autonomous Prefecture is one of the areas that most severely affected by human immunodeficiency virus (HIV) in China, and virological failure on antiretroviral therapy (ART) is serious in this area. Analyses of prevalence and determinants of ART failure, the genetic diversity and drug resistance among people living with HIV (PLWH) helps improve HIV treatment efficiency and prevent HIV transmission. METHODS: A total of 5157 PLWH were recruited from 2016 to 2017. The venous blood samples were subjected to RT-PCR, followed by sequencing of the HIV-1 pol gene, targeting the protease and reverse transcriptase fragments. HIV-1 diversity was analyzed using the DNAStar software and drug resistance mutations were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: A total of 2156 (41.81%) PLWH showed virological failure on ART. Males (ORm = 1.25), heterosexual behaviors and drug injection (ORm = 1.44) and mother to child transmission routes (ORm = 1.58), the clinical stage of AIDS (ORm = 1.35), having used illicit drugs and shared the needles (1-4 times: ORm = 1.34; more than 5 times: ORm = 1.52), having ever replaced ART regimen (ORm = 1.48) increased the risk of virological failure among PLWH, while higher education lever (ORm = 0.77) and ≥ 12 months on ART (12 ~ 36 months: ORm = 0.72; ≥36 months: ORm = 0.66) was associated with lower likelihood of virological failure. The data revealed that CRF07_BC (1508, 95.62%) were the most common strains, and the drug-resistant rate was 32.10% among PLWH with virological failure in this area. The high frequencies of drug resistance were found in EFV and NVP of NNRTIs, ABC, FTC and 3TC of NRTIs, and TPV/r in PIs. The most common mutations in NNRTIs, NRTIs and PIs were K103N/KN (64.69%), M184V/MV/I (36.29%) and Q58E/QE (4.93%), respectively. CONCLUSION: We concluded that surveillance of virological failure, HIV-1 subtypes, and drug resistance to understand HIV-1 epidemiology and guide modification of ART guidelines, and target prevention and control strategies should be formatted to reduce the virological failure and drug resistance to promote viral suppression and prevent HIV-1 transmission.


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Variação Genética , HIV-1/genética , Grupos Minoritários , Inibidores da Transcriptase Reversa/uso terapêutico , Síndrome de Imunodeficiência Adquirida/sangue , Síndrome de Imunodeficiência Adquirida/transmissão , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , China/epidemiologia , Feminino , Genes pol , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Masculino , Mutação , Prevalência , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
PLoS One ; 15(6): e0234937, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555643

RESUMO

We have previously reported on HIV-1 infected patients who fail anti-retroviral therapy but manage to re-suppress without a regimen change despite harbouring major drug resistance mutations. Here we explore phenotypic drug resistance in such patients in order to better understand this phenomenon. Patients (n = 71) failing a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, but who subsequently re-suppressed on the same regimen, were assessed for HIV-1 genotypic drug resistance through Sanger sequencing. A subset (n = 23) of these samples, as well as genotypically matched samples from patients who did not re-suppress (n = 19), were further assessed for phenotypic drug resistance in an in vitro single cycle assay. Half of the patients (n = 36/71, 51%) harboured genotypic drug resistance, with M184V (n = 18/36, 50%) and K103N (n = 16/36, 44%) being the most prevalent mutations. No significant difference in the median time to re-suppression (31-39 weeks) were observed for either group (p = 0.41). However, re-suppressors with mutant virus rebounded significantly earlier than those with wild-type virus (16 vs. 33 weeks; p = 0.014). Similar phenotypic drug resistance profiles were observed between patients who re-suppressed and patients who failed to re-suppress. While most remained susceptible to stavudine (d4T) and zidovudine (AZT), both groups showed a reduced susceptibility to 3TC and NNRTIs. HIV- 1 infected patients on an NNRTI-based regimen can achieve viral re-suppression on the same regimen despite harbouring viruses with genotypic and phenotypic drug resistance. However, re-suppression was less durable in those with resistance, reinforcing the importance of appropriate regimen choices, ongoing viral load monitoring and adherence counselling.


Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Inibidores da Transcriptase Reversa , Carga Viral/efeitos dos fármacos , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Fenótipo , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico
16.
PLoS One ; 15(6): e0234811, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32544182

RESUMO

BACKGROUND: L31 and Y93 in the NS5A region of the hepatitis C virus (HCV) are the most important substitution positions associated with resistance to direct-acting antiviral (DAA) treatment. METHODS: We analyzed the frequency of NS5A L31M/V and Y93/H in NS5A inhibitor-naive HCV genotype 1 patients who received asunaprevir plus daclatasvir combination treatment using a conventional sequencing method and a deep sequencing method that can distinguish a single substitution at either position and a double substitution at both positions with a 0.1% detection threshold. RESULTS: The frequency of substitutions at both sites using the conventional method was very low, with 1 in 14 non-responders and 0 in 42 randomly selected responder patients. On the other hand, for the deep sequencing method, cases with double substitutions in the tandem sequence were detected in 8/14 non-responders and 1/42 responders (p<0.0001). For the conventional method, substitutions were detected at any position in 6/14 non-responders and 2/42 responders (p = 0.0019), with a clear difference between the two groups. The difference was also clear with the deep sequencing method, with 11/14 non-responders and 8/42 responders. Interestingly, for the deep sequencing method, the single substitution of L31 was found in 6/14 non-responders and 7/42 responders, whereas single substitutions of Y93 or double substitutions were found in 7/14 vs. 1/42 and 8/14 vs. 1/42 patients, respectively. CONCLUSIONS: NS5A L31 and Y93 substitutions were detected in tandem by the deep sequencing methods in several genotype 1 patients, who may be more resistant to DAA treatment containing an NS5A inhibitor.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Imidazóis/uso terapêutico , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/genética , Idoso , Estudos de Casos e Controles , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Masculino , Mutação , Resposta Viral Sustentada , Falha de Tratamento
17.
PLoS One ; 15(5): e0223464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379830

RESUMO

Resistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility. This was further supported by weaker non-bonded pairwise interaction energy and binding free energy values between the drug DTG and E92Q, Y143R and G140S mutants suggesting reduced binding affinity, as indicated by interaction analysis in comparison to the WT. Our findings suggest the G140S mutant has the strongest effect on the HIV-1C IN protein structure and Dolutegravir binding. To the best of our knowledge, this is the first study that uses the consensus wild type HIV-1C IN sequence to build an accurate 3D model to understand the effect of three known mutations on DTG drug binding in a South Africa context.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/metabolismo , Integrase de HIV/genética , Integrase de HIV/metabolismo , HIV-1/enzimologia , Compostos Heterocíclicos com 3 Anéis/metabolismo , Mutação , Sequência de Aminoácidos , Domínio Catalítico/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica/genética , Estabilidade Proteica , Quinolonas/metabolismo , Quinolonas/uso terapêutico , Raltegravir Potássico/metabolismo , Raltegravir Potássico/uso terapêutico , África do Sul , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
19.
Nature ; 582(7811): 277-282, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-164175

RESUMO

The great majority of globally circulating pathogens go undetected, undermining patient care and hindering outbreak preparedness and response. To enable routine surveillance and comprehensive diagnostic applications, there is a need for detection technologies that can scale to test many samples1-3 while simultaneously testing for many pathogens4-6. Here, we develop Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (CARMEN), a platform for scalable, multiplexed pathogen detection. In the CARMEN platform, nanolitre droplets containing CRISPR-based nucleic acid detection reagents7 self-organize in a microwell array8 to pair with droplets of amplified samples, testing each sample against each CRISPR RNA (crRNA) in replicate. The combination of CARMEN and Cas13 detection (CARMEN-Cas13) enables robust testing of more than 4,500 crRNA-target pairs on a single array. Using CARMEN-Cas13, we developed a multiplexed assay that simultaneously differentiates all 169 human-associated viruses with at least 10 published genome sequences and rapidly incorporated an additional crRNA to detect the causative agent of the 2020 COVID-19 pandemic. CARMEN-Cas13 further enables comprehensive subtyping of influenza A strains and multiplexed identification of dozens of HIV drug-resistance mutations. The intrinsic multiplexing and throughput capabilities of CARMEN make it practical to scale, as miniaturization decreases reagent cost per test by more than 300-fold. Scalable, highly multiplexed CRISPR-based nucleic acid detection shifts diagnostic and surveillance efforts from targeted testing of high-priority samples to comprehensive testing of large sample sets, greatly benefiting patients and public health9-11.


Assuntos
Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Técnicas Analíticas Microfluídicas/métodos , Viroses/diagnóstico , Viroses/virologia , Animais , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Farmacorresistência Viral/genética , Genoma Viral/genética , HIV/classificação , HIV/genética , HIV/isolamento & purificação , Humanos , Vírus da Influenza A/classificação , Vírus da Influenza A/genética , Vírus da Influenza A/isolamento & purificação , Técnicas Analíticas Microfluídicas/instrumentação , RNA Guia/genética , Sensibilidade e Especificidade
20.
J Transl Med ; 18(1): 179, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: covidwho-102130

RESUMO

BACKGROUND: SARS-CoV-2 is a RNA coronavirus responsible for the pandemic of the Severe Acute Respiratory Syndrome (COVID-19). RNA viruses are characterized by a high mutation rate, up to a million times higher than that of their hosts. Virus mutagenic capability depends upon several factors, including the fidelity of viral enzymes that replicate nucleic acids, as SARS-CoV-2 RNA dependent RNA polymerase (RdRp). Mutation rate drives viral evolution and genome variability, thereby enabling viruses to escape host immunity and to develop drug resistance. METHODS: We analyzed 220 genomic sequences from the GISAID database derived from patients infected by SARS-CoV-2 worldwide from December 2019 to mid-March 2020. SARS-CoV-2 reference genome was obtained from the GenBank database. Genomes alignment was performed using Clustal Omega. Mann-Whitney and Fisher-Exact tests were used to assess statistical significance. RESULTS: We characterized 8 novel recurrent mutations of SARS-CoV-2, located at positions 1397, 2891, 14408, 17746, 17857, 18060, 23403 and 28881. Mutations in 2891, 3036, 14408, 23403 and 28881 positions are predominantly observed in Europe, whereas those located at positions 17746, 17857 and 18060 are exclusively present in North America. We noticed for the first time a silent mutation in RdRp gene in England (UK) on February 9th, 2020 while a different mutation in RdRp changing its amino acid composition emerged on February 20th, 2020 in Italy (Lombardy). Viruses with RdRp mutation have a median of 3 point mutations [range: 2-5], otherwise they have a median of 1 mutation [range: 0-3] (p value < 0.001). CONCLUSIONS: These findings suggest that the virus is evolving and European, North American and Asian strains might coexist, each of them characterized by a different mutation pattern. The contribution of the mutated RdRp to this phenomenon needs to be investigated. To date, several drugs targeting RdRp enzymes are being employed for SARS-CoV-2 infection treatment. Some of them have a predicted binding moiety in a SARS-CoV-2 RdRp hydrophobic cleft, which is adjacent to the 14408 mutation we identified. Consequently, it is important to study and characterize SARS-CoV-2 RdRp mutation in order to assess possible drug-resistance viral phenotypes. It is also important to recognize whether the presence of some mutations might correlate with different SARS-CoV-2 mortality rates.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Evolução Molecular , Genoma Viral/genética , Mutação , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , RNA Replicase/genética , Adulto , Ásia/epidemiologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Farmacorresistência Viral/genética , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , América do Norte/epidemiologia , Oceania/epidemiologia , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo
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