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1.
Emerg Infect Dis ; 25(11): 2108-2111, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436527

RESUMO

In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses' whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.

2.
Euro Surveill ; 24(12)2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30914078

RESUMO

In January 2019, two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir, were detected from epidemiologically unrelated hospitalised children in Japan. The viruses exhibited reduced susceptibility to baloxavir but were susceptible to neuraminidase inhibitors. Only one of the two children had been treated with baloxavir. An epidemiological analysis suggests possible transmission of the PA I38T mutant A(H3N2) virus among humans.

3.
Euro Surveill ; 24(6)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30755292

RESUMO

BACKGROUND: Influenza A(H3N2) virus rapidly evolves to evade human immune responses, resulting in changes in the antigenicity of haemagglutinin (HA). Therefore, continuous genetic and antigenic analyses of A(H3N2) virus are necessary to detect antigenic mutants as quickly as possible. AIM: We attempted to phylogenetically and antigenically capture the epidemic trend of A(H3N2) virus infection in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons. METHODS: We determined the HA sequences of A(H3N2) viruses detected in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons to identify amino acid substitutions and the loss or gain of potential N-glycosylation sites in HA, both of which potentially affect the antigenicity of HA. We also examined the antigenicity of isolates using ferret antisera obtained from experimentally infected ferrets. RESULTS: Influenza A(H3N2) viruses belonging to six clades (clades 3C.2A1, 3C.2A1a, 3C.2A1b, 3C.2A2, 3C.2A3 and 3C.2A4) were detected during the 2016/17 influenza season, whereas viruses belonging to two clades (clades 3C.2A1b and 3C.2A2) dominated during the 2017/18 influenza season. The isolates in clades 3C.2A1a and 3C.2A3 lost one N-linked glycosylation site in HA relative to other clades. Antigenic analysis revealed antigenic differences among clades, especially clade 3C.2A2 and 3C.2A4 viruses, which showed distinct antigenic differences from each other and from other clades in the antigenic map. CONCLUSION: Multiple clades, some of which differed antigenically from others, co-circulated in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons.

4.
Euro Surveill ; 24(3)2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30670142

RESUMO

The novel cap-dependent endonuclease inhibitor baloxavir marboxil was approved for the treatment of influenza virus infection in Japan in February 2018. Two influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic subunit (PA) were detected in baloxavir-treated children in December 2018. This mutation is known to confer reduced susceptibility to baloxavir, and the two mutant viruses exhibited 76- and 120-fold reduced susceptibility to baloxavir.

5.
Influenza Other Respir Viruses ; 13(3): 248-261, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30575288

RESUMO

BACKGROUND: Influenza B is one of the major etiologies for acute respiratory infections (ARI) among children worldwide; however, its clinical-epidemiological information is limited. We aimed to investigate the hospitalization incidence and clinical-epidemiological characteristics of influenza B-associated paediatric ARIs in central Vietnam. METHODS: We collected clinical-epidemiological information and nasopharyngeal swabs from ARI children hospitalized at Khanh Hoa General Hospital, Nha Trang, Vietnam from February 2007 through June 2013. Nasopharyngeal samples were screened for 13 respiratory viruses using Multiplex-PCRs. Influenza B-confirmed cases were genotyped by Haemagglutinin gene sequencing. We analyzed the clinical-epidemiological characteristics of influenza B Lineages (Victoria/Yamagata) and WHO Groups. RESULTS: In the pre-A/H1N1pdm09 period, influenza B-associated ARI hospitalization incidence among children under five was low, ranging between 14.7 and 80.7 per 100 000 population. The incidence increased to between 51.4 and 330 in the post-A/H1N1pdm09. Influenza B ARI cases were slightly older with milder symptoms. Both Victoria and Yamagata lineages were detected before the A/H1N1pdm09 outbreak; however, Victoria lineage became predominant in 2010-2013 (84% Victoria vs 16% Yamagata). Victoria and Yamagata lineages did not differ in demographic and clinical characteristics. In Victoria lineage, Group1 ARI cases were clinically more severe compared to Group5, presenting a greater proportion of wheeze, tachypnea, and lower respiratory tract infection. CONCLUSIONS: The current results highlight the increased incidence of influenza B-related ARI hospitalization among children in central Vietnam in the post-A/H1N1pdm09 era. Furthermore, the difference in clinical severity between Victoria lineage Group1 and 5 implies the importance of influenza B genetic variation on clinical presentation.

6.
Jpn J Infect Dis ; 71(3): 234-238, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29709975

RESUMO

Antigenic changes in the hemagglutinin protein of recent A(H3N2) viruses often arise when these viruses adapt to their egg host. By serial egg passages of a cell-propagated virus, we successfully isolated an egg-adapted influenza A(H3N2) virus, A/Saitama/103/2014, without amino acid substitutions at the antigenic sites of its hemagglutinin protein but with multiple substitutions in its neuraminidase protein. Antigenic analysis of this egg-adapted A/Saitama/103/2014 virus indicated that its antigenicity did not differ from that of the World Health Organization prototype cell-propagated vaccine virus: A/Hong Kong/4801/2014. Our results suggest that this strategy may facilitate egg-based vaccine production without antigenic alterations in hemagglutinin by egg adaptation.


Assuntos
Antígenos Virais/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vacinas contra Influenza/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Cães , Ovos , Furões , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/química , Vírus da Influenza A Subtipo H3N2/genética , Vacinas contra Influenza/química , Vacinas contra Influenza/genética , Células Madin Darby de Rim Canino , Inoculações Seriadas
7.
J Infect Chemother ; 24(6): 407-413, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29433792

RESUMO

BACKGROUND: Influenza A(H1N1)pdm09 virus infections often manifest severe respiratory symptoms, particularly in patients with a past history of allergic disease. Most of these findings were reported during the 2009 pandemic. The purpose of this study was to detail the clinical characteristics of influenza virus-induced lower respiratory infection (LRI) during the A(H1N1)pdm09-predominant 2015-2016 season. METHODS: We retrospectively reviewed the clinical characteristics of influenza-induced LRI cases in children admitted to a tertiary children's hospital. Molecular diagnostic evaluation was performed on samples obtained from the most severe cases. RESULTS: We identified 66 patients with influenza-associated hospitalization and included 21 patients with influenza virus-induced LRI for analyses. Twelve patients (57%) were admitted to the pediatric intensive care unit, seven (33%) required mechanical ventilation, and three (14%) required extracorporeal membrane oxygenation. Plastic bronchitis (PB) was identified in six patients (29%), among whom a past medical history of asthma or food allergy were noted in all six patients. A past history of allergic disease was more common among patients with, than among those without, PB (p = 0.009). A(H1N1)pdm09 was detected from all the PB cases, and phylogenetic analyses of the hemagglutinin and neuraminidase genes demonstrated that this virus belonged to subclades 6B.1 and 6B.2. In the six PB cases, we found one patient with H275Y mutation in neuraminidase. CONCLUSION: Allergic disease was a risk factor for developing PB due to influenza A(H1N1)pdm09 infection during the 2015-16 season.


Assuntos
Bronquite/virologia , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/virologia , Asma , Bronquite/diagnóstico , Criança , Pré-Escolar , Oxigenação por Membrana Extracorpórea , Feminino , Hipersensibilidade Alimentar , Hemaglutininas/genética , Humanos , Influenza Humana/diagnóstico , Unidades de Terapia Intensiva Pediátrica , Masculino , Neuraminidase/genética , Filogenia , Respiração Artificial , Estudos Retrospectivos , Estações do Ano , Centros de Atenção Terciária
8.
Cell Host Microbe ; 22(5): 615-626.e8, 2017 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-29056430

RESUMO

Low pathogenic H7N9 influenza viruses have recently evolved to become highly pathogenic, raising concerns of a pandemic, particularly if these viruses acquire efficient human-to-human transmissibility. We compared a low pathogenic H7N9 virus with a highly pathogenic isolate, and two of its variants that represent neuraminidase inhibitor-sensitive and -resistant subpopulations detected within the isolate. The highly pathogenic H7N9 viruses replicated efficiently in mice, ferrets, and/or nonhuman primates, and were more pathogenic in mice and ferrets than the low pathogenic H7N9 virus, with the exception of the neuraminidase inhibitor-resistant virus, which showed mild-to-moderate attenuation. All viruses transmitted among ferrets via respiratory droplets, and the neuraminidase-sensitive variant killed several of the infected and exposed animals. Neuraminidase inhibitors showed limited effectiveness against these viruses in vivo, but the viruses were susceptible to a polymerase inhibitor. These results suggest that the highly pathogenic H7N9 virus has pandemic potential and should be closely monitored.


Assuntos
Furões/virologia , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia , Animais , Antivirais/farmacologia , Encéfalo/patologia , Encéfalo/virologia , Linhagem Celular , Galinhas/virologia , Túnica Conjuntiva/patologia , Túnica Conjuntiva/virologia , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Aviária/virologia , Pulmão/patologia , Pulmão/virologia , Macaca/virologia , Camundongos , Neuraminidase/efeitos dos fármacos , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Replicação Viral
9.
Influenza Other Respir Viruses ; 11(5): 399-403, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28792671

RESUMO

We characterized influenza A(H1N1)pdm09 isolates from large-scale outbreaks that occurred in Nepal and India in early 2015. Although no specific viral features, which may have caused the outbreaks, were identified, an S84N substitution in hemagglutinin was frequently observed. Chronological phylogenetic analysis revealed that these Nepalese and Indian viruses possessing the S84N substitution constitute potential ancestors of the novel genetic subclade 6B.1 virus that spread globally in the following (2015/16) influenza season. Thus, active surveillance of circulating influenza viruses in the Southern Asia region, including Nepal and India, would be beneficial for detecting novel variant viruses prior to their worldwide spread.


Assuntos
Surtos de Doenças , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/epidemiologia , Influenza Humana/virologia , Substituição de Aminoácidos , Ásia/epidemiologia , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Índia/epidemiologia , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H1N1/enzimologia , Influenza Humana/etnologia , Masculino , Nepal/epidemiologia , Neuraminidase/genética , Filogenia , Análise de Sequência de DNA
10.
Front Microbiol ; 8: 584, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28443077

RESUMO

Influenza A(H3N2) has been a major cause of seasonal influenza in humans since 1968, and has evolved by antigenic drift under the constantly changing human herd immunity. Increasing evidence suggests that the antigenic change occasionally occurred concomitant with the alterations of the N-glycosylation site profile and hemagglutination activity of the virion surface protein hemagglutinin (HA). However, the structural basis of these changes remains largely unclear. To address this issue, we performed molecular dynamics simulations of the glycosylated HA trimers of the A(H3N2), which has a novel pattern of Asn-X-Ser/Thr sequons unique in the new A(H3N2) epidemic clade 3C.2a and is characterized by attenuated ability to agglutinate nonhuman erythrocytes. Comparison of the equilibrated structures of the glycosylated HA trimers with and without the 3C.2a-specific mutations reveals that the mutations could induce a drastic reduction in the apical space for the ligand binding via glycan-shield rearrangement. The results suggest that the 3C.2a strain has evolved an HA structure that is advantageous for evading pre-existing antibodies, while also increasing the ligand binding specificity. These findings have structural implications for our understanding of the phenotypic changes, evolution, and fate of influenza A(H3N2).

11.
Euro Surveill ; 21(24)2016 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-27336226

RESUMO

An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016. This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir.


Assuntos
Ciclopentanos/administração & dosagem , Guanidinas/administração & dosagem , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Oseltamivir/administração & dosagem , Substituição de Aminoácidos/genética , Antivirais/administração & dosagem , Farmacorresistência Viral , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/enzimologia , Japão , Pessoa de Meia-Idade , Mutação , Neuraminidase/antagonistas & inibidores , Neuraminidase/genética , Resultado do Tratamento
12.
Antiviral Res ; 132: 170-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27321665

RESUMO

Favipiravir, a viral RNA-dependent RNA polymerase inhibitor, has recently been approved in Japan for influenza pandemic preparedness. Here, we conducted a cell-based screening system to evaluate the susceptibility of influenza viruses to favipiravir. In this assay, the antiviral activity of favipiravir is determined by inhibition of virus-induced cytopathic effect, which can be measured by using a colorimetric cell proliferation assay. To demonstrate the robustness of the assay, we compared the favipiravir susceptibilities of neuraminidase (NA) inhibitor-resistant influenza A(H1N1)pdm09, A(H3N2), A(H7N9) and B viruses and their sensitive counterparts. No significant differences in the favipiravir susceptibilities were found between NA inhibitor-resistant and sensitive viruses. We, then, examined the antiviral susceptibility of 57 pairs of influenza viruses isolated from patients pre- and post-administration of favipiravir in phase 3 clinical trials. We found that there were no viruses with statistically significant reduced susceptibility to favipiravir or NA inhibitors, although two of 20 paired A(H1N1)pdm09, one of 17 paired A(H3N2) and one of 20 paired B viruses possessed amino acid substitutions in the RNA-dependent RNA polymerase subunits, PB1, PB2 and PA, after favipiravir administration. This is the first report on the antiviral susceptibility of influenza viruses isolated from patients after favipiravir treatment.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Influenza Humana/virologia , Orthomyxoviridae/efeitos dos fármacos , Pirazinas/farmacologia , Amidas/uso terapêutico , Antivirais/uso terapêutico , Linhagem Celular , Células Cultivadas , Efeito Citopatogênico Viral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Farmacorresistência Viral , Humanos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/tratamento farmacológico , Testes de Sensibilidade Microbiana , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/isolamento & purificação , Pirazinas/uso terapêutico , Proteínas Virais/antagonistas & inibidores
14.
Hepatol Res ; 46(8): 775-83, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26517979

RESUMO

AIM: We identified four cases of infection with hepatitis B virus genotype G and A2 recombinant (HBV/G/A2) strains, which were initially overlooked by enzyme immunoassay-based genotyping. The patients were all men who have sex with men (MSM) and inhabited several metropolitan areas of Japan, suggesting that the recombinant strains may be circulating among high-risk groups such as MSM. Here, we investigated the genomic structure and virological properties of the HBV/G/A2 strains. METHODS: Complete genome sequences of the isolates were determined and phylogenetically analyzed. Replication efficiency of HBV/G/A2 was investigated by transfecting plasmids containing 1.24-fold viral genome. The in vivo viral kinetics of HBV/G/A2 were investigated using chimeric mice with humanized livers. RESULTS: Phylogenetic analysis revealed that the four strains were almost identical (>99.7% homologous). The preS2/S region of these strains was highly homologous to that of genotype A2 and the remaining region was almost identical to that of genotype G, reflecting inter-genotypic recombination. Interestingly, in all four cases, genotype A was co-infected as a minor population. In vitro analysis revealed that HBV/G/A2 had a low replication rate. Although detectable viremia was not measurable following the inoculation of HBV/G/A2 into chimeric mice, subsequent superinfection of HBV genotype A greatly enhanced HBV/G/A2 replication and viral spread. CONCLUSION: We found that four cases of HBV/G/A2 recombinant among MSM patients in the metropolitan areas of Japan, and HBV/A co-infections are required for its efficient replication. High-risk groups such as MSM should be carefully tested for infection of genotype G-derived variants.

15.
AIDS Res Hum Retroviruses ; 32(5): 412-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26571151

RESUMO

The major circulating HIV-1 strains in Japan have been subtype B (B) followed by CRF01_AE (AE) in newly diagnosed HIV/AIDS cases. These two subtypes have distinct epidemiological characteristics; B predominates in men who have sex with men, while AE is observed mostly in heterosexuals engaging in high-risk sex. However, transmission networks of these two high-risk populations appear to be crossing over and diffusing. Here we report the emergence of previously unidentified HIV-1 AE/B recombinants in Japan. We initially identified 13 cases with discordant subtyping results with AE (gag MA)/B (pol PR-RT)/AE (env C2V3) by molecular phylogenetic analysis of 1,070 cases who visited Nagoya Medical Center from 1997 to 2012. Genetic characterization of full-length sequences demonstrated that they shared an identical recombinant structure, and was designated as CRF69_01B by the Los Alamos HIV National Laboratory. By reviewing gag, pol, and env sequences collected in the Japanese Drug Resistance HIV-1 Surveillance Network, we found five other CRF69_01B probable cases from different areas in Japan, suggesting that the strain is transmitted widely throughout the country. The time of the most recent common ancestor analyses estimated that CRF69_01B emerged between 1991 and 1995, soon after AE was introduced from neighboring countries in the mid-1990s. Understanding the current epidemic strains is important for the diagnosis and treatment of HIV/AIDS, as well as for the development of globally effective HIV vaccines.


Assuntos
Infecções por HIV/epidemiologia , HIV-1/classificação , HIV-1/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Sequência de Bases , Genótipo , Infecções por HIV/transmissão , Infecções por HIV/virologia , Homossexualidade Masculina , Humanos , Japão/epidemiologia , Masculino , Epidemiologia Molecular , Filogenia , Recombinação Genética , Análise de Sequência de DNA , Sexo sem Proteção
17.
Vaccine ; 34(3): 328-33, 2016 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-26657023

RESUMO

In April 2013, the first three fatal cases of human infection with an avian influenza A virus (H7N9) were reported in China. Because of a pandemic threat by this virus, we have commenced to develop candidate vaccine viruses (CVVs). Three 6:2 genetic reassortant viruses with different hemagglutinin (HA) sequences, NIIDRG-10, -10.1 and -10.2, were generated by a reverse genetics technique between the high egg-growth master virus, A/Puerto Rico/8/34 (H1N1) and A/Anhui/1/2013 (H7N9), kindly provided by the Chinese Center for Disease Control and Prevention. The different HA gene sequences of the three CVVs were derived from the original virus stock. NIIDRG-10 possesses HA, whose sequence is identical to that of the original A/Anhui/1/2013 (H7N9) in the Global Initiative on Sharing Avian Influenza Data (EPI439507), while NIIDRG-10.1 and -10.2 possess amino acid differences, A125T and N123D/N149D, respectively, compared with NIIDRG-10. NIIDRG-10 replicated in embryonated chicken eggs with low hemagglutination titer 128, whereas NIIDRG-10.1 and -10.2 grew well with hemagglutination titer 1024. These viruses reacted well with a ferret antiserum raised against the original A/Anhui/1/2013 virus. Ferret antiserum against NIIDRG-10.1 reacted well with A/Anhui/1/2013 similar to the homologous virus NIIDRG-10.1. These results indicated that NIIDRG-10.1 passed the two-way test of antigenic identity. In contrast, the ferret antiserum against NIIDRG-10.2 reacted with A/Anhui/1/2013 at an 8-fold lower hemagglutination inhibition titer than with the homologous virus NIIDRG-10.2, indicating an antigenic change. The total and HA protein yields of NIIDRG-10.1 were 14.7 and 6.9 µg/ml, respectively, similar to those levels of high-yield seed viruses of seasonal influenza vaccines. NIIDRG-10.1 was approved as one of the CVVs for H7N9 viruses by the WHO in 2013. The candidate vaccine derived from NIIDRG-10.1 is currently being evaluated in a phase II clinical study in Japan.


Assuntos
Subtipo H7N9 do Vírus da Influenza A/imunologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vírus Reordenados/imunologia , Animais , Anticorpos Antivirais/sangue , Ensaios Clínicos Fase II como Assunto , Furões , Testes de Hemaglutinação , Humanos , Subtipo H7N9 do Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/isolamento & purificação , Japão , Vírus Reordenados/genética , Genética Reversa
19.
PLoS Med ; 12(4): e1001810, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25849352

RESUMO

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions­a proxy for recent infection­yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs­K101E, K103N, Y181C, and G190A­accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Sequência de Bases , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/genética , Mutação , África , Américas , Fármacos Anti-HIV/farmacologia , Ásia , Europa (Continente) , Infecções por HIV/virologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Humanos , Epidemiologia Molecular , Filogenia
20.
Antimicrob Agents Chemother ; 59(5): 2607-17, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25691635

RESUMO

Between September 2013 and July 2014, 2,482 influenza 2009 pandemic A(H1N1) [A(H1N1)pdm09] viruses were screened in Japan for the H275Y substitution in their neuraminidase (NA) protein, which confers cross-resistance to oseltamivir and peramivir. We found that a large cluster of the H275Y mutant virus was present prior to the main influenza season in Sapporo /: Hokkaido, with the detection rate for this mutant virus reaching 29% in this area. Phylogenetic analysis suggested the clonal expansion of a single mutant virus in Sapporo /: Hokkaido. To understand the reason for this large cluster, we examined the in vitro and in vivo properties of the mutant virus. We found that it grew well in cell culture, with growth comparable to that of the wild-type virus. The cluster virus also replicated well in the upper respiratory tract of ferrets and was transmitted efficiently between ferrets by way of respiratory droplets. Almost all recently circulating A(H1N1)pdm09 viruses, including the cluster virus, possessed two substitutions in NA, V241I and N369K, which are known to increase replication and transmission fitness. A structural analysis of NA predicted that a third substitution (N386K) in the NA of the cluster virus destabilized the mutant NA structure in the presence of the V241I and N369K substitutions. Our results suggest that the cluster virus retained viral fitness to spread among humans and, accordingly, caused the large cluster in Sapporo/Hokkaido. However, the mutant NA structure was less stable than that of the wild-type virus. Therefore, once the wild-type virus began to circulate in the community, the mutant virus could not compete and faded out.


Assuntos
Antivirais/farmacologia , Ciclopentanos/farmacologia , Farmacorresistência Viral , Guanidinas/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Oseltamivir/farmacologia , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Japão , Proteínas Virais/genética
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