Prevalence, viral replication efficiency and antiviral drug susceptibility of rtQ215 polymerase mutations within the hepatitis B virus genome

Amini-Bavil-Olyaee, Samad; Herbers, Ulf; Mohebbi, Seyed Reza; Sabahi, Farzaneh; Zali, Mohammad Reza; Luedde, Tom; Tacke, Frank

doi:10.1016/j.jhep.2009.04.022

Cited by 27 publications

(33 citation statements)

References 27 publications

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“…1A). As anticipated (1,24), HBeAg-positive constructs with LAM resistance (rtM204I or rtL180M/rtM204V mutants) displayed significantly reduced replication. The additional presence of the "a-determinant" sG145R mutation increased the replication of LAM-resistant clones, resulting in replication efficacies at the level of those of WT HBV vectors (Fig.…”

Section: Resultssupporting

confidence: 62%

“…Supernatant was harvested 5 days after transfection. HBV virions and large envelope proteins (LHBs) were immunoprecipitated using mouse monoclonal antibody against HBV preS1 protein (clone AP1, sc-57761; Santa Cruz Biotechnology, Santa Cruz, CA) and protein A agarose (Roche Diagnostics, Mannheim, Germany) as described before (1). Laemmli sample buffer (BioRad Laboratories, Inc. Hercules, CA) complemented with 5% ␤-mercaptoethanol was added to sedimented beads, heated for 5 min, and centrifuged briefly.…”

Section: Methodsmentioning

confidence: 99%

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Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Amini-Bavil-Olyaee

Vucur

Luedde

et al. 2010

J Virol

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Immune escape variants of the hepatitis B virus (HBV) represent an emerging clinical challenge, because they can be associated with vaccine escape, HBV reactivation, and failure of diagnostic tests. Recent data suggest a preferential selection of immune escape mutants in distinct peripheral blood leukocyte compartments of infected individuals. We therefore systematically analyzed the functional impact of the most prevalent immune escape variants, the sG145R and sP120T mutants, on the viral replication efficacy and antiviral drug susceptibility of common treatment-associated mutants with resistance to lamivudine (LAM) and/or HBeAg negativity. Replication-competent HBV strains with sG145R or sP120T and LAM resistance (rtM204I or rtL180M/rtM204V) were generated on an HBeAg-positive and an HBeAg-negative background with precore (PC) and basal core promoter (BCP) mutants. The sG145R mutation strongly reduced HBsAg levels and was able to fully restore the impaired replication of LAM-resistant HBV mutants to the levels of wild-type HBV, and PC or BCP mutations further enhanced viral replication. Although the sP120T substitution also impaired HBsAg secretion, it did not enhance the replication of LAM-resistant clones. However, the concomitant occurrence of HBeAg negativity (PC/BCP), sP120T, and LAM resistance resulted in the restoration of replication to levels of wild-type HBV. In all clones with combined immune escape and LAM resistance mutations, the nucleotide analogues adefovir and tenofovir remained effective in suppressing viral replication in vitro. These findings reveal the differential impact of immune escape variants on the replication and drug susceptibility of complex HBV mutants, supporting the need of close surveillance and treatment adjustment in response to the selection of distinct mutational patterns.

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Section: Resultssupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Amini-Bavil-Olyaee

Vucur

Luedde

et al. 2010

J Virol

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“…AminiBavil-Olyaee [21] in 2009 revealed HBV rtV191I mutation in HIV-HBV co-infected and HBsAg-negative patients, during TDF therapy, and found it was resistant to LAM, but not TDF. Therefore, rtV191I mutation may be the new resistance site to LAM.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Wang

Han

Duan

et al. 2017

J Infect Dev Ctries

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Introduction: Previous studies have indicated that the drug-resistant mutations of hepatitis B virus (HBV) are a major obstacle to antiviral therapy. However, it is still unclear whether there are pre-existent resistance mutations in patients with HBV infection and the relationship between drug-resistant mutation, genotypes, and progression of hepatitis B disease. Methodology: A total of 357 treatment-naïve patients with HBV infection were involved in this retrospective study. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. Results: Lamivudine (LAM) resistance was detected in 8 patients (3.7%) with chronic hepatitis B (CHB), 13 (11.7%) patients with liver cirrhosis (LC), and 6 (21.4%) patients with hepatocellular carcinoma (HCC). Adefovir(ADV)-resistant mutations were detected in 10 (4.6%) patients with CHB, 15 (13.5%) patients with LC and 4 (14.5%) patients with HCC. Both LAM and ADV resistant mutations were detected in 2 patients (0.9%) with CHB, 1 patient (0.9%) with LC and 1 patient (3.6%) with HCC. Significant differences (p <0.01) were observed in the drug-resistance rates among patients with CHB, LC and HCC. Meanwhile, all the drug-resistant mutations were found in patients with HBV genotype C. Conclusions: This study demonstrated higher risk of pre-existing drug-resistant mutations in patients with HBV genotype C comparing to patients with HBV genotype B. Likewise, increasing prevalence of pre-existing drug-resistant mutations was shown, alongside with the progression of the disease.

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“…Entre essas a rtV214A e a rtQ215S também foram associadas com falhas na resposta ao tratamento com lamivudina (48,239). Entretanto o papel dessas mutações na resistência a esses AN não está estabelecido, em alguns casos os estudos ainda são escassos e em outros os resultados apresentados por diferentes estudos são contraditórios.…”

Section: Mutações No Gene Punclassified

Estudos moleculares sobre o vírus da hepatite B

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EPIDEMIOLOGIA DA HEPATITE B NO BRASIL E NO MUNDOA hepatite B é uma doença de distribuição universal, presente em todos os continentes, porém com variações nos níveis de endemicidade. A Organização Mundial de Saúde estima que cerca de 2 bilhões de pessoas tenham sido infectadas pelo HBV O HBV é transmitido principalmente através do sangue, mas outros fluidos como sêmen, secreções vaginais e saliva podem estar envolvidos na transmissão desse agente. Há três principais formas de transmissão do HBV: vertical, sexual e parenteral (7).Nas áreas com prevalência intermediária ou alta a maioria dos indivíduos se infecta no momento do nascimento (transmissão vertical) ou durante os primeiros anos da infância pelo contato com portadores do vírus, o que ocorre com mais frequência entre membros da mesma família. Já nas áreas de baixa prevalência a infecção é adquirida primariamente durante a vida adulta, principalmente pela via sexual (33, 34).Em geral, quando a infecção pelo HBV ocorre em indivíduos adultos, a mesma tende a evoluir para a cronicidade em cerca de 5% dos indivíduos infectados. ESTRUTURA DO HBVAs células infectadas pelo HBV produzem diferentes tipos de partículas relacionadas ao vírus, as quais podem ser identificadas por microscopia eletrônica no PROTEÍNAS VIRAIS ANTÍGENOS DE SUPERFÍCIE (ENVELOPE)O principal antígeno do envelope do HBV é o HBsAg, mas também encontramos as proteínas L ("large") e M ("medium"), que contém os antígenos correspondentes às regiões pré S1 e pré S2 do genoma viral, além de compartilharem as regiões antigênicas do HBsAg. O HBsAg é encontrado no envelope viral em sua forma não -glicosilada (p25) e glicosilada (gp29), a proteína M em duas formas glicosiladas (gp33 e gp36) e a proteína L em uma forma não -glicosilada (p39) e outra glicosilada (gp42) (60).A principal proteína do envelope do HBV é denominada de HBsAg, é altamente imunogênica e é a base da vacina utilizada contra a infecção pelo HBV, que inicialmente consistia em HBsAg isolado do plasma de indivíduos infectados e atualmente são utilizadas proteínas HBs purificadas produzidas por engenharia genética. Os anticorpos anti-HBs gerados pela vacinação ou que constituem a imunoglobulina hiperimune são predominantemente dirigidos contra um epítopo antigênico presente no HBsAg denominado de determinante "a" (59, 61).As proteínas L e M estão presentes em maior proporção nas partículas virais íntegras e partículas ocas cilíndricas e têm um papel fundamental na infecção pelo HBV, participando no processo de captação do vírus pelas células hepáticas e do processo de morfogênese da partícula viral (62).As proteínas L, M e S compartilham um domínio na extremidade carboxila com quatro hélices putativas para ancoragem na membrana. As duas extensões terminais ANTÍGENO HBx (HBxAg)Além destas proteínas, pelo menos duas outras são produzidas pelo HBV, oHBxAg e a DNA polimerase viral. A presença da proteína HBxAg foi inferida pela descoberta de uma fase de leitura aberta na sequência do genoma viral.Posteriormente, a clonagem de segmentos des...

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Prevalence, viral replication efficiency and antiviral drug susceptibility of rtQ215 polymerase mutations within the hepatitis B virus genome

Cited by 27 publications

References 27 publications

Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Differential Impact of Immune Escape Mutations G145R and P120T on the Replication of Lamivudine-Resistant Hepatitis B Virus e Antigen-Positive and -Negative Strains

Hepatitis B virus pre-existing drug resistant mutation is related to the genotype and disease progression

Estudos moleculares sobre o vírus da hepatite B

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