Basal Core Promoter and Precore Mutations in the Hepatitis B Virus Genome Enhance Replication Efficacy of Lamivudine-Resistant Mutants

Tacke, Frank; Gehrke, Christina; Luedde, Tom; Heim, Albert; Manns, Michael P.

doi:10.1128/jvi.78.16.8524-8535.2004

Cited by 112 publications

(154 citation statements)

References 60 publications

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“…Occurrence of HBV BCP and PC mutations is associated with lower levels of HBV DNA in both serum and liver without affecting HDV replication and clinical manifestations in patients [9,37] . In contrast, PC/ BCP point mutations with HBeAg negative phenotype can significantly increase HBV viremia and replication of polymerase mutated strains in HDV-negative patients [38] . Other instances of indirect effects of HBV and HDV on each other's replication include the synergistic activation of serum response element (SRE)-dependent pathways by HBxAg and L-HDAg, thus affecting factors which are involved in transcription regulation mediated by SRE [39] .…”

Section: Shirvani-dastgerdi E Et Al Hbv-hdv Interactionsmentioning

confidence: 99%

Molecular interactions between hepatitis B virus and delta virus

Shirvani-Dastgerdi¹

2015

WJV

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HBV HBsAgs. While HBsAg is the only protein required by HDV, the exact interaction sites between the S protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV proteins. Here we discuss the molecular interaction sites between HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other's viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for delta hepatitis. Core tip: Hepatitis D virus (HDV) causes accelerated liver disease in form of fulminant or chronic hepatitis in patients with hepatitis B virus (HBV) infection. HBV supports HDV replication by sharing its surface proteins. Even without overt HBV-DNA replication, transcription of HBV surface proteins (HBsAgs) remains stable in HDV infected cells, which is essential for assembly of HDV virions containing HBsAg proteins. HDV replication is oftentimes associated with a suppression of HBV-DNA levels, and several mechanisms have been suggested how HBV or HDV may influence each other's replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies. Molecular interactions between hepatitis B virus and delta virus AbstractAs a deficient virus due to the lack of envelope proteins, hepatitis D virus (HDV) causes chronic or fulminant "delta hepatitis" only in people with simultaneous hepatitis B virus (HBV) infection. HBV encodes three types of surface proteins known as small (S), medium (M) and large (L) envelope proteins. All three types of HBV surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV ribonucleoprotein (RNP) complex and 36 EDITORIALSubmit a

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Section: Shirvani-dastgerdi E Et Al Hbv-hdv Interactionsmentioning

confidence: 99%

Molecular interactions between hepatitis B virus and delta virus

Shirvani-Dastgerdi¹

2015

WJV

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“…Moreover, this issue was addressed on the background of HBeAg-positive and -negative virus strains, because precore (PC) and basal core promoter (BCP) mutations (conferring HBeAg negativity) by themselves alter the replication of LAM-resistant mutants (24). We also systematically addressed which nucleotide analogues remain effective in treating these complex compound HBV mutants.…”

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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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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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“…Primary mutations typically affect the reverse transcriptase domain of the HBV polymerase, thereby causing steric changes of the polymerase protein that escape the inhibitory effects of the nucleos(t)ide analogues (7,12,14). The most relevant hot-spot mutations in the HBV polymerase are displayed in Table 1.…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

“…The rtM204V mutation is usually accompanied by a leucine (L) to M or occasionally serine (S) change at position 180 (rtL180M/S) (6,12). HBV viral strains with the LMV-resistant mutations display drug resistance against LMV, but have a decreased replication capacity in vitro (14). Interestingly, the double point mutants L180M/M204V replicate better than the single M204I mutants, possibly due to the stabilizing effect of the L180M mutation (B domain) on the YMDD loop (C domain) in a conformational model of the HBV reverse transcriptase (7).…”

Section: Lmvmentioning

confidence: 99%

“…The most relevant hot-spot mutations in the HBV polymerase are displayed in Table 1. However, the polymerase mutants have a dramatically reduced viral replication efficacy in most cases (14). Secondary compensatory mutations occur in order to restore the viral replication fitness, thereby overcoming deleterious effects of the primary drug-resistant mutations (12).…”

Section: Molecular Mechanisms Of Drug Resistancementioning

confidence: 99%

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Treatment for hepatitis B in patients with drug resistance

Tacke¹,

Kroy²

2016

Ann. Transl. Med.

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Persistent hepatitis B virus (HBV) infections affect about 240 million patients worldwide that are at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double stranded DNA virus with four overlapping genes and a unique life cycle, which involves the generation of an RNA template for replication via reverse transcription. Mutations occur frequently during chronic infection, and particular selection pressures select distinct mutants. Nucleoside and nucleotide analogues like lamivudine (LMV), entecavir (ETV), telbivudine (LdT), adefovir dipivoxil (ADV) and tenofovir (TDF) are used to achieve long-term suppression of viral replication. Importantly, these drugs have different barriers to resistance, explaining the higher incidence of treatment failure in the past due to drug resistant viral strains for the older compounds LMV, LdT and ADV. On

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Basal Core Promoter and Precore Mutations in the Hepatitis B Virus Genome Enhance Replication Efficacy of Lamivudine-Resistant Mutants

Abstract: During chronic hepatitis B virus (HBV) infection

Cited by 112 publications

References 60 publications

Molecular interactions between hepatitis B virus and delta virus

Molecular interactions between hepatitis B virus and delta virus

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

Treatment for hepatitis B in patients with drug resistance

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