Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis B virus (HBV) variant strains may develop during therapy for chronic infection with the nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC). HBV mutants result from isoleucine (I) or valine (V) substitutions in the methionine (M) of the YMDD motif in the viral reverse-transcriptase catalytic domain. In addition, other mutations in the reverse-transcriptase "B domain" involving either a phenylalanine (F)-to-leucine (L) at amino acid 501 (F501L) or an L-to-M substitution at amino acid 515 (L515M) have been observed during 3TC and Famciclovir therapy as well. To determine the biologic consequences of these mutations on viral replication, variant viral genomes were constructed and transiently transfected into hepatocellular carcinoma (HCC) and HEK 293 human embryo kidney-derived cell lines. In transiently transfected HCC cells, the viruses bearing the YI/VDD or F501L mutations had greatly impaired replication as compared to wild-type virus, whereas the virus carrying the L515M substitution showed the least defect. Double mutants with the L515M substitution showed intermediate defect between the YI/VDD or F501L and the L515M single-mutant strains. In contrast, when transfected into HEK 293 cells, the viruses bearing the YI/VDD or L515M mutation replicated as wild-type. However, under conditions of deoxynucleotide depletion produced by hydroxyurea treatment of HEK 293 cells, all mutants but not the wild-type virus exhibited a reduced replication phenotype similar to that observed in HCC cells. In both HCC and HEK 293 cells, the mutant viruses carrying the F501L substitution showed a decreased pregenomic RNA encapsidation level, suggesting that the defect in HBV DNA synthesis occurs at the RNA packaging level. These findings show that 3TC and Famciclovir selected mutations alter the properties of the HBV reverse transcriptase, resulting in impaired viral replication within the cell.
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PMID:Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. 946 67

Treatment of chronic hepatitis B is directed at interrupting the natural history and clinical outcomes of the disease. It needs to take into account the virology and replication cycle of the hepatitis B virus (HBV), and the host immune response to HBV. Long term follow-up of patients treated with interferon supports the paradigm that a sustained, major suppression of HBV replication, particularly that associated with hepatitis B e antigen (HBeAg) seroconversion, interrupts the natural history of hepatitis B. The availability of potent but well tolerated and orally available HBV antivirals, of which lamivudine is the prototype, has allowed clearer treatment objectives to be formulated. These are: temporary or permanent reduction of hepatitis (necroinflammatory) activity, arrest of fibrotic progression, prevention of cirrhosis and liver failure, and prevention of recurrent HBV infection after liver transplantation. Lamivudine has good medium term efficacy in achieving each of these objectives. The only significant problem for the longer term is emergence of antiviral resistance conferred by mutations in the YMDD (tyrosine-methionine-aspartic acid-aspartic acid) motif of the HBV reverse transcriptase. As a result, contentious issues remain about defining when antiviral therapy is indicated, whether to treat for a defined interval or indefinitely, and when to stop treatment if HBeAg seroconversion is not achieved. Some personal views are expressed in this review. Among newer HBV antivirals in clinical studies, adefovir dipivoxil, entecavir and emtricitabine appear to be at least as potent as lamivudine in suppressing HBV replication. Famciclovir appears less potent. In vitro studies show that YMDD mutations confer cross-resistance between lamivudine, emtricitabine and beta-L-Fd4C (L-2',3'-didehydro-dideoxy-5-fluorocytidine). However, adefovir dipivoxil, lobucavir, entecavir, DAPD (beta-D-2,6-diaminopurine dioxolane) and possibly clevudine (L-FMAU) suppress replication of YMDD mutant HBV, as well as wildtype. Preliminary studies indicate clinical efficacy of adefovir dipivoxil once resistance to lamivudine has developed. Immunomodulatory approaches to treatment of chronic hepatitis B are conceptually attractive, but newer agents used to date (thymalfasin, interleukin-12, therapeutic vaccines) have not demonstrated sufficient efficacy for widespread use. The next challenge for HBV treatment is to use antivirals in combination and/or in cyclical therapy to reduce the emergence of drug resistance and increase efficacy, particularly to achieve sustainable post-treatment suppression of hepatitis B.
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PMID:Clinical potential of emerging new agents in hepatitis B. 1108 96