Viral replication Subject

Viral protease cleaves precursor proteins into proteins required for viral replication. The inhibitors of this protease (saquinavir, ritonavir, indinavir, and nelfinavir) represent abnormal proteins that possess high antiviral efficacy and are generally well tolerated in the short term. However, prolonged administration is associated with occasionally severe disturbances of lipid and carbohydrate metaboUsm Biotransformation of these drugs involves cytochrome P450 (CYP 3A4) and is therefore subject to interaction with various other drugs inactivated via this route. 

Pretazettine (395) has been the subject of numerous biological studies, and it has been shown to exhibit a number of interesting activities (96,97,101,178-187). For example, 395 was found to inhibit HeLa cell growth as well as protein synthesis in eukaryotic cells by interfering with the peptide bond formation step (97,101). Furthermore, pretazettine inhibited the purified RNA-dependent DNA polymerase (reverse transcriptase) from avian myeloblastosis virus, a typical C-type virus (178), in an unusual fashion since it physically combined with the polymerase enzyme itself rather than interacted with the nucleic acid template. Pretazettine also exhibited antiviral activity against the Rauscher leukemia virus in mouse embryo cell cultures by suppressing viral replication (179). 

PPIases also play a key role in cell entry and in the replication of several pathogenic viruses, as well as in the formation of mature virions. The vesicular stomatitis virus New Jersey serotype, which causes major diseases in animals, particularly cattle, contains several host proteins, including cyclophilin A, which are essential for viral replication. CsA and overexpression of catalytically inactive mutants of CypA drastically inhibit gene expression of the virus New Jersey serotype but have little effect on the virus Indiana serotype [102]. Although it is presently the subject of controversial publications and is still misunderstood, the involvement of PPIases - notably hCypl8 - in the HIV-1 life cycle is one of the most famous examples of the hijacking of host proteins by a lentivirus [8]. 

The stress-associated shift in Thl/Th2 cytokines observed in human subjects has also been demonstrated in restraint-stressed mice. Associated with the shift towards a Th2 response are a significant decrease in NK cell activity, decreased IFN-y production by Con A-stimulated splenocytes, and a concomitant increase in serum corticosterone levels after 24 hours of restraint.30 These observations are consistent with studies on the effects of restraint stress and the immune response to viral infection. Restraint-stressed mice exhibited a decline in NK cell activity and a decrease in the generation of virus-specific cytotoxic T lymphocytes to HSV-l after primary infection, which resulted in an increase in the replication of the virus at the site of infection.3132... 

Role of RNA intermediates (Herbert and Rich, 1999). The mutation rate of a genome is likely to increase when genetic information is passed through RNA whether RNA is a viral genome or a retrotransposon because RNA polymerase reaction is neither edited nor subject to post-replicative repair. In addition, hotspots of a genetic chain in RNA retrotransposons can result from nomandom patterns of a decreased fidelity strand transfer to other templates and untemplated extensions. 

Because viruses contain RNA and not DNA, replication of viral genetic material is not subject to the same error-checking and repair mechanisms as is cellular DNA. Thus, mutations in viral RNA are relatively more common, and viruses, should they be able to survive the mutations, can evolve rather quickly to circumvent cellular or therapeutic drug antiviral countermeasures. Antiviral defenses oftentimes recognize viral surface proteins as foreign bodies, and deal with them accordingly. Cytokines... 

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