Resistance antivirals

Kimberlin DW, Coen, DM, Biron KK, Cohen JI, Lamb RA, McKinlay M, et al. Molecular mechanisms of antiviral resistance. Antiviral Res 1995 26 369-401. 

Antonelli G, Dianzani F, Bellarosa D, Turriziani O, Riva E, Gentile A. Drug combination of AZT and ddl synergism of action and prevention of appearance of AZT-resistance. Antiviral Chem Chemother 1994 5 51-55. 

Gallant JE, Gerondelis PZ, Wainberg MA, Shulman NS, et al. 2003. Nucleoside and nucleotide analogue reverse transcriptase inhibitors A clinical review of antiretroviral resistance. Antivir Ther. 8 489-506. 

Burnham, A.J., Baranovich, T., and Govorkova, E.A. (2013) Neuraminidase inhibitors for influenza B virus infection efficacy and resistance. Antiviral Research, 100, 520-534. 

Interferons (lENs) (52,53), a family of species-specific vertebrate proteins, confer nonspecific resistance to a broad range of viral infections, affect cell proliferation, and modulate immune responses. AH three principal interferons, a-interferon (lEN-a) produced by blood leucocytes, P-interferon (lEN-P) by fibroblasts, and y-interferon (lEN-y) by lymphocytes, also have antiviral activity. The abiUty of interferons to inhibit growth of transplantable and carcinogen-induced tumor led to research showing the direct antiproliferative and indirect immune-mediated antitumor activities (see Chemotherapeutics, anticancer). IENs have been found to be efficacious in certain malignancies and viral infections, eg, hairy cell leukemia (85% response) and basal cell carcinoma (86% response). However, the interferons do have adverse side effects (54). 

Unlike idoxuridiae, BVdU, and acyclovir, viral strains susceptible to ribavirin have not been found to develop a resistance to the dmg. The resistance against ribavirin is less likely because the dmg exhibits multiple sites of antiviral action. 

Viral infections continue to be significant causes of morbidity and mortality and at the same time continue to be resistant to treatment by small molecules. Avridine (6) is an antiviral compound which has shown some activity in a variety of animal tests apparently based upon its ability to stimulate a number of cells to produce the high molecular weight endogenous antiviral substance interferon. Thus, the compound is believed to operate indirectly by stimulating the body s own natural defenses against viral penetration into host cells. Avridine is synthesized by... 

The broadest spectrum of antiviral diugs is available against HIV. However, monotherapy with any of these diugs leads to rapid treatment failure due to selection and further evolution of resistant viruses. Since acquisition of resistance mutations requires vims replication,... 

Interferons (EFNs) are a family of multifunctional secreted proteins in vertebrates. Their most prominent functions are their antiviral properties on homologous cells against a wide range of viruses. It is important to note that prior exposure to EFN is required to render cells resistant to viral infection and replication. In contrast to antibodies, EFNs have no direct neutralizing effect on viruses. 

Short replication cycles that may be completed within a few hours, a large amount of viral progeny from one infected host-cell, as well as the general inaccuracy of viral nucleic acid polymerases result in an evolution occurring in fast motion, allowing rapid adaptation of viruses to selective pressures (see chapter by Boucher and Nijhius, this volume). Generalizing, it can be stated that any effective antiviral therapy will lead to the occurrence of resistance mutations. A well studied example... 

Fig. 3 Stepwise development of antiviral resistance. Because of the rapid mutation rate of viruses, the virus population before treatment (a) contains variants, which display by chance a low level of resistance to the drug (indicated by the darker hue). Treatment with suboptimal levels of an antiviral drug (b) creates a bottleneck, which selects for these variants (c). These can further replicate in the presence of the drug and thereby acquire additional mutations, leading to resistant variants with enhanced replicative fitness (d)...

Deval J, D Abramo CM, GOtte M (2006) Selective excision of non-obUgate chain-terminators by the hepatitis C virus NS5B polymerase. In 16th international HIV Drug Resistance workshop, Sitges, Spain, June 13-17, 2006. Antivir Ther 11 Suppl 1 S3 (abstract no 1)... 

Tai CL, Chi WK, Chen DS, Hwang LH (1996) The helicase activity associated with hepatitis C virus nonstructural protein 3 (NS3). J Virol 70 8477-8484 Tong X, Chase R, Skelton A, Chen T, Wright-Minogue J, Malcolm BA (2006) Identification and analysis of fitness of resistance mutations against the HCV protease inhibitor SCH 503034. Antiviral Res 70 28-38... 

Acknowledgments This is part of the activities of the VIRGIL European Network of ExceUence on Antiviral Drug Resistance supported by a grant (LSHM-CT-2004-503359) from the Priority 1 Life Sciences, Genomics and Biotechnology for Health and is supported by a grant from the FWO (no. G.0267.04). 

Wang J, Jin Y, Rapp KL, Bennett M, Schinazi RF, Chu CK (2005) Synthesis, antiviral activity, and mechanism of drug resistance of d- and L-2, 3 -didehydro-2, 3 -dideoxy-2 -fluorocarbocycUc nucleosides, J Med Chem 48 3736-3748... 

Abstract This review provides an overview of the development of viral protease inhibitors as antiviral drugs. We concentrate on HlV-1 protease inhibitors, as these have made the most significant advances in the recent past. Thus, we discuss the biochemistry of HlV-1 protease, inhibitor development, clinical use of inhibitors, and evolution of resistance. Since many different viruses encode essential proteases, it is possible to envision the development of a potent protease inhibitor for other viruses if the processing site sequence and the catalytic mechanism are known. At this time, interest in developing inhibitors is Umited to viruses that cause chronic disease, viruses that have the potential to cause large-scale epidemics, or viruses that are sufQciently ubiquitous that treating an acute infection would be... 

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