Resistance mutation (virology)

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Resistance to a drug Resistance-graphics.1b.png
Resistance to a drug

A resistance mutation is a mutation in a virus gene that allows the virus to become resistant to treatment with a particular antiviral drug. The term was first used in the management of HIV, the first virus in which genome sequencing was routinely used to look for drug resistance. At the time of infection, a virus will infect and begin to replicate within a preliminary cell. As subsequent cells are infected, random mutations will occur in the viral genome. [1] When these mutations begin to accumulate, antiviral methods will kill the wild type strain, but will not be able to kill one or many mutated forms of the original virus. At this point a resistance mutation has occurred because the new strain of virus is now resistant to the antiviral treatment that would have killed the original virus. [1] Resistance mutations are evident and widely studied in HIV due to its high rate of mutation and prevalence in the general population. Resistance mutation is now studied in bacteriology and parasitology.

Contents

Mechanisms

Resistance mutations can occur through several mechanisms from single nucleotide substitutions to combinations of amino acid substitutions, deletions and insertions. [1] Over time, these new genetic lines will persist if they become resistant to treatments being used against them. It has been shown that pathogens will favor and become more resistant to treatment in common host genotypes through frequency-dependent selection. [2] Further, strict adherence to a retroviral regimen correlates to a strong decrease in retroviral resistance mutations. [3] There are five classes of drug that are used to treat HIV infection, and resistance mutations can effect the efficacy of these treatments as well.

In Other Viruses

Resistance mutations are found and become problematic in many viruses other than HIV. Notable examples of such viruses include the herpes simplex virus and hepatitis B virus. [9] In the herpes virus, drugs mainly target the viral DNA polymerase. As a result, mutations in the viral DNA polymerase that make it resistant to these drugs are selected for, which ultimately can cause complete resistance of the treatment. In hepatitis B, nucleoside and nucleotide analogs are used to cause early termination of viral transcription. Mutations in viral reverse transcriptase can cause the enzyme to not incorporate these nonfunctional analogs, in favor for their natural counterparts. If this mutation occurs, transcription will not be halted, and viral proteins can be created.

Research Applications

References

  1. 1 2 3 4 Clavel, François. "Mechanisms of HIV Drug Resistance: A Primer" (PDF). Physicians' Research Network. Physicians Research Network Inc. Retrieved 6 February 2016.
  2. Bangham, Jenny; Obbard, Darren; Kim, Kang-Wook; Haddril, Penelope; Jiggins, Francis (22 August 2007). "The Age and Evolution of an Antiviral Resistance Mutation in Drosophila melanogaster". Proceedings: Biological Sciences. 274 (1621): 2027–2034. doi:10.1098/rspb.2007.0611. PMC   1914336 . PMID   17550883.
  3. Harrigan, P.; Hogg, Robert; Dong, Winnie; Yip, Benita; Wynhoven, Brian; Woodward, Justin; Broome, Chanson; Broome, Zabrina; Mo, Theresa; Alexander, Chris; Montaner, Julio (1 February 2005). "Predictors of HIV Drug-Resistance Mutations in a Large Antiretroviral-Naive Cohort Initiating Triple Antiretroviral Therapy". The Journal of Infectious Diseases. 191 (3): 339–347. doi: 10.1086/427192 . PMID   15633092.
  4. Briz, Verónica; Poveda, Eva; Soriano, Vincent (2006-04-01). "HIV entry inhibitors: mechanisms of action and resistance pathways". The Journal of Antimicrobial Chemotherapy. 57 (4): 619–627. doi: 10.1093/jac/dkl027 . ISSN   0305-7453. PMID   16464888.
  5. Maga, Giovanni; Radi, Marco; Gerard, Marie-Aline; Botta, Maurizio; Ennifar, Eric (2010-03-30). "HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate". Viruses. 2 (4): 880–899. doi: 10.3390/v2040880 . ISSN   1999-4915. PMC   3185657 . PMID   21994659.
  6. Hare, C. Bradley; Mellors, John; Krambrink, Amy; Su, Zhaohui; Skiest, Daniel; Margolis, David M.; Patel, Sheran S.; Barnas, Douglas; Frenkel, Lisa; Coombs, Robert W.; Aweeka, Francesca; Morse, Gene D.; Haas, David W.; Boltz, Valerie; Palmer, Sarah; Coffin, John; Havlir, Diane V. (August 2008). "Detection of Nonnucleoside Reverse-Transcriptase Inhibitor–Resistant HIV-1 after Discontinuation of Virologically Suppressive Antiretroviral Therapy". Clinical Infectious Diseases. 47 (3): 421–424. doi:10.1086/589867. PMC   2586907 . PMID   18558886.
  7. Hicks, Charles; Gulick, Roy M. (2009-04-01). "Raltegravir: The First HIV Type 1 Integrase Inhibitor". Clinical Infectious Diseases. 48 (7): 931–939. doi: 10.1086/597290 . ISSN   1058-4838. PMID   19231980.
  8. van Maarseveen, Noortje; Boucher, Charles (2006-01-01). Geretti, Anna Maria (ed.). Resistance to protease inhibitors. London: Mediscript. ISBN   9780955166907. PMID   21249774.
  9. Strasfeld, Lynne; Chou, Sunwen (2010-06-01). "Antiviral Drug Resistance: Mechanisms and Clinical Implications". Infectious Disease Clinics of North America. 24 (2): 413–437. doi:10.1016/j.idc.2010.01.001. ISSN   0891-5520. PMC   2871161 . PMID   20466277.
  10. He, Xiaohong; Wang, Fang; Huang, Bin; Chen, Peisong; Zhong, Liangying (2015-06-15). "Detection and analysis of resistance mutations of hepatitis B virus". International Journal of Clinical and Experimental Medicine. 8 (6): 9630–9639. ISSN   1940-5901. PMC   4538069 . PMID   26309637.
  11. Rhee, Soo-Yon; Jordan, Michael R.; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Zyl, Gert U. Van; Mukui, Irene; Hosseinipour, Mina C. (2015). "HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing". PLOS ONE. 10 (12): e0145772. Bibcode:2015PLoSO..1045772R. doi: 10.1371/journal.pone.0145772 . PMC   4696791 . PMID   26717411.