A resistance mutation is a

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...

in a

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

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 human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

, 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 Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

. As subsequent cells are infected, random mutations will occur in the viral genome. When these mutations begin to accumulate, antiviral methods will kill the

wild type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

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. 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 Bacteriology is the branch and specialty of biology that studies the morphology, ecology, genetics and biochemistry of bacteria as well as many other aspects related to them. This subdivision of microbiology involves the identification, classificat ...

and parasitology.

Mechanisms

Resistance mutations can occur through several mechanisms from single nucleotide substitutions to combinations of

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

substitutions, deletions and insertions. 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 Frequency-dependent selection is an evolutionary process by which the fitness of a phenotype or genotype depends on the phenotype or genotype composition of a given population. * In positive frequency-dependent selection, the fitness of a phenotyp ...

. Further, strict adherence to a retroviral regimen correlates to a strong decrease in retroviral resistance mutations. 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. *

Entry inhibitors Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D. HIV entr ...

block the ability of HIV to enter its target cells. HIV must bind to a CD4 receptor on a T cell or the CCR5/CXCR4 co-receptors to enter the cell. They can also block the fusion of the viral and cell membranes. Entry inhibitors modify protein residues on the membrane of the T cell to make it incompatible with the HIV, thus blocking insertion of the viral genome. *

Nucleoside reverse transcriptase inhibitors Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...

(NRTI) are phosphorylated by cellular enzymes rendering it an active NRTI triphosphate stage. When the NRTIs are activated, they being to complete with cellular nucleosides that would be incorporated during reverse transcription by HIV. When the NRTIs are incorporated into the strand being transcribed, it causes the reverse transcription to be stopped. This inhibits HIV from incorporating its genome into the host cell. *

Non-nucleoside reverse transcriptase inhibitors Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicatio ...

(NNRTI) inhibit reverse transcriptase by binding to an allosteric site on it. Cessation of a non-nucleoside reverse transcriptase inhibitor regimen poses a significant danger of selection for a drug-resistant form of HIV-1. A K103N mutation in HIV-1 causes the hydrophobic pocket in which the NNRTI binds to inhibit enzyme activity in reverse transcriptase to close by means of a hydrogen bond. Without access to the

allosteric site In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

, the NNRTI will not be effective. *

Integrase inhibitor Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, bloc ...

s prevent the HIV integrase enzyme from incorporating its viral genome into the host chromosome. The enzyme contains a highly conserved region called the catalytic core, which is essential for binding to the virally encoded DNA. Integrase inhibitors block the ability of the catalytic core to form covalent bonds with the phosphodiester backbone of DNA. As a result, the viral DNA cannot be incorporated into the host genome. *

Protease Inhibitors Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...

cause the immature formation of two essential precursor proteins known as Gag and Gagpol in HIV. These proteins are essential in maintaining viral structure and for enzyme creation. Protease inhibitors bind to the active site of the viral protease, which prevents the cleavage of the Gag and Gagpol proteins. As a result, non-infections viral particles are formed.

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 Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected. Oral herpes involves the face or mouth. It may result in small blisters in groups often called col ...

virus and

hepatitis B virus ''Hepatitis B virus'' (HBV) is a partially double-stranded DNA virus, a species of the genus '' Orthohepadnavirus'' and a member of the '' Hepadnaviridae'' family of viruses. This virus causes the disease hepatitis B. Disease Despite there b ...

. 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

* A study of

hepatitis B Hepatitis B is an infectious disease caused by the '' Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. ...

in a Chinese population investigated the relationship of resistance mutations in the virus to its replication and genotype. It helped to gain insight into common mutations and their patterns. Patients undergoing treatment with a nucleoside drug were selected and fluorescence PCR and Sanger sequencing was used to sequence the viral genome. These sequences were compared against known hepatitis B sequences from

Genbank The GenBank sequence database is an open access, annotated collection of all publicly available nucleotide sequences and their protein translations. It is produced and maintained by the National Center for Biotechnology Information (NCBI; a part ...

so that the patterns of resistance could be analyzed. It was shown that many patients had a single mutation in common and many were also completely resist to a common nucleoside drug. In addition to gaining insight into mutation patterns, this study highlights the importance of using multiple types of drugs to treat chronic viral conditions. * An important part of treating HIV is patient-specific tailoring of drugs. A study identified the most common resistance mutations so that point of care tests could determine the resistance mutations of a patient, thereby allowing their provider to tailor their treatment. This point of care test would most likely be an inexpensive assay, which could significantly improve HIV treatment in impoverished areas. The researchers used datasets of the sequences of thousands of individuals around the world to identify the most common resistance mutations to NRTI, NNRTI, and protease inhibitors. Two NRTI mutations and four NNRTI mutations were commonly found, which can now be tested for using an inexpensive point-of-care. This will significantly improve care quality and effectiveness, especially in impoverished areas.

References

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External links

HIV drug resistance mutations figures

FDA-Approved HIV Medicines

Mutation