Biomaterial Database

Identification of accessory mutations associated with high-level resistance in HIV-1 reverse transcriptase. 2007

Patricia A Cane, and Hannah Green, and Esther Fearnhill, and David Dunn, and

Centre for Infections, Health Protection Agency, UK. pat.cane@hpa.org.uk

OBJECTIVE To identify accessory mutations associated with high levels of resistance to reverse transcriptase inhibitors (RTI). METHODS HIV pol sequences from routine resistance tests from over 3000 patients who were treatment experienced and infected with subtype B HIV-1 were analysed. Changes relative to the wild-type amino acid for codons 1-400 of reverse transcriptase were determined in two series: (i) samples showing the accumulation of thymidine analogue mutations (TAMs); and (ii) samples showing the accumulation of non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations. METHODS Accessory mutations were identified as occurring in those codons in which there was a statistically significant association between the distribution of amino acids and the number of TAMs/NNRTI resistance mutations. Positions already established as drug resistance positions by the International AIDS Society - USA Panel were not included in this analysis. RESULTS Twenty-four positions were identified where accessory mutations were associated with the accumulation of TAMs (20, 35, 39, 43, 60, 83, 98, 101, 122, 135, 179, 196, 203, 208, 218, 223, 228, 284, 322, 356, 359, 360, 371 and 381). Likewise changes at 25 positions (6, 20, 35, 39, 43, 53, 68, 90, 98, 101, 122, 179, 200, 203, 208, 218, 221, 223, 228, 284, 318, 320, 348, 359 and 371) were associated with NNRTI mutations. The accumulation of accessory mutations correlated with increasing numbers of TAMs and NNRTI mutations. CONCLUSIONS The development of high-level resistance to RTI is associated not only with the accumulation of recognized mutations but also with accessory mutations.

UI	MeSH Term	Description	Entries
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000596	Amino Acids	Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.	Amino Acid,Acid, Amino,Acids, Amino
D015497	HIV-1	The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte.	Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D016208	Databases, Factual	Extensive collections, reputedly complete, of facts and data garnered from material of a specialized subject area and made available for analysis and application. The collection can be automated by various contemporary methods for retrieval. The concept should be differentiated from DATABASES, BIBLIOGRAPHIC which is restricted to collections of bibliographic references.	Databanks, Factual,Data Banks, Factual,Data Bases, Factual,Data Bank, Factual,Data Base, Factual,Databank, Factual,Database, Factual,Factual Data Bank,Factual Data Banks,Factual Data Base,Factual Data Bases,Factual Databank,Factual Databanks,Factual Database,Factual Databases
D054303	HIV Reverse Transcriptase	A reverse transcriptase encoded by the POL GENE of HIV. It is a heterodimer of 66 kDa and 51 kDa subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse H activity (RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS) that plays an essential role the viral replication process.	Reverse Transcriptase, HIV,Reverse Transcriptase, Human Immunodeficiency Virus,Transcriptase, HIV Reverse
D018894	Reverse Transcriptase Inhibitors	Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template.	Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse
D019380	Anti-HIV Agents	Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS.	AIDS Drug,AIDS Drugs,Anti-AIDS Agents,Anti-AIDS Drug,Anti-HIV Agent,Anti-HIV Drug,Anti-AIDS Drugs,Anti-HIV Drugs,Agent, Anti-HIV,Agents, Anti-AIDS,Agents, Anti-HIV,Anti AIDS Agents,Anti AIDS Drug,Anti AIDS Drugs,Anti HIV Agent,Anti HIV Agents,Anti HIV Drug,Anti HIV Drugs,Drug, AIDS,Drug, Anti-AIDS,Drug, Anti-HIV,Drugs, AIDS,Drugs, Anti-AIDS,Drugs, Anti-HIV
D019943	Amino Acid Substitution	The naturally occurring or experimentally induced replacement of one or more AMINO ACIDS in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish, enhance, or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties.	Amino Acid Substitutions,Substitution, Amino Acid,Substitutions, Amino Acid
D024882	Drug Resistance, Viral	The ability of viruses to resist or to become tolerant to chemotherapeutic agents or antiviral agents. This resistance is acquired through gene mutation.	Antiviral Drug Resistance,Antiviral Drug Resistances,Drug Resistances, Viral