HIV Mutation Detail Information

Virus Mutation HIV Mutation R263K


Basic Characteristics of Mutations
Mutation Site R263K
Mutation Site Sentence The R263K mutation alone conferred an approximate 3-fold level of resistance to DTG and a 40% loss in viral replicative capacity and recombinant integrase activity.
Mutation Level Amino acid level
Mutation Type Nonsynonymous substitution
Gene/Protein/Region IN
Standardized Encoding Gene gag-pol:155348
Genotype/Subtype -
Viral Reference -
Functional Impact and Mechanisms
Disease -
Immune -
Target Gene -
Clinical and Epidemiological Correlations
Clinical Information -
Treatment DTG
Location -
Literature Information
PMID 25394027
Title The R263K mutation in HIV integrase that is selected by dolutegravir may actually prevent clinically relevant resistance to this compound
Author Wainberg M,Anstett K,Mesplede T,Quashie P,Han Y,Oliveira M
Journal Journal of the International AIDS Society
Journal Info 2014 Nov 2;17(4 Suppl 3):19518
Abstract INTRODUCTION: Drug resistance against dolutegravir (DTG) or the nucleosides with which it has been co-administered has never been observed in patients receiving this drug in first-line therapy. In contrast, a R263K mutation that confers low-level resistance (3-4 fold) to DTG has been selected by DTG in culture. Our group has ascribed the absence of resistance to DTG to the high fitness cost exacted by the R263K mutation and an inability of HIV to generate compensatory mutations. MATERIALS AND METHODS: We generated recombinant integrase enzymes and viruses containing various combinations of mutations and studied these enzymatically and in culture. We also selected for resistance against raltegravir (RAL) using viruses containing the R263K mutation. RESULTS: The R263K mutation alone conferred an approximate 3-fold level of resistance to DTG and a 40% loss in viral replicative capacity and recombinant integrase activity. Secondary mutations selected at positions H51Y or E138K did not individually affect either enzyme activity or DTG resistance, but the combination of R263K together with H51Y or E138K increased DTG resistance to about 7-fold accompanied by a approximately 75% loss in each of viral replication capacity, and both in vitro and in vivo integrase activity. Conversely, combinations of R263K together with multiple resistance mutations for RAL and/or EVG at positions 92,143, 148 and 155 resulted in even further diminished enzymatic activity that may be incompatible with viral survival. Modelling of the 3-dimensional structure of integrase suggests that R263K is located in a region that may not permit further mutagenesis if secondary mutations at H51Y or E138K are also present. Moreover, integrase that contains R263K together with substitutions at positions 92, 143, 148 and 155 may be enzymatically inactive. The use of the R263K-containing virus to select for resistance to RAL led to the appearance of RAL-containing mutations but the loss of R263K. CONCLUSIONS: Secondary mutations to R263K following selection with DTG have all led to diminished viral and enzymatic fitness, helping to explain why resistance to DTG in previously drug-naive subjects has never been observed. The use of DTG in first-line therapy may prevent the facile development of drug resistance and help to forestall ongoing HIV transmission.
Sequence Data -
Mutation Information
Note
Basic Characteristics of Mutations
  • Mutation Site: The specific location in a gene or protein sequence where a change occurs.
  • Mutation Level: The level at which a mutation occurs, including the nucleotide or amino acid level.
  • Mutation Type: The nature of the mutation, such as missense mutation, nonsense mutation, synonymous mutation, etc.
  • Gene/Protein/Region: Refers to the specific region of the virus where the mutation occurs. Including viral genes, viral proteins, or a specific viral genome region. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main
  • Gene/Protein/Region studied in the article is marked.
  • Genotype/Subtype: Refers to the viral genotype or subtype where the mutation occurs. If the article does not specifically indicate the relationship between the mutation and its correspondence, the main Genotype/Subtype studied in the article is marked.
  • Viral Reference: Refers to the standard virus strain used to compare and analyze viral sequences.
Functional Impact and Mechanisms
  • Disease: An abnormal physiological state with specific symptoms and signs caused by viral infection.
  • Immune: The article focuses on the study of mutations and immune.
  • Target Gene: Host genes that viral mutations may affect.
Clinical and Epidemiological Correlations
  • Clinical Information: The study is a clinical or epidemiological study and provides basic information about the population.
  • Treatment: The study mentioned a certain treatment method, such as drug resistance caused by mutations. If the study does not specifically indicate the relationship between mutations and their correspondence treatment, the main treatment studied in the article is marked.
  • Location: The source of the research data.
Literature Information
  • Sequence Data: The study provides the data accession number.