Integrase variability and susceptibility to HIV integrase inhibitors: impact of subtypes, antiretroviral experience and duration of HIV infection.
BACKGROUND
Little is known about the extent and predictors of polymorphisms potentially influencing the susceptibility to HIV integrase inhibitors (INIs).


METHODS
Genetic sequences of HIV integrase were obtained from INI-naive patients at two European clinics. The 39 amino acid changes at 29 integrase positions so far associated with INI resistance were examined according to HIV clade, prior antiretroviral exposure and duration of HIV infection.


RESULTS
Integrase sequences were obtained from 418 patients, 294 (70.3%) infected with clade B and 124 (29.7%) infected with non-B variants (predominantly CRF02, A, C and D). Overall, 40% of patients were antiretroviral experienced and 32.8% were recent seroconverters. The most prevalent INI resistance-associated mutations were V72I (63.9%), V201I (54.8%), T206S (25.4%), I203M (9.8%) and K156N (7.4%). Major INI resistance mutations at positions 66, 92, 143, 148 and 155 were not detected. The mean number of polymorphic sites was greater in non-B than in B variants (2.17 versus 1.59; P < 0.001), and in antiretroviral-experienced than in drug-naive patients (1.89 versus 1.68; P = 0.034), whereas no significant differences were seen comparing recent seroconverters and chronically infected persons.


CONCLUSIONS
Major INI resistance-associated mutations are very rare, if indeed ever present, in INI-naive patients. However, polymorphisms at positions which may influence the genetic barrier and/or drive the selection of specific INI resistance pathways are common, especially in HIV non-B subtypes.
Garrido
Carolina
C
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Geretti
Anna Maria
AM
Zahonero
Natalia
N
Booth
Clare
C
Strang
Angela
A
Soriano
Vincent
V
De Mendoza
Carmen
C
D019380:Anti-HIV Agents / Q000494:pharmacology*; D016000:Cluster Analysis; D024882:Drug Resistance, Viral; D005060:Europe; D005260:Female; D005838:Genotype; D006678:HIV / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D011506:Proteins; D017422:Sequence Analysis, DNA
D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; C484600:IMPACT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D019427:HIV Integrase