15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

NATURAL POLYMORPHISM OF THE HIV-1 INTEGRASE GENE AND MUTATIONS ASSOCIATED WITH INTEGRASE INHIBITOR RESISTANCE

Antivir Ther. 2006, 11:S28 (abstract no. 23)

M Lataillade, J Chiarella and MJ Kozal
Yale University School of Medicine, New Haven, CT, USA

BACKGROUND: HIV-1 integrase inhibitors (INIs) are currently in late stage clinical trials and may soon be available in the clinic. More than 20 mutations within the integrase gene (IN) have been associated with resistance to the different INIs. In this study, we evaluated clinical HIV-1 strains from INI naïve patients to determine the prevalence and patterns of polymorphisms in the IN gene and the frequency of naturally occurring amino acid (aa) substitutions associated with INI resistance.

METHODS: HIV-1 clade B strains from INI naïve patients were analysed. RT-PCR using multiple IN primer sets was performed to amplify the entire IN gene (867 bases). All samples were sequenced using ABI technology and a subset was analysed with DNA microarray technology. BioEdit software was used for pairwise comparisons. A consensus sequence was determined and compared to the reference strain HXB2.

RESULTS: Full-length HIV-1 clade B IN genes from 61 patients were sequenced. Additionally, 176 full-length IN clade B sequences from unique INI-naïve patients obtained from the HIV Los Alamos database were analysed. Analysis of the 237 IN genes revealed that 62% of the aa positions were found to be polymorphic. IN aa residues within the catalytic triad (DDE) and the HHCC motif were relatively well conserved. Of the 23 aa substitutions associated with INI resistance, 12 occurred as natural polymorphisms (V72I, A128T, E138K, V151I, S153Y/A, M154I, N155H, V165I, V201I, T206S, S230N); residues V72I, V165I, V201I and T206S occurred at high frequency; 72I was the consensus aa at this position. However, a number of major aa substitutions known to confer high level INI resistance (e.g. at positions T66I, L74M, F121Y, T125K, G140S, S230R, V249I, C280Y) were not found to occur as natural polymorphisms.

CONCLUSIONS: In this sample of HIV-1 clade B clinical strains, the IN gene displayed a high level of diversity with 62% of the aa positions being polymorphic. INI mutations associated with INI resistance occurred frequently as natural polymorphisms. Major INI mutations associated with high level resistance to the compounds in late stage development were infrequent and this may help explain the excellent virological responses demonstrated in clinical trials.

2006-06-13
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