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16th International HIV Drug Resistance Workshop12-16 June 2007, Barbados |
SPECIFIC MUTATIONS RELATED TO RESISTANCE TO HIV-1 INTEGRASE INHIBITORS ARE ASSOCIATED WITH REVERSE TRANSCRIPTASE MUTATIONS IN HAART-TREATED PATIENTS
Antivir Ther. 2007; 12:S6 (abstract no. 4)
F Ceccherini-Silberstein1, I Malet2, L Fabeni1, V Svicher1, C Gori3, S Dimonte1, S Bono1, A Artese4, R D’Arrigo3, C Katlama2, A Antinori3, A d’Arminio Monforte5, V Calvez2, AG Marcelin2 and CF Perno3
1University of Rome Tor Vergata, Rome, Italy; 2Hôpital Pitié-Salpétrière, Paris, France; 3INMI “L. Spallanzani”, Rome, Italy; 4University of Catanzaro, Catanzaro, Italy; 5University of Milan, Milan Italy
BACKGROUND: A tight interaction between HIV integrase (IN) and reverse trascriptase (RT) is mandatory for the successful completion of HIV replication process. Selected mutation(s) of IN can abrogate RT function. While 37 IN mutations have been associated with in vitro and/or in vivo resistance to IN inhibitors (INI), their relationship with RTI treatment and with RT mutations has not been assessed and characterized.
METHODS: Gene sequences of the entire IN and RT (1–320 residues) from 448 HIV-1 B-subtype patients, (134 drug-naïve and 314 patients failing HAART) were compared to consensus-B and analysed. Amino acid positions with variability <1% were considered invariant. Associations between mutations and RTI treatment were assessed by Fisher exact tests; associations among mutations were assessed by binomial correlation coefficient and hierarchical clustering.
RESULTS: IN-protein sequence was invariant at 178/288 residues (61.8% conservation) in untreated patients, and at 194/288 residues (67.4% conservation) in RTI-treated patients (P=0.026). Residues required for successful HIV-1 integration were invariant (catalytic-triad, HHCC zinc-binding site and residues crucial for LEDGF/p75 binding). Twenty-four out of 37 INI-resistance mutations were absent (0%) in both untreated and RTI-treated patients (H51Y-E92Q-F121Y-T125K-A128T-E138K-G140ASY143RC- Q146K-S147G-Q148KRH-S153AY-N155HSK160D- S230R-V249I-R263K-C280Y). Eight additional IN-residues showed >5% variability (I72V-T125AVM154I- K156N-V165I-V201I-T206S-S230N) in both untreated and RTI-treated patients. M154I and V165I mutations occurred at 6% frequency in untreated patients, reaching in RTI-treated patients 21.3% (P<0.001) and 13.4% (P=0.022), respectively. M154L was absent (0%) in drug-naïve patients, at 5.7% frequency in RTI-treated patients (P=0.003), and was positively associated with INI-resistance mutation V165I (P<0.0001), and RTI-resistance mutations F227L (P=0.01) and T215Y (P=0.05). In addition, V165I and T206S IN-mutations were positively associated with RTI-resistance mutations F227L (P=0.04) and L210W (P=0.005), respectively. Of interest, frequency of IN-mutation I72V was higher in untreated patients compared to RTI-treated patients (P<0.001), positively associated with the ‘protective’ RT-mutation R83K (P=0.03), and negatively associated with D67G and M184V NRTI-resistance mutations (P<0.03). Bootstrap analysis confirmed the clustering of selected INI-mutations with RTI-mutations.
CONCLUSIONS: The association between selected INI- and RTI-mutations supports the hypothesis of a tight interaction of these two HIV proteins, and a potential coevolution of some of their mutations. Beside theoretical implications, these results support the importance of IN-sequencing in RTI-treated patients starting INI-containing regimens.
2007-06-12
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