16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

EFFECTS OF PROTEASE AND REVERSE TRANSCRIPTASE INHIBITOR-RESISTANCE MUTATIONS ON INTEGRASE POLYMORPHISM IN MULTIDRUG RESISTANCE CASES

Antivir Ther. 2007; 12:S4 (abstract no. 2)

H Suzuki, M Fujino, M Matsuda, H Yen, Y Iwantani and W Sugiura
AIDS Research Center, National Institute of Infectious Diseases, Japan

BACKGROUND: HIV protease (Pr), reverse transcriptase (RT) and integrase (IN) are encoded in tandem in the pol gene and are translated as one precursor protein, which is processed by Pr into the final enzymes. RT and IN also form a complex during the early stage of the viral life cycle. Since these three enzymes interact, acquisition of mutations in one protein may affect selection of mutations in others. Thus, the aim of this study was to clarify any interference between IN, Pr and RT, and effects of acquiring PI and RTI resistance mutations on integrase polymorphisms.

METHODS: Multidrug resistance (MDR) cases were randomly selected from patient samples sent to the NIID between 2002 and 2006 for routine drug-resistance genotyping. Newly diagnosed treatment-naïve (naïve) cases were collected between January 2003 and December 2006. Viral RNA extracted from 200 µl plasma was reverse transcribed, and 1.3 Kbps protease–RT and 0.9 Kbps integrase regions were amplified by nested PCR. PCR products were analysed by auto-sequencer. Drugresistant mutations were defined by the IAS-USA chart of drug-resistance definitions.

RESULTS: Fifty-three MDR cases (subtype B: 47; CRF01_AE: 5, C: 1), and 51 naïve cases (B: 41; CRF01_AE: 8, AG: 2) were enrolled. Integrase mutations observed in MDR and newly diagnosed cases were compared for subtypes B and CRF01_AE. For subtype B, we found the following mutations: D10E (naïve: 97%, MDR: 87%), K14R (3%, 9%), S17N (29%, 41%), V31I (11%, 28%), V72I (68%, 63%), L101I (41%, 50%), T112V (11%, 13%), S119T (16%, 37%), A124T (89%, 51%), T125A (16%, 27%), K156N (35%, 22%), V201I (38%, 49%), S230N (3%, 16%), N232D (100%, 89%), L234I (10%, 2%) and S283G (5%, 9%). No diketo acid-related resistance mutation was observed in either the MDR or naïve group. However, S119T and S230N were observed in higher frequencies in the MDR group (P<0.05). For CRF01_AE cases, no diketo acid resistance or significant differences were observed between MDR and naïve cases.

CONCLUSION: Accumulation of PI and RTI resistance mutations apparently affected integrase polymorphism to some extent. However, the data for MDR patients were encouraging in that no diketo-acid-related resistance mutation was observed in either the MDR or naïve group.

2007-06-12
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