Seventh International Congress on Drug Therapy in HIV Infection Glasgow, UK - 14-17 November 2004

Int Cong Drug Therapy HIV 2004 Nov 14-18;7:Abstract No. PL5.4

Narges Hassani Espili , Alona Pavlova , Tobias Bergroth , Anders Sönnerborg , Johan Lennerstrand
Clinical Virology, Karolinska Institutet, Huddinge, Sweden

It has been reported that the M184V mutation in HIV-1 reverse transcriptase (RT) interferes with ATP mediated excision of zidovudine (AZT)-MP. However, depending on the type of RT assay used, there have been contradictory results regarding the effects of the M184V mutation on excision. We have now investigated the effect of known AZT suppression mutations (M184V, Y181C and L100I) for tenofovir unblocking, in a background of multi-nucleoside resistance mutations.

Site directed RT mutants were constructed carrying: M41L, D67N, K70R, L210W, T215Y (TAM mutant), and M41L, T69S-SG, L210W, T215Y (69S-SG mutant). The M184V mutation was added to wild type, TAM mutant and the 69S-SG mutant, respectively. Also, Y181C respective L100I was added to the 69S-SG mutant. Tenofovir resistance was studied by recombinant virus assay (Virco, Belgium). The ATP mediated excision of tenofovir was studied for the purified RT mutants with a non-radioactive RT assay (Cavidi Tech, Sweden).

The 69S-SG mutants were analyzed with the recombinant virus assay, and the relative increase in IC₅₀ for tenofovir compared to wild type virus was: 69S-SG, 17.8; 69S-SG+184V, 3.2; 69S-SG+181C, 7.5; and 69S-SG+100I, 4.8. In studies of RT mutants in the RT assay with ATP added, the level of tenofovir-DP IC₅₀ relative to wild type RT were as follows: 184V, 0.5; TAM, 2.8; TAM+184V, 1.5; 69S-SG, 10.2; 69S-SG+184V, 2.8; 69S-SG+181C, 2.5; and 69S-SG+100I, 2.9.

The M184V, Y181C and L100I mutation reduces the ATP mediated excision of incorporated tenofovir. Thus, our biochemical data is consistent with cell culture data. This indicates that there would be a benefit with tenofovir therapy combined with therapy rendering suppression mutations.

SESSION 5: ADHERENCE, RESISTANCE, CLINICAL PHARMACOLOGY AND DISEASE MONITORING

2004-11-14
PL5.4

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