HIV-1 expressing the 3TC-associated M184V mutation in reverse transcriptase (RT) shows increased sensitivity to adefovir and PMPA as well as decreased replication capacity in vitro.
Originally Published on May 12, 1999
Miller M; Anton KE; Mulato AS; Lamy PD; Margot NA; Cherrington JM.
Int Conf AIDS. 1998;12:784-5 (abstract no. 41214).
ABSTRACT:
The 3TC-associated M184V mutation in RT has been shown to increase the in vitro sensitivity to AZT in AZT-resistant viruses and this can provide clinical benefit in some patients. In this study, the capacity of the M184V mutation to alter the in vitro susceptibility to adefovir, a nucleoside RT inhibitor whose prodrug Preveon is currently in phase III HIV clinical trials, was investigated.
METHODS: During clinical trials investigating the anti-HIV activity of Preveon, a number of patients developed the M184V mutation due to concomitant 3TC therapy. Recombinant viruses from baseline (M184wt) and post-treatment (M184V) plasma samples were prepared from 4 patients who had AZT-resistance mutations in RT and from 4 patients with AZT-sensitive viruses. Site-directed recombinant HXB2D HIV-1 expressing the M184V, M184I, T215Y and the double T215Y/M184V mutations were also constructed. Drug-susceptibility assays and growth kinetic analyses were performed for these viruses. RESULTS: Matched patient recombinant pairs from all 4 patients who developed the M184V mutation in the context of high-level AZT resistance showed 3-4 fold increases in sensitivity to adefovir resulting in near wild-type IC50 values for adefovir. Increases in AZT sensitivity were also observed in viruses from all 4 patients, but only those from 2 patients reverted to wild-type AZT values. There were also 2-3 fold increases in sensitivity to a related nucleotide analog PMPA. Increases in adefovir and PMPA sensitivity were also detected for the site-directed HXB2D double mutant T215Y/M184V as compared to the T215Y single mutant. Among AZT-sensitive clinical isolates, increased adefovir sensitivity was more variable and ranged from no change to a 3-fold increase. Two-fold increases in adefovir sensitivity were also noted for the M184V and M184I site-directed recombinants, rendering these viruses mildly hypersensitive. In growth kinetics studies, the M184V mutation resulted in attenuated virus growth in all genetic backgrounds, including those demonstrating high-level AZT resistance.
CONCLUSIONS: These in vitro drug susceptibility assays demonstrate that the M184V mutation in both AZT-resistant and AZT-sensitive genetic backgrounds results in increased sensitivity for adefovir to wild-type or near wild-type IC50 values, suggesting that patients with viruses possessing the T215Y and M184V mutations may derive clinical benefit from Preveon therapy. The reduced in vitro replication capacity of viruses containing the M184V mutation may also contribute to this benefit. The clinical significance of these in vitro findings is under investigation.
