3rd International Workshop on HIV Drug Resistance 2-5 August 1994, Kauai, Hawaii, USA

IN VITRO STUDIES WITH 3TC-RESISTANT HIV-1: GROWTH·PROPERTIES AND CROSS-RESISTANCE PROFILE

Int Wkshop HIV Drug Res 1994 Aug 2-5;3:33 (abstract no. 32)

S.D. Kemp and B.A. Larder
Wellcome Research Labs., UK

Our recent in vitro studies of HIV-1 3TC resistance have focused on evaluating the relative growth properties of 3TC resistant virus and assessing the ability of the virus to become co-resistant to other inhibitors. Treatment of HIV-infected individuals with 3TC results in the rapid appearance of resistant virus (see Schuurman et al. Antimicrob Agents Chemother. 1993 Oct;37(10):2231-4). Resistance is due to a mutation at codon 184 of RT, M184→V or MI84→I. Interestingly, the M184→I mutation appears initially during therapy, but is rapidly replaced by the M184→V mutation. Since these in vivo data suggest a growth advantage for virus harbouring the MI84→V, we compared the growth properties of 3TC-resistant mutant viruses created by site-directed mutagenesis. Virus was serially passaged as either pure populations, or initially as 50:50 mixtures, both in the absence of inhibitor, or in the presence of a constant amount of 3TC or FTC.

The status of codon 184 was determined at each passage by automated DNA sequence analysis of PCR products. The 184V mutant virus was clearly able to outgrow the 1841 mutant virus, both in the presence or absence of inhibitor. Sensitivity studies revealed that virus harbouring the 184V mutation was more resistant to both 3TC and FTC than virus harbouring the 1841 mutation. These results might explain why the 184V mutation becomes dominant during 3TC therapy. Cross resistance studies indicate that the 184V mutation confers resistance to ddC and ddI, suggesting that combinations of these inhibitors may not be as clinically useful as inhibitors with non-overlapping resistance profiles. As 3TC-resistant virus remains susceptible to AZT we have attempted to select dual resistant virus. Passage of the AZT-resistant cloned strain HIVRTMN (41L+215Y) in 3TC alone, resulted in selection of highly 3TC resistant virus, with restored AZT sensitivity, presumably due to suppression by mutation at codon 184. Similar passage experiments in the presence of both 3TC and AZT have so far failed to select dual resistance. These data suggest that both 3TC and AZT may be good candidates for combination therapy.

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1994-08-02
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