Re. Jeeninga et al., Evolution of AZT resistance in HIV-1: The 41-70 intermediate that is not observed in vivo has a replication defect, VIROLOGY, 283(2), 2001, pp. 294-305
The human immunodeficiency virus type 1 (HIV-I) is notorious for its abilit
y to evolve drug-resistance in patients treated with potent antivirals. Res
istance to inhibitors of the viral reverse transcriptase (RT) enzyme is fre
quently mediated by a single amino acid substitution within RT. Resistance
against the nucleoside analogue AZT is remarkable in that multiple amino ac
id changes accumulate over time to yield virus variants with high-level dru
g resistance. We now report that in addition to drug-resistance properties,
the relative replication capacity of the virus variants affects the evolut
ion of AZT resistance. Some of the typical AZT-resistance mutations have a
negative impact on virus replication, and the 41-70 double mutant was found
to represent a particularly poor virus. Furthermore, introduction of addit
ional AZT-resistance mutations (41-70-215) leads to nearly complete restora
tion of virus replication. These results may explain the absence of the 41-
70 double mutant in clinical samples and indicate that the evolution of AZT
resistance is also influenced by virus replication parameters. Prolonged p
assage of the replication-impaired 41-70 virus in the absence of AZT yielde
d several fast-replicating variants. These revertants have compensatory cha
nges in the RT polymerase, some of which have been observed previously in A
ZT-treated patients. Because we could select for these changes without drug
pressure, these changes are likely to Improve the RT enzyme function and t
he HIV-I replication capacity, (C) 2001 Academic Press.