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BACKGROUND:
Susceptibility of HIV-1 to zidovudine is increased by at least five
mutations in reverse transcriptase (RT): K65R, L74V, L100I, Y181C and M184V.
In some cases these ‘suppressive mutations’ restore susceptibility to
zidovudine despite of the presence of resistance mutations such as K70R or
T215F/Y. In general, susceptibility to stavudine and tenofovir is modulated
by RT resistance mutations in a manner that qualitatively parallels that of
zidovudine. Thus, we evaluated the effect of suppressive mutations on
susceptibility to stavudine and tenofovir.
METHODS:
A clinical sample database of over 16000 matched genotypes and
phenotypes was queried for samples containing T215F or Y without, or with
one or more, suppressive mutations (K65R, L74I and V, L100I, Y181C, I, and
V, and M184I and V; different variants at each position were grouped
together). Samples containing multi-nucleoside RT inhibitor (NRTI)
resistance mutations (T69ins or Q151M) were excluded, as were samples with
mixtures at positions that were part of the query. NRTI fold change (FC) in
IC50 vs NL4-3 reference was compared between groups of viruses using the
Mann-Whitney non-parametric test.
RESULTS:
Median zidovudine FC for T215Y/F samples with no suppressive mutations (n =966),
L74I/V
alone
(that is, no other suppressive mutations,
n=87),L100I
alone (n=54),
Y181I/C/V alone (n=283) or M184I/V alone (n=1423) was 145-,
102-, 78-, 75- and 12-fold, respectively (P<0.05 for each suppressive
mutation group vs no suppressive mutations). The corresponding FC values for
tenofovir were 2.8-,
2.2-, 2.1-, 2.4- and 1.3-fold, respectively (all
P<0.05), and for stavudine were 2.4-,
3.3-, 2.5-, 2.8- and 1.8-fold, respectively (all
P<0.05 except L100I). The number of
samples with K65R and T215F/Y was too low to provide meaningful comparisons.
Combinations of two or more suppressive mutations were generally additive in
suppressing zidovudine and tenofovir resistance. For example, median
zidovudine and tenofovir FC for samples with L100I+M184IV (n=28)
were 3.8- and 0.8-fold, and for Y181I/C/V+M184I/V (n=174) were 10-
and 1.1-fold, respectively. Lower FC in groups with suppressive mutations
could not be explained by fewer thymidine analogue mutations (median number
3 to 4 for all groups). As expected, FC for didanosine, zalcitabine (ddC)
and abacavir was higher in groups containing L74I/V and/or M184I/V, and was
not significantly affected by L100I or Y181C/I/V.
CONCLUSIONS:
M184I/V increases susceptibility to zidovudine, tenofovir and stavudine.
Other suppressive mutations in RT affect tenofovir and zidovudine, but not
stavudine. Susceptibility to stavudine decreased in the presence of L74I/V
and Y181I/C/V. Additive effects were observed when suppressive mutations
were present together. Combined mutations were capable of re-sensitizing
tenofovir (FC<1.4) and zidovudine (FC<2.5) in the presence of multiple
thymidine analogue mutations. Since genotype interpretation algorithms do
not account for the effects of most suppressive mutations, these
observations provide an explanation for phenotype/genotype discordance for
zidovudine and tenofovir. |
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