Sixteen freshly isolated varicella-zoster virus (VZV) strains were evaluated in vitro, in parallel with two reference strains expressing a functional
thymidine kinase (TK+) (Oka and YS) and two
thymidine kinase-deficient mutants (TK-) (07-1 and YS-R), for their susceptibility to a broad range of
antiviral compounds. The following compounds were included:
acyclovir (ACV),
brivudine (BVDU),
sorivudine (BVaraU), other BVDU congeners such as BTDU, CTDU, CVDC and CVDU,
ganciclovir (GCV),
FIAC, araT, araA, araC,
foscarnet (PFA),
phosphonoacetic acid (PAA), the acyclic
nucleoside phosphonates HPMPC,
cHPMPC,
HPMPA,
cHPMPA,
HPMPc3A, PMEA and
PMEDAP, the N7-isomeric acyclic
nucleoside analogue N7AP,
penciclovir (PCV), compounds
882C87 and H2G and two
oxetanocin derivatives OXT-A and
OXT-G. Fourteen of the 16 clinical isolates displayed the following order of decreasing selectivity against VZV: BVaraU > BVDU > CVDU approximately CVDC > H2G > N7AP approximately CTDU approximately BTDU approximately
OXT-G approximately
882C87 > ACV >
FIAC approximately araT >
HPMPC approximately
cHPMPC approximately
HPMPA approximately
HPMPc3A approximately
cHPMPA > PCV approximately GCV approximately OXT-A >
PMEDAP approximately PMEA > PFA approximately PAA approximately araA > araC. Two VZV strains (isolated from the cerebrospinal fluid of an
AIDS patient) that were shown to have a truncated TK were clearly resistant to all the compounds that need the viral TK for their phosphorylation, while sensitivity to the acyclic
nucleoside phosphonates, PFA, PAA, OXT-A and araA, remained unchanged. A slight (5- and 10-fold) increase was noted in the 50% inhibitory concentration of N7AP and
OXT-G, respectively, for the TK- VZV strains as compared to the TK+ VZV strains.
Ganciclovir and
FIAC also showed a marked decrease in their activity against these two strains, but this was not as pronounced as for the other viral TK-dependent drugs. From our results, it appears that although acyclic
nucleoside phosphonates may not have as favourable a therapeutic index as drugs requiring the viral TK, they should be considered for the treatment of TK- VZV life-threatening
infections that are resistant to the viral TK-dependent drugs.