MUTATION IN REGION-III OF THE DNA-POLYMERASE GENE CONFERRING FOSCARNET RESISTANCE IN CYTOMEGALOVIRUS ISOLATES FROM 3 SUBJECTS RECEIVING PROLONGED ANTIVIRAL THERAPY

Three human immunodeficiency virus-infected subjects with progressive cytomegalovirus (CMV) retinitis despite prolonged antiviral therapy ha d buffy coat CMV isolates that were resistant to both ganciclovir and foscarnet, Genetic analysis of the resistant isolates showed that each contained a well-known ganciclovir resistance mutation in the viral U L97 phosphotransferase sequence, as well as a mutation (Ala to Val at codon 809, V809) in conserved region III of the DNA polymerase (Pol) s equence. A segment of the Pol sequence from one of the clinical isolat es was transferred to CMV laboratory strain AD169 by homologous recomb ination. The recombinant virus containing V809 showed 6.3-fold increas ed foscarnet resistance and 2.6-fold increased ganciclovir resistance. Occurrence of the V809 mutation in 3 unrelated cases suggests that it is a clinically significant viral genetic marker for foscarnet resist ance and decreased susceptibility to ganciclovir.