To examine the involvement of
ganciclovir-resistant strains in the development of central nervous system (
CNS) disease caused by human cytomegalovirus (HCMV), 14
AIDS patients with
CNS disease caused by HCMV were studied for the presence of HCMV strains with UL97 gene mutations associated with
ganciclovir resistance by using amplification and direct sequencing of HCMV
DNA in cerebrospinal fluid (CSF). The CSF of all seven patients who had not received
ganciclovir prior to the development of
CNS disease and four patients who had been receiving the
drug for 3 to 8 months contained wild-type UL97 sequences. The CSF of three patients who had received
ganciclovir for 12 to 30 months contained HCMV strains with
nucleotide changes leading to single-amino-acid substitutions within conserved UL97 sites implicated in
nucleotide binding (position 460) and substrate recognition (position 591). Patients containing mutant and wild-type strains revealed a similar spectrum of clinical and histopathologic manifestations. These findings indicate that
CNS disease in
AIDS patients receiving prolonged
ganciclovir therapy can be caused by
ganciclovir-resistant HCMV strains. Direct genotypic analysis of HCMV
DNA within CSF should help to identify
ganciclovir-resistant virus and to guide anti-HCMV
therapy.