Detection of human cytomegalovirus mutations associated with ganciclovir resistance in cerebrospinal fluid of AIDS patients with central nervous system disease

Abstract

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.