DETECTION OF HUMAN CYTOMEGALOVIRUS MUTATIONS ASSOCIATED WITH GANCICLOVIR RESISTANCE IN CEREBROSPINAL-FLUID OF AIDS PATIENTS WITH CENTRAL-NERVOUS-SYSTEM DISEASE

To examine the involvement of ganciclovir-resistant strains in the dev elopment of central nervous system (CNS) disease caused by human cytom egalovirus (HCMV), 14 AIDS patients with CNS disease caused by HCMV we re studied for the presence of HCMV strains with UL97 gene mutations a ssociated with ganciclovir resistance by using amplification and direc t sequencing of HCMV DNA in cerebrospinal fluid (CSF). The CSF of all seven patients who had not received ganciclovir prior to the developme nt of CNS disease and four patients who had been receiving the drug fo r 3 to 8 months contained wild-type UL97 sequences. The CSF of three p atients who had received ganciclovir for 12 to 30 months contained HCM V strains with nucleotide changes leading to single-amino-acid substit utions within conserved UL97 sites implicated in nucleotide binding (p osition 460) and substrate recognition (position 591). Patients contai ning mutant and wild-type strains revealed a similar spectrum of clini cal and histopathologic manifestations. These findings indicate that C NS disease in AIDS patients receiving prolonged ganciclovir therapy ca n be caused by ganciclovir-resistant HCMV strains. Direct genotypic an alysis of HCMV DNA within CSF should help to identify ganciclovir-resi stant virus and to guide anti-HCMV therapy.