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.
Full Text
The Full Text of this article is available as a PDF (182.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Baldanti F., Silini E., Sarasini A., Talarico C. L., Stanat S. C., Biron K. K., Furione M., Bono F., Palù G., Gerna G. A three-nucleotide deletion in the UL97 open reading frame is responsible for the ganciclovir resistance of a human cytomegalovirus clinical isolate. J Virol. 1995 Feb;69(2):796–800. doi: 10.1128/jvi.69.2.796-800.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chee M. S., Lawrence G. L., Barrell B. G. Alpha-, beta- and gammaherpesviruses encode a putative phosphotransferase. J Gen Virol. 1989 May;70(Pt 5):1151–1160. doi: 10.1099/0022-1317-70-5-1151. [DOI] [PubMed] [Google Scholar]
- Chou S., Erice A., Jordan M. C., Vercellotti G. M., Michels K. R., Talarico C. L., Stanat S. C., Biron K. K. Analysis of the UL97 phosphotransferase coding sequence in clinical cytomegalovirus isolates and identification of mutations conferring ganciclovir resistance. J Infect Dis. 1995 Mar;171(3):576–583. doi: 10.1093/infdis/171.3.576. [DOI] [PubMed] [Google Scholar]
- Cinque P., Vago L., Brytting M., Castagna A., Accordini A., Sundqvist V. A., Zanchetta N., Monforte A. D., Wahren B., Lazzarin A. Cytomegalovirus infection of the central nervous system in patients with AIDS: diagnosis by DNA amplification from cerebrospinal fluid. J Infect Dis. 1992 Dec;166(6):1408–1411. doi: 10.1093/infdis/166.6.1408. [DOI] [PubMed] [Google Scholar]
- Drew W. L., Miner R. C., Busch D. F., Follansbee S. E., Gullett J., Mehalko S. G., Gordon S. M., Owen W. F., Jr, Matthews T. R., Buhles W. C. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis. 1991 Apr;163(4):716–719. doi: 10.1093/infdis/163.4.716. [DOI] [PubMed] [Google Scholar]
- Gozlan J., Salord J. M., Roullet E., Baudrimont M., Caburet F., Picard O., Meyohas M. C., Duvivier C., Jacomet C., Petit J. C. Rapid detection of cytomegalovirus DNA in cerebrospinal fluid of AIDS patients with neurologic disorders. J Infect Dis. 1992 Dec;166(6):1416–1421. doi: 10.1093/infdis/166.6.1416. [DOI] [PubMed] [Google Scholar]
- Hanks S. K., Quinn A. M., Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988 Jul 1;241(4861):42–52. doi: 10.1126/science.3291115. [DOI] [PubMed] [Google Scholar]
- Hanson M. N., Preheim L. C., Chou S., Talarico C. L., Biron K. K., Erice A. Novel mutation in the UL97 gene of a clinical cytomegalovirus strain conferring resistance to ganciclovir. Antimicrob Agents Chemother. 1995 May;39(5):1204–1205. doi: 10.1128/aac.39.5.1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Littler E., Stuart A. D., Chee M. S. Human cytomegalovirus UL97 open reading frame encodes a protein that phosphorylates the antiviral nucleoside analogue ganciclovir. Nature. 1992 Jul 9;358(6382):160–162. doi: 10.1038/358160a0. [DOI] [PubMed] [Google Scholar]
- Lurain N. S., Spafford L. E., Thompson K. D. Mutation in the UL97 open reading frame of human cytomegalovirus strains resistant to ganciclovir. J Virol. 1994 Jul;68(7):4427–4431. doi: 10.1128/jvi.68.7.4427-4431.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lurain N. S., Thompson K. D., Holmes E. W., Read G. S. Point mutations in the DNA polymerase gene of human cytomegalovirus that result in resistance to antiviral agents. J Virol. 1992 Dec;66(12):7146–7152. doi: 10.1128/jvi.66.12.7146-7152.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Morgello S., Cho E. S., Nielsen S., Devinsky O., Petito C. K. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome: an autopsy study of 30 cases and a review of the literature. Hum Pathol. 1987 Mar;18(3):289–297. doi: 10.1016/s0046-8177(87)80012-6. [DOI] [PubMed] [Google Scholar]
- Stanat S. C., Reardon J. E., Erice A., Jordan M. C., Drew W. L., Biron K. K. Ganciclovir-resistant cytomegalovirus clinical isolates: mode of resistance to ganciclovir. Antimicrob Agents Chemother. 1991 Nov;35(11):2191–2197. doi: 10.1128/aac.35.11.2191. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sullivan V., Biron K. K., Talarico C., Stanat S. C., Davis M., Pozzi L. M., Coen D. M. A point mutation in the human cytomegalovirus DNA polymerase gene confers resistance to ganciclovir and phosphonylmethoxyalkyl derivatives. Antimicrob Agents Chemother. 1993 Jan;37(1):19–25. doi: 10.1128/aac.37.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sullivan V., Talarico C. L., Stanat S. C., Davis M., Coen D. M., Biron K. K. A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells. Nature. 1992 Jul 9;358(6382):162–164. doi: 10.1038/358162a0. [DOI] [PubMed] [Google Scholar]
- Wolf D. G., Smith I. L., Lee D. J., Freeman W. R., Flores-Aguilar M., Spector S. A. Mutations in human cytomegalovirus UL97 gene confer clinical resistance to ganciclovir and can be detected directly in patient plasma. J Clin Invest. 1995 Jan;95(1):257–263. doi: 10.1172/JCI117648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolf D. G., Spector S. A. Diagnosis of human cytomegalovirus central nervous system disease in AIDS patients by DNA amplification from cerebrospinal fluid. J Infect Dis. 1992 Dec;166(6):1412–1415. doi: 10.1093/infdis/166.6.1412. [DOI] [PubMed] [Google Scholar]