CYTOMEGALOVIRUS: A TALE OF RESISTANCE
Abstract
Cytomegalovirus (CMV) is a pathogen that affects the majority of the world’s population. It may exhibit a wide spectrum of clinical manifestations, ranging from asymptomatic infection in the healthy, congenital disease of the newborn to downright life-threatening illness in the immunocompromised. Initiating timely and adequate therapy can prove lifesaving. At times the virus develops resistance to specific drugs, an occurrence that can lead to the patient’s demise. This mini-review explores the molecular aetiology and incidence of resistance, the antiviral arsenal that is at our disposal, as well as the diagnostic approaches to uncovering drug resistance.
References
Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev. 2010 Oct; 23(4):689-712.
Knox GE. Cytomegalovirus: import of sexual transmission. Clin Obstet Gynecol. 1983 Mar; 26(1):173-177.
Chakravarty A, Kashyap B, Rathi K. The seroepidemiological study on cytomegalovirus in women of child bearing age with special reference to pregnancy and maternal-fetal transmission. Indian J Pathol Microbiol. 2005 Oct; 48(4):518-521.
Centres for Disease Control and Prevention. Cytomegalovirus (CMV) and Congenital CMV Infection. Available from: https://www.cdc.gov/cmv/overview.html [Accessed 5th October 2019].
Strasfeld L, Chou S. Antiviral drug resistance: mechanisms and clinical implications. Infect Dis Clin North Am. 2010 Jun; 24(2):413–437.
Boeckh M, Fries B, Nichols WG. Recent advances in the prevention of CMV infection and disease after hematopoietic stem cell transplantation. Pediatr Transplant. 2004 Jun;8 Suppl 5:19-27.
Boeckh M, Ljungman P, 2009. How we treat CMV in hematopoietic cell transplant recipients. Blood. 2009 Jun; 113(23):5711-5719.
Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin. Microbiol. 2000 Jan; 13(1):83-121.
Sun HY, Wagener MM, Singh N. Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review. Am J Transplant. 2008 Oct; 8(10):2111-2118.
Swanson EC, Schleiss MR. Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am. 2013 Apr; 60(2):335–349.
Stanojević M. Antivirusni lekovi. In: Savić B, Mitrović S, Jovanović T, editors. Medicinska mikrobiologija. Beograd, Srbija: Medicinski fakultet Univerziteta u Beogradu, CIBID; 2019. p.395.
Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level resistance of cytomegalovirus to ganciclovir is associated with alterations in both the UL97 and DNA polymerase genes. J Infect Dis. 1997 Jul; 176(1):69–77.
Eckle T, Lang P, Prix L, Jahn G, Klingebiel T, Handgretinger R, et al. Rapid development of ganciclovir-resistant cytomegalovirus infection in children after allogeneic stem cell transplantation in the early phase of immune cell recovery. Bone Marrow Transplant. 2002 Oct; 30(7):433-439.
Wolf DG, Yaniv I, Honigman A, Kassis I, Schonfeld T, Ashkenazi S. Early emergence of ganciclovir-resistant human cytomegalovirus strains in children with primary combined immunodeficiency. J Infect Dis. 1998 Aug; 178(2):535-538.
Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis. 2002 Oct; 35(7):866–872.
Boivin G, Goyette N, Gilbert C, Covington E. Analysis of cytomegalovirus DNA polymerase (UL54) mutations in solid organ transplant patients receiving valganciclovir or ganciclovir prophylaxis. J Med Virol. 2005 Nov; 77(3):425-429.
Boivin G, Goyette N, Gilbert C, Roberts N, Macey K, Paya C et al. Absence of cytomegalovirus-resistance mutations after valganciclovir prophylaxis, in a prospective multicenter study of solid-organ transplant recipients. J Infect Dis. 2004 May; 189(9):1615-1618.
Boivin G, Goyette N, Rollag H, Jardine AG, Pescovitz MD, Asberg A et al. Cytomegalovirus resistance in solid organ transplant recipients treated with intravenous ganciclovir or oral valganciclovir. Antivir Ther. 2009;14(5):697-704.
Prix L, Hamprecht K, Holzhüter B, Handgretinger R, Klingebiel T, Jahn G. Comprehensive restriction analysis of the UL97 region allows early detection of ganciclovir-resistant human cytomegalovirus in an immunocompromised child. J Infect Dis. 1999 Aug; 180(2):491-495.
Springer KL, Chou S, Li S, Giller RH, Quinones R, Shira JE, et al. How evolution of mutations conferring drug resistance affects viral dynamics and clinical outcomes of cytomegalovirus-infected hematopoietic cell transplant recipients. J Clin Microbiol. 2005 Jan; 43(1):208-213.
Göhring K, Hamprecht K, Jahn G. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients. Comput Struct Biotechnol J. 2015 Feb; 13:153-9.
Blanco L, Bernad A, Blasco MA, Salas M. A general structure for DNA-dependent DNA polymerases. Gene. 1991 Apr; 100:27-38.
Cihlar T, Fuller MD, Mulato AS, Cherrington JM. A point mutation in the human cytomegalovirus DNA polymerase gene selected in vitro by cidofovir confers a slow replication phenotype in cell culture. Virology. 1998 Sep; 248(2):382-393.
Hall JD, Orth KL, Sander KL, Swihart BM, Senese RA. Mutations within conserved motifs in the 3’-5’ exonuclease domain of herpes simplex virus DNA polymerase. J Gen Virol. 1995 Dec; 76(Pt 12):2999-3008.
Teo IA, Griffin BE, Jones MD. Characterization of the DNA polymerase gene of human herpesvirus 6. J Virol. 1991 Sep; 65(9):4670-4680.
Bauer DJ. A history of the discovery and clinical application of antiviral drugs. Br Med Bull. 1985 Oct; 41(4):309-14.
Gilbert C, Bestman-Smith J, Boivin G. Resistance of herpesviruses to antiviral drugs: clinical impacts and molecular mechanisms. Drug Resist Updat. 2002 Apr; 5(2):88-114.
Kalil AC, Freifeld AG, Lyden ER, Stoner JA. Valganciclovir for cytomegalovirus prevention in solid organ transplant patients: an evidence-based reassessment of safety and efficacy. PLoS One 2009; 4(5):e5512.
Crumpacker CS. Ganciclovir. N Engl J Med. 1996 Sep; 335(10):721-729.
Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections. Drugs. 1994 Aug; 48(2):199-226.
Deray G, Martinez F, Katlama C, Levaltier B, Beaufils H, Danis M, et al. Foscarnet nephrotoxicity: mechanism, incidence and prevention. Am J Nephrol. 1989;9(4):316-321.
De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev. 2003 Oct; 16(4):569-596.
Safrin S, Cherrington J, Jaffe HS. Clinical uses of cidofovir. Rev Med Virol. 1997 Sep; 7(3):145-156.
Lalezari J, Schacker T, Feinberg J, Gathe J, Lee S, Cheung T, et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis. 1997 Oct; 176(4):892-898.
Akhter K. Cytomegalovirus (CMV) Treatment & Management. Available from: https://emedicine.medscape.com/article/215702-treatment [Accessed: Accessed 5th October 2019].
Chou S, Waldemer RH, Senters AE, Michels KS, Kemble GW, Miner RC, et al. Cytomegalovirus UL97 phosphotransferase mutations that affect susceptibility to ganciclovir. J Infect Dis. 2002 Jan; 185(2):162-169.
Chou S, Lurain NS, Thompson KD, Miner RC, Drew WL. Viral DNA polymerase mutations associated with drug resistance in human cytomegalovirus. J Infect Dis. 2003 Jul; 188(1):32-39.
Chou S, Marousek G, Parenti DM, Gordon SM, LaVoy AG, Ross JG, et al. Mutation in region III of the DNA polymerase gene conferring foscarnet resistance in cytomegalovirus isolates from 3 subjects receiving prolonged antiviral therapy. J Infect Dis. 1998 Aug; 178(2):526-530.
Scott GM, Weinberg A, Rawlinson WD, Chou S. Multidrug resistance conferred by novel DNA polymerase mutations in human cytomegalovirus isolates. Antimicrob Agents Chemother. 2007 Jan; 51(1):89-94.
Chou S, Miner RC, Drew WL. A deletion mutation in region V of the cytomegalovirus DNA polymerase sequence confers multidrug resistance. J Infect Dis. 2000 Dec; 182(6):1765-1768.
Chou S, Marousek G, Guentzel S, Follansbee SE, Poscher ME, Lalezari JP, et al. Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease. J Infect Dis. 1997 Sep; 176(3):786-9.