Bone marrow transplantation in a child with Wiskott‐Aldrich syndrome latently infected with acyclovir‐resistant (ACV^r) herpes simplex virus type 1: Emergence of foscarnet‐resistant virus originating from the ACV^r virus

Abstract

A human leukocyte antigen (HLA)-matched unrelated bone marrow transplantation (BMT) was performed in a 13-year-old patient with the congenital immunodeficiency syndrome, Wiskott-Aldrich syndrome. The patient had a history of acyclovir (ACV)-resistant (ACV(r)) herpes simplex virus type 1 (HSV-1) infections prior to BMT. After BMT, the skin lesions caused by HSV-1 relapsed on the face and genito-anal areas. Ganciclovir (GCV) therapy was initiated, but the mucocutaneous lesions worsened. An HSV-1 isolate recovered from the lesions during this episode was resistant to both ACV and GCV. The ACV(r) isolate was confirmed to have the same mutation in the viral thymidine kinase (TK) gene as that of the previously isolated ACV(r) isolates from the patient. After treatment switch to foscarnet (PFA), there was a satisfactory remission but not a complete recovery. Although the mucocutaneous lesions improved, a PFA-resistant (PFA(r)) HSV-1 was isolated 1 month after the start of PFA therapy. The PFA(r) HSV-1 isolate coded for the same mutation in the viral TK gene as the ACV(r) HSV-1 isolates. Furthermore, the PFA(r) isolate also expressed a mutated viral DNA polymerase (DNA pol) with an amino acid (Gly) substitution for Val at position 715. This is the first report on the clinical course of a BMT-associated ACV(r) HSV-1 infection that subsequently developed resistance to foscarnet as well.

Drug Resistance Patterns of Recombinant Herpes Simplex Virus DNA Polymerase Mutants Generated with a Set of Overlapping Cosmids and Plasmids

“…In the first case, we were able to confirm the role of mutation D907V located outside conserved regions in the phenotype of resistance to ACV. This finding, combined with previous confirmation of the role of a TK mutation in the same clinical isolate (7), establishes the additive effect of mutations in two genes with respect to the final ACV resistance phenotype (6,42). In the second case, our data now support a role for the S724N (region II) mutation but not for a concomitant DNA Pol mutation (P920S) located outside a conserved region in the ACV resistance phenotype.…”

“…Mutations located in conserved region II of the HSV DNA pol gene are frequently associated with resistance to ACV and pyrophosphate analogues (1,22,34,42). Two (A719T and S724N) of the four mutations located within this region conferred similar phenotypes and were also associated with ADV resistance.…”

Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up

“…Antiviral drugs with a non-TK-dependent mode of action, such as PFA, have been used since the emergence of ACVresistant strains (7,28), and PFA-resistant strains have appeared (8,13,33,34). In our study, among the 22 ACVresistant patients who received PFA, 14 excreted PFA-resistant strains (64%).…”

Genotypic Characterization of the DNA Polymerase and Sensitivity to Antiviral Compounds of Foscarnet-Resistant Herpes Simplex Virus Type 1 (HSV-1) Derived from a Foscarnet-Sensitive HSV-1 Strain

“…HSV-1 TAS and the mutant HSV-1 isolates, which were selected from the infected cells in MEM-2FBS with PFA, were tested for their sensitivities to PFA, CDV, S2242, ACV, GCV, and PCV by plaque reduction assay, as described previously (25)(26)(27)(28). The 50% inhibitory concentration (IC 50 ) of each antiviral agent was calculated as the concentration at which the plaque number decreased to half of that in medium without antiviral agents.…”