Reactivation of acyclovir-resistant thymidine kinase-deficient herpes simplex virus harbouring single base insertion within a 7 Gs homopolymer repeat of the thymidine kinase gene

Abstract

HSV infections are treated efficiently and prevented by acyclovir, although resistant strains have been reported. Resistance to acyclovir involves mainly mutations in the viral gene encoding thymidine kinase; mutations may lead to an altered or, more frequently, deficient TK. These acyclovir-resistant TK deficient strains are not able to reactivate from a latent infection in an experimental model, compared to TK positive strains. A case is reported of a bone marrow transplant child who developed HSV infection at 11 days post-transplantation. Acyclovir-resistant HSV 1 was isolated on day 19 post-transplantation. The patient was cured of his infection. A resistant virus was detected 20 months later that harboured the same TK gene mutation as the first resistant virus. This mutation is an insertion of one guanine in a homopolymer repeat of seven guanines located at codon 146 of TK. It has previously been reported and associated with the expression of a deficient TK activity and the ability to reactivate in mice. These results corroborate the clinical relevance of this mutation, which is associated with acyclovir-resistant recurrent infections in humans.

Herpes Simplex Virus Resistance to Acyclovir and Penciclovir after Two Decades of Antiviral Therapy

“…Another case has been described in a bone marrow transplant recipient, from whom an acyclovir-resistant, TK-deficient HSV-1 mutant was isolated 20 months after healing of the original HSV infection. This isolate also was identical to the original isolate (52).…”

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

“…After healing of an infection caused by a TK-negative drug-resistant HSV strain and stopping antiviral therapy, recurrences are most often associated with a drugsensitive strain, although some cases of spontaneous recurrences of ACV-resistant viruses have been reported (1,78,100,113,125,126,142,146,152,153,178,201,205,232,246). Laboratory diagnosis of ACV resistance is required to guide clinicians toward different treatment options in cases of therapy failure.…”

Expression of Extremely Low Levels of Thymidine Kinase from an Acyclovir-Resistant Herpes Simplex Virus Mutant Supports Reactivation from Latently Infected Mouse Trigeminal Ganglia

“…Many drug-resistant HSV isolates generate low levels of active TK, and it has been proposed that these viruses generate insufficient TK to activate ACV but enough to support pathogenesis in an immunocompromised patient (14,19). The mutation that most commonly confers resistance is a single-guanine (G) insertion in a run of seven Gs ("G string") in tk (10,11,22,23). Viruses with this mutation generate low levels of full-length active TK via a net ϩ1 ribosomal frameshift that compensates for the added base (12,18,19,26).…”