Pathogenicity of Acyclovir-Resistant Herpes Simplex Virus Type 1 from an Immunodeficient Child

Sibrack, Cornelia D.; Gutman, Laura T.; Wilfert, Catherine M.; McLaren, Colin; Clair, M H St; Keller, Paul M.; Barry, David W.

doi:10.1093/infdis/146.5.673

Cited by 161 publications

(72 citation statements)

References 38 publications

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“…Acyclovir-resistance is a problem of growing clinical importance as the numbers of immunocompromised patients increase due to AIDS, transplants, and cancer chemotherapy (56). Acyclovir-resistant tk-deficient viruses have been isolated from patients, some of whom had poor responses to acyclovir (26)(27)(28)(29)(30)(31)(32)(33)(34)(35) …”

Section: Discussionmentioning

confidence: 99%

“…This resistance stems from the requirement for viral tk to activate acyclovir efficiently (12,13,(22)(23)(24)(25). Such tk-deficient, acyclovir-resistant mutants can arise during treatment of human herpesvirus infections with acyclovir, especially in immunocompromised patients, and increasingly have been associated with poor response to acyclovir therapy (26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Iftk is not required for the establishment of latent infection, acyclovir-resistant mutants may be able to persist in an infected patient.…”

Section: Infection Of Mammalian Hosts By Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

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Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Coen

Kosz-Vnenchak

Jacobson

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

338

306

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Herpes simplex virus infection of mammalian hosts involves lytic replication at a primary site, such as the cornea, translocation by axonal transport to sensory ganglia and replication, and latent infection at a secondary site, ganglionic neurons. The virus-encoded thymidine kinase, which is a target for antiviral drugs such as acyclovir, is not essential for lytic replication yet evidently is required at the secondary site for replication and some phase of latent infection. To determine the specific stage in viral pathogenesis at which this enzyme is required, we constructed virus deletion mutants that were acyclovir resistant and exhibited no detectable thymidine kinase activity. After corneal inoculation of mice, the mutants replicated to high titers in the eye but were severely impaired for acute replication in trigeminal ganglia and failed to reactivate from ganglia upon cocultivation with permissive cells. Nevertheless, latency-associated transcripts were expressed in neuronal nuclei of ganglia from mutantinfected mice and superinfection of the ganglia with a second virus rescued the latent mutant virus. Thus, contrary to a widely accepted hypothesis, the thymidine kinase-negative mutants established latent infections, implying that neither thymidine kinase activity nor ganglionic replication is necessary for establishment of latency. Rather, thymidine kinase appears to be necessary for reactivation from latency. These results suggest that acyclovir-resistant viruses could establish latent infections in clinical settings and have implications for the use of genetically engineered herpesviruses to deliver foreign genes to neurons.

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Section: Discussionmentioning

confidence: 99%

Section: Infection Of Mammalian Hosts By Herpes Simplex Virus (Hsv)mentioning

confidence: 99%

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Coen

Kosz-Vnenchak

Jacobson

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

338

306

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“…Such patients frequently experience more severe and prolonged HSV disease than immunocompetent individuals and the extended treatment required to manage the disease may, in some cases, lead to the appearance of ACV-resistant variants (Sibrack et al, 1982a;Wade et al, 1982;Erlich et al, 1989;Nugier et al, 1992;Christophers et al, 1998;E. Kern, International Task Force on Herpesvirus Resistance, personal communication).…”

Section: Introductionmentioning

confidence: 99%

Characterization of a neurovirulent aciclovir-resistant variant of herpes simplex virus

Grey

Sowa

Collins

et al. 2003

Journal of General Virology

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“…ACV-resistant HSV strains have been observed in vivo since the first large therapeutic trials (5,10,36). These resistant strains are detected in vitro by phenotypic tests which determine the antiviral concentration inhibiting viral replication by 50%.…”

mentioning

confidence: 99%

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

et al. 2004

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Herpes simplex virus (HSV) infections are very common in the general population and among immunocompromised patients. Acyclovir (ACV) is an effective treatment which is widely used. We deemed it essential to conduct a wide and coordinated survey of the emergence of ACV-resistant HSV strains . We have formed a network of 15 virology laboratories which have isolated and identified, between May 1999 and April 2002, HSV type 1 (HSV-1) and HSV-2 strains among hospitalized subjects. The sensitivity of each isolate to ACV was evaluated by a colorimetric test (C. Danve, F. Morfin, D. Thouvenot, and M. Aymard, J. Virol. Methods 105:207-217, 2002). During this study, 3,900 isolated strains among 3,357 patients were collected; 55% of the patients were immunocompetent. Only six immunocompetent patients excreted ACV-resistant HSV strains (0.32%), including one female patient not treated with ACV who was infected primary by an ACV-resistant strain. Among the 54 immunocompromised patients from whom ACV-resistant HSV strains were isolated (3.5%), the bone marrow transplantation patients showed the highest prevalence of resistance (10.9%), whereas among patients infected by human immunodeficiency virus, the prevalence was 4.2%. In 38% of the cases, the patients who excreted the ACV-resistant strains were treated with foscarnet (PFA), and 61% of them developed resistance to PFA. The collection of a large number of isolates enabled an evaluation of the prevalence of resistance of HSV strains to antiviral drugs to be made. This prevalence has remained stable over the last 10 years, as much among immunocompetent patients as among immunocompromised patients.Herpes simplex virus (HSV) infections are very common; they are localized on the face and torso in the case of HSV type 1 (HSV-1) and in the genital region in the case of HSV-2. HSV-1 infections in the genital region are on the increase (40). Ocular herpes is less frequent, and neonatal herpes and herpetic meningoencephalitis are very rare but have a severe functional and vital prognosis (37).Since acyclovir (ACV) {9-[(2-hydroxyethoxy)methyl)guanine]} was introduced to the market in 1983, it has been used primarily in the prevention and treatment of HSV infections. ACV-resistant HSV strains have been observed in vivo since the first large therapeutic trials (5, 10, 36). These resistant strains are detected in vitro by phenotypic tests which determine the antiviral concentration inhibiting viral replication by 50%. Several methods have been used to evaluate the sensitivity of the HSV strains to ACV, including techniques to detect the intensity of the cytopathic effect, such as the plaque reduction (17, 31) and colorimetric (11,22,26) techniques, but also the detection of DNA replication by hybridization (39) or antigen production by flow cytometry (30).Previous surveys among immunocompetent patients have shown a prevalence of resistance to ACV varying between 0 and 0.6%, whereas among immunocompromised patients, the prevalence varied between 3 and 6% (9,16,29). The use of ACV is co...

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Pathogenicity of Acyclovir-Resistant Herpes Simplex Virus Type 1 from an Immunodeficient Child

Cited by 161 publications

References 38 publications

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Thymidine kinase-negative herpes simplex virus mutants establish latency in mouse trigeminal ganglia but do not reactivate.

Characterization of a neurovirulent aciclovir-resistant variant of herpes simplex virus

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

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