A low thymidine kinase-producing mutant of herpes simplex virus type 1 causes latent trigeminal ganglia infections in mice

Gordon, Y. Jerold; Gilden, Donald H.; Shtram, Y.; Asher, Yael; Tabor, Eynat; Wellish, Mary; Devlin, Mary; Snipper, D.; Hadar, Julia; Becker, Yechiel

doi:10.1007/bf01315702

Cited by 39 publications

(20 citation statements)

References 17 publications

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“…The correlation between plaque morphology, infected cell glycoprotein pattern, and thermosensitivity held true for all the L and the S variants (10 L and nine S variants) that we examined, although they had been derived from different isolates and from different patients. Furthermore, regarding the two pairs of variants that we tested in mice, the L variants were found to be more pathogenic than the S variants, which agrees with other reports [Becker, 1981a;Gordon et al, 1983;Rapp, 19631. The phenotypic expression of the variants that behaved like the HSV-1 prototype strain F with respect to the infected cell glycoprotein pattern was the L plaque (Fig.…”

Section: Discussionsupporting

confidence: 92%

Study of herpes simplex virus type 1 populations obtained from recurrences and primary infections

Mannini-Palenzona

Bartoletti

Foà-Tomasi

et al. 1985

Journal of Medical Virology

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The analysis of 23 clinical isolates of herpes simplex virus type 1 (HSV-1) showed that 15 of 15 isolates that had undergone a few passages in tissue culture (fresh isolates) and two of eight isolates that had never been passaged (new isolates) were composed of a mixed population with respect to plaque morphology in Vero cells. Cloning and characterization of 10 large plaque viruses (L variants) and nine small plaque viruses (S variants), obtained from seven different isolates, showed the following. BamHI DNA restriction patterns of the L and the S variants from a single isolate differed only with respect to the electrophoretic mobility of the fragments that contain reiteration of specific sequences; they did not differ regarding the presence or the absence of restriction endonuclease cleavage sites. The L and S variants differed with respect to the electrophoretic profiles of infected cell glycoproteins, thermosensitivity of growth and plaquing efficiency at 39 degrees C, and, at least in the case of the two couples of variants that we tested, pathogenicity for the mouse. The hypothesis that the L variants might arise from the S variant during in vivo replication is discussed.

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Section: Discussionsupporting

confidence: 92%

Study of herpes simplex virus type 1 populations obtained from recurrences and primary infections

Mannini-Palenzona

Bartoletti

Foà-Tomasi

et al. 1985

Journal of Medical Virology

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“…Several ofthese viruses, like mutant 615.9, were reported to express truncated TK polypeptides and/or contain frameshift mutations so that they would be expected to be completely TK-(7, 13, 39). As described here for 615.9, acyclovir-resistant mutants that express rather low levels of TK can reactivate from latency and exhibit other pathogenic phenotypes (17)(18)(19)(20). For several of these, it has often proven difficult to detect TK activity by standard enzyme assays (18,20); this has also been true for mutant 615.9 (E.P.…”

Section: Resultsmentioning

confidence: 96%

“…One possible resolution of this paradox is that the clinical isolates expressed low levels of TK that were not detected. There are HSV mutants that are severely impaired for TK activity and thus acyclovir-resistant, yet express low levels ofTK that are sufficient for certain pathogenic phenotypes, including the ability to reactivate (17)(18)(19)(20).We report here a clinical acyclovir-resistant isolate that encodes a gene predicted to express an inactive truncated TK polypeptide due to a single-base insertion mutation. Despite this, the virus retains a low level ofTK activity and the ability to reactivate from latency and expresses both the predicted truncated polypeptide and low levels of full-length TK polypeptide.…”

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confidence: 99%

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A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant.

Hwang

Horsburgh

Pelosi

et al. 1994

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

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Clinical resistance to antiviral drugs requies that a virus evade drug therapy yet retain pathogenicity. Thymidine kinase (TK)-negative mutants ofherpes simplex virus are resistant to the drug, acyclovir, but are attenuated for pathogenicity in animal models. However, numerous cases of clinical resistance to acyclovir have been associated with viruses that were reported to express no TK activity. We studied an acyclovir-resistant clinical mutant that contains a single-base insertion in its tk gene, predicting the synthesis of a truncated TK polypeptide with no TK activity. Nevertheless, the mutant retained some TK activity and the ability to reactivate from latent infections of mouse trigeminal ganglia. The mutant expressed both the predicted truncated polypeptide and a low level of a polypeptide that comigrated with full-length TK on polyacrylamide gels and reacted with anti-TK antiserum, providing evidence for a frameshifting mechanism. In vitro transcription and tanslation ofmutant tkgenes, incuding constructs in which reporter epitopes could be expressed only if frameshiffing occurred, also gave rise to truncated and full-length polypeptides. Reverse transcriptase-polymerase chain reaction analysis coupled with open reading fram cloning failed to detect alterations in tktrspts that could account for the synthesis offull-length polypeptide. Thus, synthesis of full-length TK was due to an unusual net +1 frmeshlft during translation, a phenomenon hitherto confined in eukaryotic cells to certain RNA viruses and retrotransposons. Utilization of cellular frameshifting mechanisms may permit an otherwise TK-negative virus to exhibit clinical acyclovir resistance.Herpes simplex virus (HSV) is an important human pathogen, especially in patients with AIDS. A major advance in antiviral therapy has been the use of acyclovir to treat HSV infections, but acyclovir resistance is a problem of increasing clinical significance in immunocompromised patients (1). Clinical resistance implies that HSV can mutate to evade drug therapy yet retain pathogenicity. Because the sensitivity of HSV to acyclovir is due largely to the viral thymidine kinase (TK), which activates the drug (2), HSV tk mutations can confer acyclovir resistance (3). Indeed, there have been numerous cases ofpatients who suffered severe HSV disease despite acyclovir therapy and shed acyclovir-resistant viruses that were reported to express no detectable TK activity and/or full-length TK polypeptides (4-13).Although TK is not essential for viral replication in cell culture, it is important for viral pathogenesis in animal models. In particular, TK-mutants fail to reactivate from latent infections of mouse sensory ganglia (14-16), due to the tk mutation (16). Thus, the association of virus that appears TK-with severe HSV disease has been puzzling. One possible resolution of this paradox is that the clinical isolates expressed low levels of TK that were not detected. There are HSV mutants that are severely impaired for TK activity and thus acyclovir-resistant...

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“…The HSV-1 thymidine kinase (TK) gene has been shown to be needed for efficient virus replication and spread in nervous tissue [Gordon et al, 1983[Gordon et al, , 1983aMeignier et al, 1988;Tenser et al, 19791, and in vivo complementation of TK deficient (TK-) HSV strains by TK competent (TK+) viruses is frequently required to allow the TK-virus full expression of its neuroinvasive potential [Vann and Atherton, 19911. Herpes simplex virus-1 TK competence is not necessary to establish latency [Tenser et al, 19791, but not all mammalian species are equally permissive for latency by TK-HSV strains [Meignier et al, 19881.…”

Section: Introductionmentioning

confidence: 99%

A thymidine kinase deficient HSV‐2 strain causes acute keratitis and establishes trigeminal ganglionic latency, but poorly reactivates in vivo

Stroop¹,

Banks

Qavi

et al. 1994

Journal of Medical Virology

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The incidence of herpetic keratitis following intranasal or direct ocular infection with thymidine kinase-negative (TK-) strains of herpes simplex virus (HSV)-2 has not been well studied, and the role of the TK gene in the establishment of latency and virus reactivation is controversial. To determine whether a TK- strain of HSV-2 could establish trigeminal ganglionic latency and be reactivated in vivo to produce recurrent keratitis or nervous system infection, an animal model of acute and recurrent infection was utilized. Rabbits were infected by the intranasal or ocular routes, and latency was reactivated by immunosuppression. Virus shedding in nasal and ocular secretions was monitored, and the eyes were examined for the presence of corneal epithelial lesions during acute and reactivated infections. Central nervous system (CNS) and trigeminal ganglionic tissues were assayed by histologic, virologic, and in situ hybridization techniques. All rabbits intranasally infected shed virus in both ocular and nasal secretions, whereas only 30% of rabbits infected in the eyes shed virus in nasal secretions. Virus was recovered from cocultivation cultures, but not from cell-free homogenates, of trigeminal ganglionic and CNS tissues from animals inoculated by both routes. The incidence of keratitis was much greater after direct ocular inoculation, although both routes of inoculation produced CNS and ganglionic inflammatory lesions. Keratitis healed in 92% of the animals infected by the ocular route by 26 days post infection. Of rabbits initially infected in the eyes and then subjected to drug-induced reactivation, only 30% shed virus, which was limited to a 24 hour period; there was no reappearance of epithelial keratitis, no animal became blind, and none died. In contrast, latently infected control rabbits uniformly reactivated. These studies show that this TK-HSV-2 strain (i) replicates in the eye, (ii) is neuroinvasive but non-neurovirulent following intranasal and direct ocular infection; (iii) sheds in the eye more frequently and for longer periods after ocular than after intranasal inoculation; (iv) induces epithelial keratitis that usually heals spontaneously; (v) establishes latency in trigeminal ganglionic neurons, but no other ganglionic cells; and, (vi) reactivates in a small proportion of animals, but does not produce recurrent ocular lesions following drug-induced immunosuppression. Thus, the TK gene appears directly involved in HSV latency and reactivation in vivo.

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A low thymidine kinase-producing mutant of herpes simplex virus type 1 causes latent trigeminal ganglia infections in mice

Cited by 39 publications

References 17 publications

Study of herpes simplex virus type 1 populations obtained from recurrences and primary infections

Study of herpes simplex virus type 1 populations obtained from recurrences and primary infections

A net +1 frameshift permits synthesis of thymidine kinase from a drug-resistant herpes simplex virus mutant.

A thymidine kinase deficient HSV‐2 strain causes acute keratitis and establishes trigeminal ganglionic latency, but poorly reactivates in vivo

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