"The end of innocence" revisited: resistance of herpesviruses to antiviral drugs.

Field, A K; Biron, K K

doi:10.1128/cmr.7.1.1-13.1994

Cited by 5 publications

(5 citation statements)

References 69 publications

(85 reference statements)

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“…The design of acyclovir, a nucleoside analogue that is selectively phosphorylated by the thymidine kinase of HSV and subsequently inhibits the viral DNA polymerase, is a prime example of how viral enzymes can be selectively targeted to prevent viral DNA replication (Elion, 1982;Smee et al, 1983;Field & Biron, 1994). Additionally, the effectiveness of nucleoside analogues such as cidofovir at reducing pathologies associated with MuHV-4 infection suggests that the TK of KSHV may represent a potential target to limit lytic replication of the virus and subsequent disease (Staskus et al, 1997;Neyts & De Clercq, 1998;Dal Canto et al, 2000;Gangappa et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

KSHV ‐ TK is a tyrosine kinase that disrupts focal adhesions and induces Rho‐mediated cell contraction

et al. 2014

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Paradoxically, the thymidine kinase (TK) encoded by Kaposi sarcoma-associated herpesvirus (KSHV) is an extremely inefficient nucleoside kinase, when compared to TKs from related herpesviruses. We now show that KSHV-TK, in contrast to HSV1-TK, associates with the actin cytoskeleton and induces extensive cell contraction followed by membrane blebbing. These dramatic changes in cell morphology depend on the auto-phosphorylation of tyrosines 65, 85 and 120 in the N-terminus of KSHV-TK. Phosphorylation of tyrosines 65/85 and 120 results in an interaction with Crk family proteins and the p85 regulatory subunit of PI3-Kinase, respectively. The interaction of Crk with KSHV-TK leads to tyrosine phoshorylation of this cellular adaptor. Auto-phosphorylation of KSHV-TK also induces a loss of FAK and paxillin from focal adhesions, resulting in activation of RhoA-ROCK signalling to myosin II and cell contraction. In the absence of FAK or paxillin, KSHV-TK has no effect on focal adhesion integrity or cell morphology. Our observations demonstrate that by acting as a tyrosine kinase, KSHV-TK modulates signalling and cell morphology.

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Section: Introductionmentioning

confidence: 99%

KSHV ‐ TK is a tyrosine kinase that disrupts focal adhesions and induces Rho‐mediated cell contraction

et al. 2014

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“…The use of ganciclovir can lead to granulocytopenia, anaemia, leucopenia and thrombocytopenia (Von Bueltzingsloewen et al, 1993;Appelbaum et al, 1988;Scadden et al, 1994); therapy with foscarnet may produce renal dysfunction (Chrisp & Clissold, 1991). Moreover, virus strains resistant to each of these drugs have been identified (Knox et al, 1991;Drew, 1991;Field & Biron, 1994).…”

mentioning

confidence: 99%

Comparison of benzimidazole nucleosides and ganciclovir on the in vitro proliferation and colony formation of human bone marrow progenitor cells

Nassiri¹,

Emerson²,

Devivar

et al. 1996

Br J Haematol

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Recently we have shown that certain benzimidazole ribonucleosides are potent and selective inhibitors of human cytomegalovirus (HCMV) replication. Because antiviral drugs used to treat HCMV and human immunodeficiency virus (HIV) infections can suppress marrow progenitors, we have evaluated the most promising of the new benzimidazoles for their effects on human bone marrow cells in vitro. In an initial study of the bone marrow toxicity of one of the most active compounds, 100 microM 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (BDCRB) inhibited cell proliferation by 20% over a 10 d period compared to 52% inhibition by 100 microM ganciclovir, the drug currently most used to treat HCMV infections. The effects of these drugs and selected other benzimidazole nucleosides were evaluated more extensively in haemopoietic progenitor cell colony formation assays. Colony formation was determined at 2 weeks and scored as either burst forming units-erythroid (BFU-E), or colony forming units-granulocyte/macrophage (CFU-GM). At the highest concentration tested, 100 microM BDCRB only moderately affected BFU-E or CFU-GM formation (31% and 47% inhibition, respectively). This concentration is 10-fold higher than that required to produce a 10000-fold reduction in virus titre. Evaluation of the 2-chloro analog of BDCRB (TCRB) which is less potent against HCMV, its 5'-deoxy analog (5'-dTCRB) which is more potent, and the 2-unsubstituted compound (DRB) gave the following order of haemopoietic toxicity: DRB > TCRB > or = 5'-dTCRB > BDCRB. In contrast to the benzimidazoles, ganciclovir decreased colony formation by 84% for BFU-E and 86% for CFU-GM at 100 microM. These results establish that certain benzimidazole nucleosides are less toxic to haemopoietic progenitors than the preferred drug now being used clinically for HCMV infections. The results also establish that different structure-activity relationships exist for antiviral activity and progenitor cell toxicity, thereby suggesting that different mechanisms are involved in the two types of drug action.

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“…Mechanisms of VZV resistance to antiviral agents are primarily related to reduced or altered viral TK or altered TK substrates specificity, and infrequently to altered viral DNA polymerase (6,17). VZV resistance is usually associated with mutations in VZV TK with inability to phosphorylate ACV or, less frequently, to mutations in viral DNA polymerase (18,19). While ACV-resistant VZV is rare in immunocompetent individuals, it has been described primarily in those with acquired human immunodeficiency syndrome, where prolonged exposure to sub-A B Fig.…”

Section: Discussionmentioning

confidence: 99%

Brincidofovir treatment of acyclovir‐resistant disseminated varicella zoster virus infection in an immunocompromised host

Mullane

Nuss

Ridgeway

et al. 2016

Transplant Infectious Dis

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Brincidofovir (BCV) is a broad-spectrum antiviral agent active in vitro against double-stranded DNA viruses including herpesviruses, adenoviruses, polyomaviruses, and poxviruses. We report successful BCV use in management of disseminated acyclovir- and cidofovir-resistant varicella zoster virus in an immunocompromised hematopoietic stem cell transplant patient with chronic graft-versus-host disease who was intolerant to foscarnet.

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"The end of innocence" revisited: resistance of herpesviruses to antiviral drugs.

Cited by 5 publications

References 69 publications

KSHV ‐ TK is a tyrosine kinase that disrupts focal adhesions and induces Rho‐mediated cell contraction

KSHV ‐ TK is a tyrosine kinase that disrupts focal adhesions and induces Rho‐mediated cell contraction

Comparison of benzimidazole nucleosides and ganciclovir on the in vitro proliferation and colony formation of human bone marrow progenitor cells

Brincidofovir treatment of acyclovir‐resistant disseminated varicella zoster virus infection in an immunocompromised host

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