Antiviral drug resistance in herpesviruses other than cytomegalovirus

Abstract

The discovery of acyclovir (ACV), a nucleoside analogue, more than 30 years ago, represents a milestone in the management of HSV and VZV infections. The modest activity of ACV against CMV prompted the development of another nucleoside analogue, ganciclovir, for the management of systemic and organ-specific CMV diseases. Second-line agents such as the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir have been approved subsequently. In contrast to ACV and ganciclovir, the latter drugs do not require selective phosphorylation by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug-resistant mutants has been constantly reported particularly in severely immunocompromised patients such as bone marrow and solid organ transplant recipients as well as HIV-infected individuals. In this manuscript, we discuss the characteristics of the antiviral agents currently approved for the management of HSV, VZV and CMV diseases. In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed. The emergence of antiviral drug resistance is also observed with other members of the Herpesviridae family, namely HSV-1, HSV-2, VZV and HHV-6, which are the focus of this review. More specifically, we describe the laboratory methods for assessing drug susceptibilities, the frequency and clinical significance of drug-resistant infections and their management.

Antiviral Activity of Myticin C Peptide from Mussel: an Ancient Defense against Herpesviruses

“…In particular, herpes simplex virus 1 (HSV-1) and 2 (HSV-2) are major human pathogens responsible for long-term latent infections, with periods of recurring viral replication (19). Due to the lack of effective vaccines, the moderate to high toxicity of the available antiherpes compounds, and the appearance of resistant viral strains, new inhibitors for these viruses have been extensively researched (20,21). The aims of this work were to confirm that mussels (Mytilus galloprovincialis) are more resistant than oysters to the ostreid herpesvirus 1 microvariant (OsHV-1 Var), one of the most important bivalve pathogens, and to determine the putative role of myticin C, a constitutively expressed molecule in mussels, in resistance against herpesviruses.…”

Antiviral Drug Resistance in Herpesviruses

“…In VZV clinical isolates, resistance to ACV is mostly associated with mutations in the viral TK and, less frequently, with mutations in the viral DNA polymerase (Gilbert et al 2002;Piret and Boivin 2014). The genome of VZV has a lower GC content (46 %) than those of HSVs (68 %) and only a few homopolymer stretches are present in the ORF36 gene (Andrei et al 2012).…”

Moderne Diagnostik sexuell übertragbarer Infektionen

“…Darüber hinaus kann durch die Sequenzanalyse amplifizierter Regionen der Thymidin-Kinase (TK) und DNA-Polymerase die Suszeptibilität gegen Acyclovir und andere antivirale Substanzen analysiert werden. Traditionell werden resistente Viren phänotypisch in zellkulturbasierten Assays nachgewiesen, die aber zeit-und arbeitsintensiv sind und resistente Viren in heterogenen Viruspopulationen aufgrund der vergleichsweise geringeren Fitness schlechter erfassen [21]. Die Aussagekraft der genetischen Analyse ist allerdings ebenfalls begrenzt, da bislang nicht alle relevanten Mutationen charakterisiert sind.…”

“…Die Aussagekraft der genetischen Analyse ist allerdings ebenfalls begrenzt, da bislang nicht alle relevanten Mutationen charakterisiert sind. Während Deletionen und Insertionen, die zu Verschiebungen des Leserahmens im TK-Gen führen, eindeutig mit der Resistenzbildung verbunden sind, existieren zahlreiche Polymorphismen, für die nicht bekannt ist, ob sie natürlicherweise vorkommen oder ebenfalls resistenzassoziiert sind [21]. Um moderne Sequenziertechniken für die HSV-Resistenzanalyse zu nutzen, sind die Charakterisierung individueller Mutationen durch phänotypische Analyse sowie die Zugänglichkeit dieser Informationen über Web-basierte Datenbanken erforderlich.…”