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Project

Dynamics of cytomegalovirus infection: evolution towards antiviral drug resistance

Herpesviruses are large DNA viruses that establish lifelong latency following a primary infection. When the host immune system is weakened, they can reactivate causing significant morbidity and mortality in immunocompromised hosts. Despite their medical importance, only a few antivirals are approved for prophylaxis and treatment of diseases caused by human herpesvirus (HHVs). Emergence of drug-resistance is a major concern among immunocompromised individuals. Herpesviruses encode for a DNA polymerase with proofreading capacity and are considered to be genetically stable, however they can rapidly evolve in response to strong selective pressure (e.g. antiviral drug treatment). Mutations in the 3’-5’ exonuclease domain of the viral DNA polymerase may decrease enzyme fidelity leading to an increased mutation rate, known as a mutator phenotype. In this project, we will use the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) technology and next-generation sequencing (NGS) to study potential mutator phenotypes in human cytomegalovirus and herpes simplex virus type 1 and 2. The DNA polymerase mutations to be studied were previously identified in clinical samples or after in vitro selection with antiviral pressure. The impact of these mutations on the biological properties, genetic diversity and pathogenicity of human herpesviruses will be determined. 

Date:1 Feb 2021 →  Today
Keywords:(anti)mutator phenotypes, human herpesviruses, genetic diversity, CRISPR/Cas9 genome editing, herpesvirus compartmentalization, pathogenicity
Disciplines:Virology
Project type:PhD project