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Identifying novel drug-resistance hot spots in human herpesviruses
Belgium (BeMSA) - KU Leuven, Leuven
Laboratory of Virology and Chemotherapy - Rega Institute
Type of Research Project
- Basic science
What is the background of the project?
Human herpesviruses are prevalent pathogens that usually cause insignificant disease in healthy persons. However, primary infection or reactivation of one of the eight human herpesviruses can result in severe disease in immunocompromised patients. Those patients often require prolonged antiviral therapy increasing the risk for selection of drug-resistant viruses. Almost all currently approved antivirals have a common mechanism of action; interfering with deoxyribonucleic acid (DNA) replication. Specific mutations in the viral genes thymidine kinase (TK), protein kinase (PK) and DNA polymerase (DP) can cause (multi)-drug resistance to those antivirals, which make the infections difficult to treat.
What is the aim of the project?
In this project, we will monitor the selection of drug-resistance in vitro under pressure of antivirals and compare the evolution of drug-resistance between single drug and multi-drug treatment. This will show if combination therapy will result in slower selection of drug-resistance.
What techniques and methods are used?
Wild-type virus will be cultured in vitro in the presence of increasing concentrations of antiviral agents (single drug or combination of drugs). Viral clones will be isolated following different passages of the virus in presence of the drug(s) by serial dilution in human fibroblasts cultures grown in 96-well microtiter plates. DNA will be extracted from individual viral clones and used in a polymerase chain reaction (PCR) to amplify the genes of interest. PCR amplicons will be purified and sequenced by Sanger sequencing. If mutations are found in any of the three viral genes, we will test the sensitivity of the selected clones to several antiviral agents, including acyclovir, ganciclovir, cidofovir, adefovir and foscarnet.
What is the role of the student?
- The tasks of the student will be performed on his/her own
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
The student is expected to isolate viral clones from viral strains, select clones and amplify the genes of interest using PCR. Those genes of interest will be sequenced and the student is expected to analyse and interpret those sequences. Different clones carrying different mutations in the genes of interest will be selected and used in an antiviral assay. The student will perform and readout the antiviral assay.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Preliminary readings will be provided. The student can attend labmeetings and seminars that take place in the Institute.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- No specific outcome is expected
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic laboratory skills: sterile working, pipetting etc.
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Students in biomedical fields
- Field HJ; Vere Hodge RA. 2013. Recent developments in anti-herpesvirus drugs. Br Med Bull 106:213-49
- Andrei G. et al. 2013. Heterogeneity and Evolution of Thymidine Kinase and DNA Polymerase Mutants of Herpes Simplex Virus Type 1: Implications for Antiviral Therapy. J Infect Dis 207:1295-1305
- Andrei G. et al. 2007. DNA polymerase mutations in drug-resistant herpes simplex virus mutants determine in vivo neurovirulence and drug–enzyme interactions. Antivir Ther 12:719-32
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