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MBPhD Programme

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JOYCE, Aengus

Entered:

2004

Current Position:

Clinical Year 3 (post PhD)

PhD title:

"Minority Species Assays and Drug Resistance in the HIV-1 Virus"

Principal Supervisor:

Dr D Pillay & Prof. The Hon R Tedder

Funding Source:

Astor Foundation

Description of Project:

Reverse transcriptase, the enzyme responsible for replicating the retroviral genome, is very error-prone. Consequently, the viral population in the host is genetically diverse, with a primary dominant species and multiple less frequent sub-populations (quasi-species). Natural selection operates on the quasi-species in the form of host immune responses and antiviral chemotherapy, driving adaptation of the virus to the host and the emergence of drug resistant mutants that ultimately escape chemotherapeutic suppression. Standard drug resistance testing generally cannot resolve subspecies present below 20% of the total population. More sensitive methods (e.g. single genome sequencing, heteroduplex generator assay) can detect lower percentages, but these are often, expensive, time consuming, or unable to cope with viral genetic variability (e.g. ARMS, etc.). We are using a modified form of two-step proofreading allele-specific PCR that can be highly sensitive, quantitative, and specific, and can cope with genetic variability around the SNP site. Applications include: (1) Improved antiviral therapy due to early detection of emerging resistance (2) More sensitive estimation of the true incidence of transmitted drug resistant HIV (3) Probing the evolution of drug resistance, viral tropism, and patterns of genetic variation (4) Assessing the danger posed by single dose therapy (e.g. to prevent vertical transmission) and structured treatment interruptions, specifically focusing on the K65R tenofovir resistance associated mutation in patients enrolled in the DART study.

http://www.ctu.mrc.ac.uk/dart/summary.asp