Simultaneous host and pathogen ’omics to interrogate the HIV reservoir

Project Overview

Background

HIV genomes integrated into host DNA that persist during treated HIV infection are the source of rebound viraemia when therapy is stopped. However, the vast majority of these integrated proviruses are thought to be replication incompetent, and unable to contribute to new viral production. Current techniques to analyses these viral genomes are labour-intensive and generally involve single cell limiting dilution methods. As both ‘next generation sequencing’ (NGS) methodologies and novel single cell technologies become widespread the potential to combine the two to characterise proviral latency and integration site analysis is enormous.

At the same time the host transcriptome and epigenetic landscape likely impacts viral rebound on stopping ART, and these data need to be considered in conjunction with the viral genomics.

Aims and Objectives

The aim of this project will be to apply Next Generation Sequencing (NGS) approaches simultaneously to both host and the HIV provirus. The candidate will apply and improve methods to produce full-length viral haplotype and integration site data (already developed in the lab) from cohorts of individuals with treated early HIV infection, many of whom will receive experimental interventions and stop antiretroviral therapy.

Simultaneously, unbiased transcriptomic profiling (RNASeq) and analysis of DNA accessibility (ATAC-Seq) will be incorporated to allow a global interrogation of viral and host genomics, with potential to extend this to single cell analyses. Following method development, clinical samples from UK cohorts will be analysed to characterise the reservoir and to inform the source of rebound viraemia on treatment interruption. The work will therefore have both a cross-sectional and longitudinal component, promising significant analytical power. Working collaboratively with other group members and projects to link cell phenotype and subset with viral phylogenetics to identify the source of viraemia will be an important part of the work.

The candidate would be expected to have interests in both the laboratory wet-lab and bioinformatic components of the project, to achieve a unified problem-solving approach.

 

Training Opportunities

The candidate will be primarily supervised by Professor John Frater (Nuffield Dept of Medicine). The candidate will be expected to become proficient at molecular and analytic skills relevant to NGS and DNA amplification (PCR, qPCR). An interest or background in bioinformatics approaches to NGS analysis would be advantageous. Full training will be provided in the laboratory and analytic skills required to undertake the DPhil. Over the course of the DPhil the candidate will be expected to contribute at lab meetings, journal clubs and other academic forums as well as to the overall duties of the research group. Suitable candidates should have a good honours degree (1st Class or 2.1 minimum) in Biology, Immunology or Microbiology. A relevant Masters degree will be considered as an advantage. Candidates should have excellent written and oral communication skills. It would also be advantageous if they had previous experience of experimental research.

Further enquiries to: Suki Kenth; Email: suki.kenth@ndm.ox.ac.uk

Theme

Immunology & Infectious Disease and Tropical Medicine & Global Health

Admissions

Project reference number: 931

Funding and admissions information

Supervisors

Name Department Institution Country Email
Professor John Frater Experimental Medicine Division Oxford University, Peter Medawar Building GBR john.frater@ndm.ox.ac.uk
Professor Paul Klenerman Experimental Medicine Division Oxford University, Peter Medawar Building GBR paul.klenerman@medawar.ox.ac.uk

There are no publications listed for this DPhil project.