About the Project
This project will investigate genetic predictors of response to antiretroviral treatment for HIV infection, based on high density genotyping of 5200 individuals (HIV NIHR BioResource), linked to phenotypic data from the UK Collaborative HIV Cohort Study and UK HIV Drug Resistance Database, two of the world’s most productive HIV cohort studies.
Genome-wide association studies (GWAS) of HIV have mainly addressed correlates of acquisition and disease progression in the absence of treatment: little work has been done in the context of combination antiretroviral therapy (ART). Suppression of viral replication by ART may be insufficient to prevent premature cardiovascular events or hepato-renal pathology, and the risk of non-AIDS cancers may also be raised.
Project Description:
Although >90% of those starting antiretroviral therapy (ART) experience a good virological response, there remains heterogeneity in immunological responses. In most, CD4 counts increase to levels approaching those of uninfected individuals, but in many the CD4:CD8 ratio remains below 1 despite viral suppression. Lower CD4:CD8 ratios in people living with HIV are associated with higher rates of serious non-AIDS clinical events including cardiovascular disease (CVD) and some cancers.
The NIHR BioResource is a collaboration between seven NIHR Biomedical Research Centres to establish a federated database of healthy individuals and patients with neurological, cardiovascular, or infectious/inflammatory or immune disorders or with rare diseases, consented for recall for research on the basis of genotype and/or phenotype. High density genotyping, providing comprehensive coverage of all common Single Nucleotide Polymorphisms (SNPs), is performed on the Affymetrix UK Biobank array.
The recently-created HIV NIHR BioResource aims to collect host genome sequences of up to 10,000 participants. It is collecting and storing blood samples and derivatives, together with patient information (clinical history, lifestyle factors and potential predictors of CVD). By end 2017 it will include genotyped samples from ~5200 individuals, with ongoing recruitment. Lifestyle factors captured on linked questionnaire data include: smoking history, alcohol use, body mass index, hypertension, and use of concomitant medications which may modify CVD risk.
The HIV NIHR BioResource links with the UK Collaborative HIV Cohort Study (UK CHIC) and the UK HIV Drug Resistance Database (UK HDRD): two of the world’s largest and most productive HIV cohort studies: UK CHIC holds information on >45,000 patients.. These provide historical longitudinal data on CD4 and CD8 counts, HIV RNA values, start/stop dates of ART drugs, and extensive data on key laboratory markers of toxicities or comorbidities. The combined dataset is a unique resource: one of world’s largest genomic-clinical HIV datasets within a predominantly ART-treated population. It will enable investigation of genetic contributions to switches in antiretroviral therapy for toxicity reasons; renal disease progression and cART-associated nephrotoxicity; central nervous system diseases; and cART-associated hepatotoxicity.
This PhD project will focus on identification of genetic predictors of the linked outcomes CD4:CD8 ratio; Dyslipidaemia; Diabetes; and Major cardiovascular events.
Identification of genetic predictors of these outcomes could facilitate early identification of individuals who might benefit from individualised treatments, increased monitoring or intensified prevention measures. The potential mediating role of nadir CD4 count will be investigated, as will moderating effects of specific ART drugs. Analyses will consider potential biases introduced through the selection of patients into the HIV BioResource and propose appropriate methodology to reduce the impact of these.
Funding Notes
PLEASE NOTE: Applications will open at 9:00 am Monday 25th SEPTEMBER and close at 5.00 pm on Friday 24th NOVEMBER 2017 and are being administered by Cardiff University.
This is a 3.5 year GW4 studentship funded by the MRC and covers: a stipend (at the standard Research Councils UK rate; currently £14,553 per annum for 2017-2018), research and training costs, tuition fees and additional funds to support fieldwork, conferences.
Applications from Monday 25 SEPTEMBER should be made to http://www.gw4biomed.ac.uk/
Please DO NOT apply TO BRISTOL, all applications are being dealt with by Cardiff University via the GW4 website above.