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Title: HIV-1 in the United Kingdom : population dynamics and genetic evolution
Author: Foster, Geraldine
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2014
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Background: Phylogenetic characterisation of local HIV-1 epidemics can be used to understand emerging transmission networks. We analysed subtype-unassigned sequences in the UK HIV Drug Resistance Database (UK HIV DRD) to map the emergence and origin of genetically diverse recombinant strains using phylogenetic analyses, near full-length sequencing of plasma HIV-1 and CD4 cell count decline. Methods: 55,556 genotyped pol sequences (protease amino acids 1-99, RT amino acids 1-234) were analysed for evidence of recombination. Near full-length single genome sequencing of plasma HIV-1 was performed on stored specimens from six patients with a putative A1/D novel recombinant strain. Recombination and phylogenetic analyses were performed using RIP, PhyML, jpHMM, Simplot, SCUEAL and FastTree v2.3.1. Evolutionary analysis of putative novel recombinants was performed using Bayesian Evolutionary Analysis by Sampling Trees (BEAST). Geographic screening for additional instances of recombinant structures was performed using HIV BLAST and the Los Alamos National HIV database. Demographic data were available for 50/72 patients. CD4 cell count decline was assessed using linear regression. Results: The proportion of subtype-unassigned HIV-1 strains in the UK HIV DRD increased significantly during 1999-2008 (p=<0.01). 2,030 putative B-recombinant sequences were analysed for evidence of transmission of novel recombinant strains; 15 novel recombinant clusters comprising 94 individuals were identified. The proportion of intravenous drug users (IVDU), males and people of white ethnicity was significantly higher among novel recombinant clusters than among people infected with pure subtypes and recognised CRFs. Geographic screening showed co-circulation of novel strains in seven countries over three continents and import and export of novel strains from the UK was identified. Near full-length sequencing of six plasma specimens showed five patients sharing an identical A1/D strain; this was registered as CRF50_A1D and 67 further instances in the UK HIV DRD were identified. Geographic analysis showed close relation of component subtype A1 and D regions to East African strains; monophyletic clustering indicated a single introduction of this variant into the UK. Time scaled analysis showed a time to most recent common ancestor of approximately 1992. Demographic data showed the earliest CRF50 transmissions were confined to men who have sex with men (MSM), with subsequent transmissions to heterosexuals and IVDUs. Analysis of the sixth, complex, sequence demonstrated onward recombination of CRF50 with a subtype B strain (median divergence year 2000). CD4 cell count analysis suggested infections with CRF50 progressed in a similar manner to subtype B infections. Conclusions: Significant increasing genetic diversity of HIV-1 in the UK is linked to both UK and international transmissions among multiple exposure routes. These findings highlight the changing dynamics of HIV transmission in the UK and the converging of the two previously distinct MSM and heterosexual epidemics.
Supervisor: Geretti, Anna; Hall, Neil Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine