رسالة جامعية
Population and single genome kinetics driving the evolution of multiple linked multiclass drug resistance mutations in the viral protease and reverse transcriptase of HIV-1 subtype C in children receiving early protease inhibitor based combination therapy
| العنوان: | Population and single genome kinetics driving the evolution of multiple linked multiclass drug resistance mutations in the viral protease and reverse transcriptase of HIV-1 subtype C in children receiving early protease inhibitor based combination therapy |
|---|---|
| المؤلفون: | Lange, CM |
| المساهمون: | Pillay, D, Gupta, RK, Hué, S |
| المصدر: | Doctoral thesis, UCL (University College London). |
| بيانات النشر: | UCL (University College London) |
| سنة النشر: | 2015 |
| المجموعة: | University College London: UCL Discovery |
| مصطلحات موضوعية: | HIV, children, early ART, drug resistance, single genome sequencing, genetic linkage |
| الوصف: | This thesis examines the evolution of HIV-1 subtype C multiple linked multi-class antiretroviral resistance mutations in the viral protease (PR) and reverse transcriptase (RT) genes of vertically infected children. Emergence of PI resistance on the backdrop of pre-existing non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance could compromise long-term treatment options in such children. We characterised multi-class drug resistance using single genome sequencing (SGS) in children with viraemia while receiving PI-based ART. We applied SGS of HIV-1 protease (PR) and reverse transcriptase (RT) to longitudinal samples from a cohort of the Children with HIV Early Antiretroviral Therapy (CHER) trial with viral loads >1000c/ml after 40 weeks of early ART. Bulk sequencing revealed NVP-selected resistance in 50% of these children while SGS revealed NVP-selected resistance in 70%. Two children had baseline NRTI and PI mutations, suggesting previous maternal ART. Linked multi-class drug resistance following PI-based ART was detected by SGS in 2/10 children. In one child, the majority species contained M184V in RT linked to L10F, M46I/L, I54V and V82A in PR and a triple-class drug resistant variant with these mutations linked to the NNRTI mutation V108I. In the second child, the majority species contained M184V and V82A linked within viral genomes. I correlated nucleotide variation of PR-RT with the number of single genomes obtained at each time point and ART status and used maximum likelihood trees, recombination analysis, positive selection analysis and co-evolution analysis to describe the evolution of PR-RT of the viral populations. Six children who received early ART for 40/96 weeks only or received continuous ART for the duration of the CHER trial had clusters of identical sequences from baseline and week 40 of ART. These sequences did not harbour known drug resistance mutations. Therefore one could hypothesize viral replication from a persisting viral reservoir that was established from infection that ... |
| نوع الوثيقة: | doctoral or postdoctoral thesis |
| وصف الملف: | text |
| اللغة: | English |
| العلاقة: | https://discovery.ucl.ac.uk/id/eprint/1469608/1/PhD_Thesis_Clange.pdfTest; https://discovery.ucl.ac.uk/id/eprint/1469608Test/ |
| الإتاحة: | https://discovery.ucl.ac.uk/id/eprint/1469608/1/PhD_Thesis_Clange.pdfTest https://discovery.ucl.ac.uk/id/eprint/1469608Test/ |
| حقوق: | open |
| رقم الانضمام: | edsbas.6FABD9D2 |
| قاعدة البيانات: | BASE |
| الوصف غير متاح. |