HIV diversity generally increases over the course of infection. Diverse HIV populations arise as a product of interactions between the frequently mutating virus and various immunologic and other selective pressures. The relationship between HIV diversity and disease progression is not well understood. HIV diversity may also serve as a marker for the duration of infection that could be used as a biomarker for incidence testing. Studies of these two important issues have been hampered by the high cost of methods for analysis of HIV diversity. A scalable diversity assay that is not based on sequencing would facilitate the large studies of HIV diversity that are necessary to understand the relationship between HIV diversity and clinical outcome. Similar studies are also necessary to ascertain the practicality of using HIV diversity as a biomarker for analysis of HIV incidence. A high resolution melting (HRM) diversity assay that allows rapid quantification of HIV diversity has been developed. This dissertation describes the development, evaluation, and validation efforts that were required to make the assay suitable for large-scale studies. The assay was then used to study the relationship between HIV diversity and clinical outcome and was examined for potential use as a tool for estimation of HIV incidence. The HRM diversity assay facilitated the first multi-region study of the relationship between HIV diversity and clinical outcome. That study demonstrated a complex relationship between HIV diversity and clinical outcome that differed depending on the genome region analyzed. Higher diversity in one HIV genome region predicted more rapid disease progression, while higher diversity in a second HIV genome region did not predict more rapid disease progression. These studies also demonstrated the suitability of the HRM diversity assay as a component of a multi-assay algorithm (MAA) for HIV incidence estimation. Inclusion of the HRM diversity assay in a MAA along with serologic assays allowed robust estimation of HIV incidence without the need for CD4 + T cell counts. In the course of this dissertation research, a powerful tool for analysis of HIV diversity was developed and applied to answer key research questions about HIV diversity.
|Advisor:||Eshleman, Susan H.|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 74/12(E), Dissertation Abstracts International|
|Subjects:||Evolution and Development, Biomedical engineering, Virology, Epidemiology|
|Keywords:||HIV-1, High resolution melting diversity assay, Pathogenesis|
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