UBC Theses and Dissertations
The use of genetic sequencing technologies to determine HIV-1 viral tropism and to evaluate the effects of maraviroc on patient viral populations McGovern, Rachel Ann
HIV-1 infection is reliant on the ability of the virus to enter target cells characterized by the expression of either the CCR5 or CXCR4 co-receptor at the cell surface. It is now well established that the V3 loop of the HIV-1 envelope is the primary determinant of co-receptor use, and that genetic analysis of the V3 loop can be used to infer co-receptor use, or “tropism”. This became clinically relevant with the development of the entry inhibitor, maraviroc (MVC), an anti-HIV compound designed to inhibit HIV-1 cell entry exclusively at the CCR5 co-receptor. As such, the more pathogenic CXCR4-using variants are likely to thrive during MVC therapy. Anti-HIV treatment guidelines now strongly suggest a tropism test be performed when considering the clinical use of MVC. There are two primary objectives discussed in this thesis, 1) the validation of a population-based sequencing tropism assay designed to predict virological response to MVC; 2) to apply a next generation sequencing tropism assay to investigate the selective pressures exerted by MVC on mixed tropic HIV-1 populations. The validation studies presented in this thesis demonstrate the reliability of a population-based sequencing assay to infer virological response to MVC in two large, multinational cohorts. The results of these studies have promoted the worldwide expansion of this genotypic assay as a practical and affordable option for tropism inference. In addition, a more intensive investigation into the selective pressures exerted by MVC on mixed tropic HIV-1 populations demonstrated the reproducible outgrowth of preexisting variants most genetically characteristic of CXCR4-using virus. The results of these studies suggest MVC may be effective against a broader range of variants than previously thought. In general, the four studies described in this thesis demonstrate the clinical utility of genetic sequencing when considering the use of MVC.
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