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The use of genetic sequencing technologies to determine HIV-1 viral tropism and to evaluate the effects of maraviroc on patient viral populations

University of British Columbia

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.

Text

2015-10-24

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/54867

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/