Evolution of the human immunodeficiency virus type 1 envelope glycoprotein during chronic infection Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Ince, William L.
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • A hallmark of Human Immunodeficiency Virus Type 1 (HIV-1) chronic infection is the rapid and continual evolution and diversification of the viral Envelope glycoprotein (Env), which results in multiple co-existing env genetic variants. Env mediates virus entry into host cells by engaging the primary receptor CD4 and either of two coreceptors, CCR5 or CXCR4. CXCR4-tropic variants typically emerge in late stage disease, coincident very low CD4+ T cell counts and severe immunosuppression, and rarely establish infection. Over the course of infection, Env diversifies as a result of immune escape selection and selection for differential usage of CD4 and co-receptors, presumably in order to expand into new target cell types, although the selective forces driving Env evolution in late stage disease remain poorly understood. In the work present here, I examined how variation affects compartmentalization of genetic and phenotypic subpopulations and the likely forces driving some of this variation in late stages of infection. First, I used a heteroduplex tracking assay (HTA) to measure the lifespan of cells producing different genetic variants in the population by measuring the decay rates of variants when subjects were placed on suppressive therapy. I found that all variants, regardless of their co-receptor tropism phenotype, decayed at the same rate indicating they are replicating in the same cell types or cell types with similar infected life spans. I further examined the relationship between CCR5 and emergent CXCR4 variants and found that they frequently recombine, further indicated an overlap in target cell type. I also examined the evolution of Env in a humanized mouse model. I found that, consistent with a lack of a strong humoral immune response, Env evolved a more open conformation and enhanced CD4 affinity. I also found that in this phenotypic background, CXCR4 -tropic variants emerged, and showed evidence of tissue compartmentalization. Finally I attempted to link the phenotypes conferred by a more open Env conformation, that evolved in the immunosuppressed environment in the mouse, to evolution of CXCR4 and provided evidence that the environmental constrains of imposed by humoral immunity select against the open Env conformation that potentiates evolution of CXCR4 tropism.
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  • In Copyright
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics and Molecular Biology."
Advisor
  • Swanstrom, Ronald
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  • Chapel Hill, NC
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  • Open access
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