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IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION

Judge, Chelsey J
http://orcid.org/0000-0001-6757-0495
http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Pathology.
HCV-infection affects approximately 170 million worldwide, with 60-85 percent of acute-infections resulting in chronic-infection, and a significant proportion are co-infected with HIV. HCV-infection causes increased morbidity and mortality in HCV-HIV co-infection. HIV-infection alters HCV-disease pathogenesis, accelerating progression to cirrhosis and liver failure. While HCV-therapy has greatly improved, the cost remains a barrier and is not expected to completely remove HCV from the population. We need a better understanding of the immune-response to HCV to develop successful vaccine strategies. HCV-containment and -clearance is dependent on efforts of the innate and adaptive immune-response. CD4 memory T-cells are critical in viral-clearance, by producing IFN¿ and mediating CD8 T-cell responses. NK cells have been shown to exert an important role in control of HCV-infection by lysis of infected-cells and cytokine release. Monocytes may partly shape this HCV-directed response, via direct-contact with CD4 T-cells and NK cells and in production of soluble factors. IL-7 has been demonstrated to enhance NK cell IFN¿ production, and the IL-7 receptor a chain (CD127) is expressed on NK cells. We measured CD127 expression on NK cell subsets of uninfected donors, chronic HCV-infected treatment-naive, HIV-infected on ART and HCV-HIV co-infected subjects on ART. We demonstrate that CD56bright NK cell CD127 expression negatively correlated with HCV plasma levels in HCV mono-infection and HCV-HIV co-infection. We observed IL-7-induced NK cell activation, cell-cycling, IFN¿ release and cytolytic function, with impairments in HCV- and HIV-infections. These findings offer a role for IL-7-dependent NK cell function in control of chronic viral infections. Within chronic HCV- and HIV-infection, there have been observations of elevated levels of IL-6 and sCD14, produced in part by monocytes, which contribute to immune-activation. We extended these studies to evaluate the role of immune-activation, monocyte-subset frequency, and CD4-memory T-cells in host control of HCV and IFNa-treatment-induced HCV-clearance during HCV-HIV co-infection. We found that CD4 effector memory T-cells positively associated with therapy-induced HCV-decline and anti-viral function, while sCD14 and CD14bright16- monocytes negatively associated with CD4 effector memory T-cell frequency, HCV-decline and anti-viral function. The data support a role for CD4-memory T-cells in HCV-containment, and connect immune-activation and CD14bright16- monocyte frequency to impaired HCV-clearance.
Donald Anthony, MD, PhD (Advisor)
Dave Canaday, MD (Committee Chair)
Scott Sieg, PhD (Committee Member)
Daniel Popkin, MD, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
140 p.
Immunology
natural killer cells, HCV, HIV, immune system, cellular immunology, immune activation, monocytes, innate immunity, IL-7, immune evasion, CD4 memory T-cells, CD56bright NK cells

Recommended Citations

Citations

  • Judge, C. J. (2017). IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387

    APA Style (7th edition)

  • Judge, Chelsey. IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387.

    MLA Style (8th edition)

  • Judge, Chelsey. "IL-7-MEDIATED CD56BRIGHT NK CELL FUNCTION IS IMPAIRED IN HCV IN PRESENCE AND ABSENCE OF CONTROLLED HIV INFECTION, WHILE CD14BRIGHTCD16- MONOCYTES NEGATIVELY CORRELATE WITH CD4 MEMORY T CELLS AND HCV DECLINE DURING HCV-HIV CO-INFECTION." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1481187921533387

    Chicago Manual of Style (17th edition)

case1481187921533387
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.