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The impact of inflammatory cytokines, il-6 and il-1beta, on the pathogenesis of immune failure in HIV disease

Shive, Carey Lynn

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Pathology.
HIV disease is characterized by the disruption of immune homeostasis and persistent immune activation. The use of anti-retroviral therapy dramatically reduces mortality caused by HIV, however, treated HIV-infected patients are still at increased risk for co-morbidities related to cardiovascular disease, liver disease, malignancies, and renal disease. Patients with persistently low levels of CD4 T cells despite having therapy-controlled viral replication (immune failure patients) are at increased risk for these morbidities and have increased inflammation. Plasma levels of the inflammatory cytokine IL-6 and soluble CD14 are elevated in immune failure patients and are strongly linked to morbid outcomes and mortality. While it is clear that soluble indices of inflammation are linked to HIV disease progression, it remains unclear what is driving elevated levels of inflammation, particularly when viral replication is controlled with therapy. How this inflammation contributes to pathology in HIV disease and in immune failure patients remains unknown. We demonstrated that plasma IL-6 is likely not driven by HIV itself, and instead propose that IL-6 is produced in response to systemic translocation of microbial products from a damaged gut. We identified evidence of increased inflammation and increased cell cycling in immune failure patients. When PBMCs from uninfected donors were treated with the inflammatory cytokines IL-6 and IL-1ß, we could recapitulate the memory CD4 T cell cycling and turnover found in immune failure patients, and mimic the reduced responsiveness to IL-7, and the down-regulation of IL-7Ra. Furthermore, we demonstrated that IL-1ß could induce cycling and proliferation of memory CD4 T cells without up-regulating the survival factor Bcl2. This CD4 T cell cycling was not a direct effect of IL-1ß on T cells, was dependent on CD14+ cells, and was induced by a, yet unknown, soluble factor in the absence of exogenous antigen. We propose that by blocking the effects of IL-6 and IL-1ß in vivo we can decrease CD4 T cell turnover and increase responsiveness to IL-7. We hope this therapy will lead to the reconstitution of CD4 T cells in immune failure patients and reduce chronic inflammation in patients infected with HIV.
Michael Lederman, MD (Advisor)
John Nedrud, PhD (Committee Chair)
Eric Pearlman, PhD (Committee Member)
Scott Sieg, PhD (Committee Member)
Alan Levine, PhD (Committee Member)
Clive Hamlin, PhD (Committee Member)
150 p.

Recommended Citations

Citations

  • Shive, C. L. (2014). The impact of inflammatory cytokines, il-6 and il-1beta, on the pathogenesis of immune failure in HIV disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396627515

    APA Style (7th edition)

  • Shive, Carey. The impact of inflammatory cytokines, il-6 and il-1beta, on the pathogenesis of immune failure in HIV disease. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396627515.

    MLA Style (8th edition)

  • Shive, Carey. "The impact of inflammatory cytokines, il-6 and il-1beta, on the pathogenesis of immune failure in HIV disease." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396627515

    Chicago Manual of Style (17th edition)