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Chronic inflammation in HIV infection: effects on mechanisms of T cell lymph node egress, homeostasis, and turnover

Mudd, Joseph C
http://rave.ohiolink.edu/etdc/view?acc_num=case1396615555

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Pathology.
Lymphoid tissues are major sites of inflammation in HIV infection and this is manifested clinically by a generalized lymphadenopathy. We hypothesized that lymphocytes could be sequestered in HIV-1+ lymph nodes (LN) through impairments in the Sphingosine-1-phosphate (S1P)/Sphingosine-1-phosphate-receptor-1(S1P1) axis. To test this hypothesis, we developed novel assays for S1P-induced Akt phosphorylation and actin polymerization. In HIV-1+ LNs, CD4 and CD8 T cells had impaired responses to S1P in all maturation subsets. We find that LN T cells expressing the S1P1-antagonizing factor CD69 are undable to respond to S1P in either assay. Chronic inflammation in HIV-1+ LNs may contribute to impairment in T cell egress through decreased S1P responsiveness and to immune dysregulation in a key organ of immune homeostasis. Some treated HIV+ individuals display residual inflammation despite undetectable viremia. This has been associated with suboptimal CD4 T cell reconstitution. We explored underlying mechanisms that may link residual inflammation to suboptimal CD4 T cell reconstitution. We find that the pro-inflammatory cytokines IL-6 and IL-1ß induce memory T cell turnover in vitro. IL-6 and IL-1ß also impaired T cell responsiveness to IL-7, a major determinant of T cell homeostasis. In lymphoid tissues, we find elevated expression of IL-1ß in HIV-infected patients that does not normalize with ART. Induction of CD4 T cell turnover and diminished T cell responsiveness to IL-7 by IL-1ß and IL-6 exposure may contribute to the lack of CD4 T cell reconstitution in treated HIV infected subjects. Chronic inflammation that persists in treated HIV-infection has been linked to non-AIDS serious events such as cardiovascular disease. CD8 T cells can express the fractalkine receptor, CX3CR1, that allows rolling and tethering along vascular endothelium. We find that treated HIV-infected patients display increased frequencies of CX3CR1+ CD8 T cells when compared to proportions of CX3CR1 CD8 T cells of healthy controls. The thrombin-binding receptor, PAR-1, is highly expressed on CX3CR1+ CD8 T cells and is increased on CD8 T cells of treated HIV+ patients. Taken together, these findings highlight a central role of inflammation in driving immune dysfunction as well as contributing to the risk of adverse clinical events such as cardiovascular disease.
Michael Lederman, MD (Advisor)
131 p.
Immunology

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Citations

  • Mudd, J. C. (2014). Chronic inflammation in HIV infection: effects on mechanisms of T cell lymph node egress, homeostasis, and turnover [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396615555

    APA Style (7th edition)

  • Mudd, Joseph. Chronic inflammation in HIV infection: effects on mechanisms of T cell lymph node egress, homeostasis, and turnover. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396615555.

    MLA Style (8th edition)

  • Mudd, Joseph. "Chronic inflammation in HIV infection: effects on mechanisms of T cell lymph node egress, homeostasis, and turnover." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396615555

    Chicago Manual of Style (17th edition)

case1396615555
377
© 2014, some rights reserved.Creative Commons License Chronic inflammation in HIV infection: effects on mechanisms of T cell lymph node egress, homeostasis, and turnover by Joseph C Mudd is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.