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Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection

Fields, Maria
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850

Abstract Details

2014, PhD, University of Cincinnati, Medicine: Immunology.
HIV infection remains an important public health problem worldwide, at the end of 2011 UNAIDS estimated that there were 34.0 million people living with HIV infection. In addition, 2.5 million people were newly infected with HIV, and there were 1.7 million AIDS-related deaths worldwide. HIV causes a gradual loss of immune competence, leading to acquired immunodeficiency syndrome (AIDS). HIV-associated defects in cell-mediated immunity (CMI) are of particular importance, as these impairments lead to a poor control of HIV replication and of other pathogens whose clearance depends on CMI. Notably, a number of immune deficits caused by HIV infection can be partially restored in vitro. In addition, persistent immunological dysfunction is observed in HIV-infected patients under HAART, suggesting the existence of active regulatory mechanisms. Regulatory T cells (Treg) constitute a subset of CD4+ T cells that plays a major role in the homeostasis of the immune system. Compared to healthy individuals, Treg accumulate in the lymphoid tissues and peripheral blood of HIV-infected individuals, even in the absence of detectable viral replication. Treg may be detrimental to the host by substantially decreasing HIV-specific immune responses during HIV infection. However, Treg may also play a beneficial role, by controlling immune activation limiting cellular targets available for HIV infection, as well as decrease the pathology associated with immune activation in HIV. The role of Treg in the setting of acute HIV infection and the mechanisms underlying Treg relative accumulation during HIV infection are still unclear. First, we hypothesize that Treg could decrease acute HIV infection of relevant HIV target cells (CD4+T cells and DC), because of Treg natural ability to decrease T cell activation and DC maturation, which are crucial processes for a successful HIV infection and dissemination. Our results indicate that Treg decreases cell-free and cell-mediated HIV infection of T cells and DC:Tcon cell clusters. Furthermore, there is a clear involvement of CTLA-4 in the Treg-mediated suppression of HIV infection in the DC;Tcon infection model. Importantly, Treg suppresses HIV infection in both models in a cAMP-dependent manner, highlighting the importance of this mechanism in Treg mediated suppression in different systems. Second, set out to determine the molecular factors driving Treg persistence during treated chronic HIV-infection. HAART induces lipid alteration and Treg appear to primarily depend on lipid oxidation for energy generation. We thus hypothesize that lipid changes during HAART contribute to the Treg persistence during treated HIV infection. Increased Treg frequency in treated HIV-infected individuals was positively associated with plasma HDL levels. Treg were more efficient at HDL internalization than naive but not memory CD4+ T cells. Culture of Treg from healthy donors in the presence of HDL promoted their accumulation; whereas HDL did not affect naive and memory T cells. Importantly, the Akt signaling pathway may be involved in the HDL effect. Gaining better understanding of the mechanism regulating Treg dynamics remains an important are of study, as this knowledge will help to determine whether we can successfully manipulate Treg function or numbers to the advantage of the infected host.
Claire Chougnet, Ph.D. (Committee Chair)
Li Wu, Ph.D. (Committee Member)
Fred Finkelman, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
271 p.
Immunology
Treg; HIV; cAMP; CTLA-4; HDL; Actin

Recommended Citations

Citations

  • Fields, M. (2014). Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850

    APA Style (7th edition)

  • Fields, Maria. Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection. 2014. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850.

    MLA Style (8th edition)

  • Fields, Maria. "Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection." Doctoral dissertation, University of Cincinnati, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1408709850

    Chicago Manual of Style (17th edition)

ucin1408709850
884
© 2014, some rights reserved.Creative Commons License Homeostasis and function of Regulatory T Cells during Human Immunodeficiency Virus infection by Maria Fields 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 University of Cincinnati and OhioLINK.