Lymphoid tissue damage in HIV and SIV infections depletes naive T cells and limits immune reconstitution after anti-retroviral therapy.
2012-06
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Lymphoid tissue damage in HIV and SIV infections depletes naive T cells and limits immune reconstitution after anti-retroviral therapy.
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2012-06
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HIV infection causes the Acquired Immunodeficiency Syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. HIV primarily infects and depletes CD4+ T cells, a cell type that is central to the maintenance of host's immunocompetency. The slow depletion of CD4+ T cells has been attributed to direct mechanisms such as viral killing and indirect mechanisms such as increased apoptosis accompanying the chronic immune activation associated with HIV infections. Highly active anti-retroviral therapy (HAART) can potently suppress HIV viral replication and largely normalize associated immune activation thereby significantly increasing the CD4+ T cells. Yet more than a decade after the introduction of HAART, it is clear that relatively few individuals will achieve normal levels of peripheral blood CD4+ T cells, and up to 20% of the patients have little or no increase despite the impact of HAART on the viral replication. This limited immune reconstitution is most prevalent in patients starting HAART in the chronic stage of infection and strongly correlates with significantly higher morbidity and mortality compared to uninfected populations. This suggests that there is a persistent defect in the homeostasis of CD4+ T cell population that is not fully corrected by HAART. However, the underlying mechanisms of this limited immune reconstitution after HAART remain elusive. More recently, there is increasing evidence showing that there is progressive fibrotic damage during HIV infection to the structure of lymphoid tissue (LTs) and the extent of this damage strongly correlates with the extent of depletion of naïve CD4+ T cells before HAART and the extent of immune reconstitution after HAART. Since LT structure is critical for the homeostasis of naïve T cells, we hypothesized that the LT damage during HIV infection contributes to CD4+ T cell depletion and limits immune reconstitution after HAART. In this dissertation, I tested this hypothesis by providing experimental data to show the mechanisms of LT damage and how LT damage contributes to CD4+ T cell depletion and limited immune reconstitution. The understanding of these mechanisms points to novel avenues to improve immune reconstitution in HIV-infected patients.
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University of Minnesota Ph.D dissertation. June 2012. Major: Microbiology, Immunology and Cancer Biology. Advisor: Ashley T. Haase, M.D., 1 computer file (PDF); x, 193 pages, appendix p. 191-193.
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Zeng, Ming. (2012). Lymphoid tissue damage in HIV and SIV infections depletes naive T cells and limits immune reconstitution after anti-retroviral therapy.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/130578.
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