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"MECHANISMS OF TRAIL EXPRESSION BY HUMAN PLASMACYTOID DENDRITIC CELLS DURING HIV INFECTION"

by
Virian D. Serei
MD/PhD Program
B.S. 2009, Rutgers University, New Brunswick, NJ


Thesis Advisor: Patricia Fitzgerald-Bocarsly, Ph.D.
Professor
Department of Pathology and Laboratory Medicine

Wednesday, May 20, 2015
10:00 A.M., MSB C-600


Abstract

Despite the success of anti-retroviral therapy (ART) in suppressing viral loads and stabilizing CD4 counts, treated HIV-infected patients still experience chronic immune activation. Central to the pathogenesis of HIV-infection is the plasmacytoid dendritic cell (pDC). These antigen presenting cells are critical to innate anti-viral immune defense through their massive production of IFN-. However, during HIV-infection, circulating pDC decrease in number and are impaired in their ability to produce IFN-. pDC numbers and function do not recover despite successful ART, and are thought to be chronically stimulated in vivo to produce IFN- which contributes to the activated immune state found in HIV-infected individuals on ART. A consequence of chronic IFN- production is the expression of TNF-related apoptosis inducing ligand (TRAIL). This molecule is proposed to be involved in the bystander loss of uninfected CD4+ T cells, contributing to the loss of CD4+ T cells that is seen in HIV-patients. Soluble TRAIL has previously been shown to be elevated in the serum of viremic HIV-infected subjects as well as on the surface of pDC from viremic HIV-infected subjects. Studies have not agreed on the contribution of TRAIL-expressing pDC to bystander CD4+ T cell death in HIV-infected patients. Furthermore, many studies on TRAIL expression on pDC are on untreated HIV-infected subjects, as opposed to subjects on ART. In this study, we studied the mechanisms and functions of TRAIL expression on pDC during HIV-infection. We found that HIV-infected subjects on ART had elevated basal levels of TRAIL-expressing pDC. Despite impairment of IFN- production, HIV-stimulated pDC from HIV-infected subjects on ART upregulated higher levels of TRAIL than healthy controls. Proinflammatory cytokines TNF- and IL-6, as well as type I and III IFN, enhanced TRAIL-expression by HIV-stimulated pDC. p-STAT1 expression corresponded to TRAIL expression by pDC from HIV-infected subjects. TRAIL expression by pDC was not dependent on activation of the p65 subunit of NF-B, but corresponded to p50 translocation. Furthermore, HIV-infected subjects were severely impaired in their ability to phosphorylate p65 in response to viruses and exogenous TNF-. Despite this impairment, p50 nuclear translocation was intact and corresponded to TRAIL expression in pDC from HIV-infected subjects. TRAIL was also co-expressed with CD40 and CD86 on pDC after TLR7 or 9 stimulation. Functional studies showed that HIV-stimulated pDC were able to kill H9 and H9/IIIB cells in a TRAIL-dependent manner, but were inhibitory towards allogeneic CD4+ T cell stimulation in a TRAIL independent manner. Despite successful ART, our study showed that a proinflammatory milieu can influence pDC from HIV-infected subjects to express TRAIL, giving them cytotoxic potential. We also showed that HIV-patients had a severe impairment in the ability to activate p65, which could have additional consequences that are detrimental to pDC function and an already dysfunctional immune system.


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