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This dissertation, Mechanism of Human Immunodeficiency Virus Induced Immune Dysregulation: TAT & IL-18 Interaction by Sze-ki, Leung, 梁詩琪, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Mechanism of Human Immunodeficiency Virus Induced Immune Dysregulation: TAT & IL-18 Interaction submitted by Leung Sze Ki for the degree of Master of Philosophy at The University of Hong Kong in August 2005 Acquired immunodeficiency syndrome (AIDS) has become a major worldwide pandemic since its first recognition in 1981. AIDS is caused by the human immunodeficiency virus type 1 (HIV-1). The HIV-1 genome encodes a transactivating protein, Tat, which functions to transactivate HIV-1 long terminal repeat (LTR), enhance virus replication, and dysregulate immune response including cytokine expression for virus survival. Interleukin (IL)-18 is a prototype pro-inflammatory cytokine, which was originally described as an interferon-γ inducing factor. It has been shown that IL-18 can stimulate HIV-1 production in a human chronically infected T cell line and a promonocytic cell line. However, it is not known whether Tat interacts with IL-18 in stimulating HIV-1 production. Tat can act as a regulator of cellular kinases including PKR, a double-stranded RNA-activated protein kinase. PKR has been recognized for regulating the effects of interferon and it may also play a critical role in mediating the subversive effects of HIV Tat in the host immune system. In light of the roles of Tat and IL-18 in regulating HIV-1 replication, we hypothesize that PKR may serve as a regulatory protein to mediate the effects of Tat to induce IL-18 expression, resulting in the enhancement of HIV-1 survival. Recombinant Tat protein was used to examine the effects of Tat on IL-18 expression on primary human blood monocytes (PBM). PBM were incubated with Tat for indicated time points and the levels of IL-18 were monitored by RT-PCR and Q-PCR. A PKR inhibitor, 2-aminopurine (2-AP), was used to study the role of PKR in Tat-regulated IL-18 expression. After mapping out the mechanism of Tat-induced IL-18 expression, luciferase reporter assay was used to study the functional aspects of IL-18 on Tat-induced HIV-1 LTR transcription. Our results showed that Tat protein induced IL-18 mRNA in PBM, while suppression of PKR with 2-AP abrogated the Tat-induced effects. These findings indicated that Tat-induced IL-18 expression is regulated by PKR. In addition to this, IL-18 had been shown to synergistically enhance Tat-induced HIV-1 LTR transcription in promonocytic U937 cells. In summary, the signaling mechanisms presented here provide additional insights into the role of Tat protein and IL-18 in HIV-1 pathogenesis. The results shed light on the biological significance of IL-18 in HIV infection and raise the fascinating possibility that IL-18 may act as a pro-inflammatory agent, induced by HIV-1, to act against the host. DOI: 10.5353/th_b3460547 Subjects: InterleukinsHIV (Viruses)ImmunogeneticsProtein kinases

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