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Dissertation
Modulation of human immunodeficiency virus type 1 (HIV-1) replication by mu-opioid and cyclic adenosine monophosphate (cAMP) pathways in human bone marrow progenitor cells
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2009
DOI:
https://doi.org/10.17918/00000467
Abstract
Although studies have shown that human progenitors cells (HPCs) express the human immunodeficiency virus type 1 (HIV-1) receptor CD4 and the co-receptor CXCR4 at mRNA and protein levels, attempts for detecting in vitro and in vivo infection of these cells have been inconsistent. In light of several recent reports suggesting that the bone marrow (BM) might serve as a potential long-lived reservoir for HIV-1, we sought to define conditions which might increase infection of undifferentiated HPCs. We utilized the CD34+/CD38+ human BM progenitor cell line TF-1 for our studies which has been shown to express CD4, CXCR4 and CCR5, consequently supporting productive infection by the 'CXCR4-utilizing' HIV-1 IIIB and the 'CCR5-utilizing' BaL strains. Since prolonged [mu]-opioid exposure has been reported to enhance HIV-1 replication in peripheral blood mononuclear cells, efforts to recapitulate it in TF-1 cells yielded a replication-inhibitory effect, emphasizing cell-type specific differences. Utilizing the specific adenyl cyclase activator forskolin to enhance cyclic-AMP (cAMP) response in these cells revealed the importance of the Protein Kinase A (PKA) pathway and the downstream transcription factor cyclic-AMP response element binding protein-1 (CREB-1) in enhancing CXCR4 and CCR5 transcription, HIV-1 long terminal repeat (LTR) activity and IIIB replication. Furthermore, identification of cAMP response elements (CREs) in both the CXCR4 5' untranslated region (UTR) and the HIV-1 LTR pointed towards a common molecular mechanism behind these physiological effects. Given that patients in late stage HIV-1 disease have elevated levels of Prostaglandin E2, a natural cAMP inducing ligand, our studies highlight a critical and likely contribution of cAMP signaling in enhancing HIV-1 infection of HPCs in vivo.
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Details
- Title
- Modulation of human immunodeficiency virus type 1 (HIV-1) replication by mu-opioid and cyclic adenosine monophosphate (cAMP) pathways in human bone marrow progenitor cells
- Creators
- Anupam Banerjee
- Contributors
- Brian Wigdahl (Advisor)Michael R. Nonnemacher (Advisor) - Drexel University, Microbiology and Immunology
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 254 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970305104721