Human herpesvirus-8 (HHV-8, also known as Kaposi's sarcoma associated herpesvirus, KSHV) is a gamma-2 herpesvirus and is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma and a subset of Multicentric Castleman's disease. We have previously shown that HHV-8 uses DC-SIGN (CD209) for entry into susceptible cell types, including immature dendritic cells. In the present study, we demonstrate that DC-SIGN expression renders previously non-permissive cells permissive to HHV-8 infection. Also, we have demonstrated that HHV-8 infection of dendritic cells and endothelial cells results in the expression of some viral lytic proteins initially but subsequently switches to only latent protein expression. However, infection appears to be non-productive as the infected cells maintain viral DNA copies at a low level but this level does not increase over time, nor is encapsidated viral DNA found in the supernatant. Secondly, we demonstrate that the glycoprotein B homologue of HHV-8 binds to DC-SIGN in a dose-responsive manner and that DC-SIGN binds HHV-8 in a region of the carbohydrate recognition domain that is unique, though overlapping, with the HIV-1 gp120 and ICAM-2/3 binding sites. Lastly, we demonstrate that infection of immature DC results in the expression of IL-6, TNF-a, MIP-1a, MIP-1b, and IL-12p40, but not bioactive IL-12p70. This cytokine release occurs quickly after infection and is maintained for up to 72 hours post-infection, suggesting that virus binding is sufficient for at least some of the cytokine release and that the virus may be active in skewing infected cells to illicit a TH2 response. The significance of these findings from a public health standpoint centers on the fact that while HHV-8-related cancers have decreased in incidence in the United States, they still represent a serious global health concern in other countries. Our findings give insight into the initial interactions of HHV-8 and its target cells and as a result, can be used for the design of targeted therapies to prevent viral infection and spread.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12032008-163008 |
| Date | 29 January 2009 |
| Creators | Hensler, Heather Rae |
| Contributors | Dr. Paul Kinchington, Dr. Todd Reinhart, Dr. Charles R. Rinaldo, Dr. Frank J. Jenkins |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12032008-163008/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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