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Hensler, Heather Rae (2009) HUMAN HERPESVIRUS-8 INTERACTIONS WITH DENDRITIC CELLS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Hensler, Heather
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJenkins, Frank
Committee MemberRinaldo, Charles Rrinaldo@pitt.eduRINALDO
Committee MemberKinchington, Paulkinch@pitt.eduKINCH
Committee MemberReinhart, Toddreinhar@pitt.eduREINHAR
Date: 29 January 2009
Date Type: Completion
Defense Date: 30 September 2008
Approval Date: 29 January 2009
Submission Date: 3 December 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cytokines; DC-SIGN; KSHV; dendritic cells; HHV-8
Other ID:, etd-12032008-163008
Date Deposited: 10 Nov 2011 20:07
Last Modified: 15 Nov 2016 13:52


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