eprintid: 9996 rev_number: 5 userid: 6 dir: disk0/00/00/99/96 datestamp: 2011-11-10 20:07:50 lastmod: 2016-11-15 13:52:58 status_changed: 2011-11-10 20:07:50 type: thesis_degree metadata_visibility: show contact_email: h-hensler@northwestern.edu item_issues_count: 0 eprint_status: archive creators_name: Hensler, Heather Rae creators_email: h-hensler@northwestern.edu title: HUMAN HERPESVIRUS-8 INTERACTIONS WITH DENDRITIC CELLS ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: cytokines; DC-SIGN; KSHV; dendritic cells; HHV-8 abstract: 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. date: 2009-01-29 date_type: completed institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Jenkins, Frank J etdcommittee_name: Rinaldo, Charles R etdcommittee_name: Kinchington, Paul etdcommittee_name: Reinhart, Todd etdcommittee_email: jenkinsfj@pitt.edu etdcommittee_email: rinaldo@pitt.edu etdcommittee_email: kinch@pitt.edu etdcommittee_email: reinhar@pitt.edu etdcommittee_id: etdcommittee_id: RINALDO etdcommittee_id: KINCH etdcommittee_id: REINHAR etd_defense_date: 2008-09-30 etd_approval_date: 2009-01-29 etd_submission_date: 2008-12-03 etd_access_restriction: 5_year etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2011.9996 thesis_type: dissertation degree: PhD committee: Frank J. Jenkins (jenkinsfj@pitt.edu) - Committee Chair committee: Charles R. Rinaldo (rinaldo@pitt.edu) - Committee Member committee: Paul Kinchington (kinch@pitt.edu) - Committee Member committee: Todd Reinhart (reinhar@pitt.edu) - Committee Member etdurn: etd-12032008-163008 other_id: http://etd.library.pitt.edu/ETD/available/etd-12032008-163008/ other_id: etd-12032008-163008 citation: Hensler, Heather Rae (2009) HUMAN HERPESVIRUS-8 INTERACTIONS WITH DENDRITIC CELLS. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/9996/1/henslerhr2008etd.pdf