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The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Immunology II Abstract 42 MODULATION BY KSHV OF LIGANDS THAT MEDIATE NK CELL RECOGNITION Alexis Madrid and Don Ganem HHMI and Dept of Microbiology, UCSF, San Francisco, CA 94143-0552 Abstract Natural Killer (NK) cells express an array of activating and inhibitory receptors on their surfaces. The inhibitory receptors generally recognize MHC class I (MHC-I) molecules on healthy cells, which are therefore not targeted for destruction. Activating receptors recognize a variety of cellular ligands, many of which are upregulated in pathologic conditions. The balance of activating and inhibitory signals within the NK cell determines whether a target cell will be destroyed and an immune response mounted. KSHV encodes proteins that downregulate MHC-I on infected cells, thus potentially exposing these cells to NK cell mediated lysis. Therefore we hypothesized that KSHV would also have evolved mechanisms to evade killing by NK cells, and one potential way to evade killing is through downregulation of NK activating ligands. To test this hypothesis, we infected several human cell lines with KSHV, and measured the cell surface levels of the various NK activating ligands. The surface display of most NK ligands tested was not affected during infection. However, we found that one NK activating ligand, NKp44-L, is consistently downregulated during both latent and lytic KSHV infection. We then screened a KSHV ORF library in order to search for the viral gene product responsible for this activity, and identified this protein as Kaposin B. However, Nkp44-L downregulation is not due to Kaposin B’s known function in activating the p38/MK2 signaling pathway, and likely reflects an additional activity of the molecule. Studies of the mechanism by which Kaposin B downregulates NKp44-L are ongoing and will be reported. Presenting author Email: Alexis.madrid@ucsf.edu 68
The 11 th International Workshop on KSHV & Related Agents, Birmingham, UK Immunology II Abstract 43 SCREENING FOR NATURALLY OCCURRING ANTI-KCP (KSHV COMPLEMENT CONTROL PROTEIN; ORF4) ANTIBODIES IN KSHV-INFECTED PATIENTS AND GENERATION OF SPECIFIC MONOCLONAL ANTIBODIES FOR PATHOGENESIS STUDIES Anna M. Blom 1a , Marcin Okroj, 1a Linda Mark, 1a Zoltan Korodi, 1b Rosamaria Tedeschi, 2 Joakim Dillner 1b and O. Brad Spiller 3 a Department of Laboratory Medicine, b Department of Medical Microbiology, 1 Lund University, University Hospital Malmö, S-205 02, Malmö, Sweden. 2 Department of Microbiology, Oncological Center, Aviano 33081, Italy. 3 Department of Child Health, Cardiff University, School of Medicine, Cardiff CF14 4XN, United Kingdom. Abstract ORF4 encodes a complement regulating protein expressed in the late virus replication phase, referred to as the KSHV Complement Control Protein (KCP). KCP is expressed on the virion surface and can be induced on the surface of KSHV-positive primary effusion lymphoma (PEL) B-lymphocytes. KCP mediates protection from complement attack and an integral heparin binding motif enables virion KCP to enhance virus infection through extracellular matrix binding. Using recombinant soluble KCP and transfected cells hyperexpressing various recombinant portions of KCP, serum from different KSHV-infected patient groups were investigated for anti-KCP reactivity. Specific anti-KCP IgG, but not IgM, was found predominantly in patients that had high titres of antibodies against other lytic KSHV proteins and the second (CCP2) of the 4 complement control domains in KCP was found to be the dominant epitope recognised. Patient anti-KCP antibodies enhanced complement attack on KCP-expressing CHO cells, suggesting neutralisation. Anti-KCP antibodies were found in all KSHV-infected lymphoma patients except one examined, but only 3/16 KS patients, suggesting differential KCP expression between these two diseases. Recombinant soluble and cell-expressed KCP were used to generate and characterise monoclonal anti-KCP antibodies against each CCP domain. These monoclonal antibodies differentially regulated decay-accelerating factor activity, cofactor activity and heparin binding. Primary conjugated anti-KCP monoclonal antibodies labelled with FITC, PE, APC or HRP have now been created and await appropriate KSHV patient groups for longitudinal flow cytometric and histological assessment through disease progression and treatment. Presenting author Email: spillerb@Cardiff.ac.uk 69
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