Kaposi's sarcoma, the most prevalent malignancy in AIDS patients, is characterized by proliferating spindle cells of endothelial cell (EC) origin, infiltration by inflammatory cells and the presence of the KS herpesvirus (KSHV) in lesions. The ultimate goal of our work is to understand how viral immune evasion mechanisms contribute to viral pathogenesis and the d evelopment of KS. We focus on the function of two closely related open reading frames, K3 and K5. These proteins, aka MIR1 and MIR2, are viral homologs of the cellular membrane-associated RI NG-CH (MARCH) protein family comprising transmembrane ubiquitin Ii gases that recruit cellular ubiquitin-conjugating enzymes for degradation of transmembrane proteins. While K3 predominantly targets host proteins invovled in alerting the cellular immune system, our work revealed that K5 substrates include EC-specific adhesion molecules (ALCAM, CD3IIPECAM, VE-Cadherin, alpha and beta- Catenin) and the interferon-induced antiviral protein B ST2/Tetherin. We therefore hypothesize that K5 modulates innate immune defense as well as angioproliferative and inflammatory processes during KS development. Specifically, we will address two major questions: 1) What are the consequences of K5 expression for the function of KSHV-infected ECs and their interaction with innate immune cells? Using ECbased in vitro models of KS we will examine the modulation of EC/EC and EC/leukocyte adhesion by KSHV. 2) Why and how does KSHV eliminate BST2/Tetherin? Preliminary data show that K5 ubiquitinates and degrades BST2/Tetherin which tethers enveloped viral particles to host cell membranes. We will examine the hypothesis that K5 counteracts the inhibition of KSHV egress by BST2. Upon completion of these studies we will have a better understanding of viral modulation of host processes that are expected to be central to the establishment and maintenance of longterm infection in healthy individuals and KS development in the immunocompromised.

Public Health Relevance

It is unknown how Kaposi's sarcoma (KS) is caused by the KS herpesvirus. Our work revealed that the KSHV gene product K5 destroys several endothelial cell transmembrane proteins which likely contributes to some of the typical features of KS such as aberrant endothelial structures, chro nic inflammation and the inability of the host to eliminate the virus. In this proposal, we will study how K5 destroys host transmembrane proteins and the functional consequences of their destruction for viral escape of innate immune defense mechanisms and KS development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA094011-06A2
Application #
7756389
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2001-12-01
Project End
2011-06-30
Budget Start
2009-07-17
Budget End
2010-06-30
Support Year
6
Fiscal Year
2009
Total Cost
$328,310
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Viswanathan, Kasinath; Smith, M Shane; Malouli, Daniel et al. (2011) BST2/Tetherin enhances entry of human cytomegalovirus. PLoS Pathog 7:e1002332
Bartee, Eric; Eyster, Craig A; Viswanathan, Kasinath et al. (2010) Membrane-Associated RING-CH proteins associate with Bap31 and target CD81 and CD44 to lysosomes. PLoS One 5:e15132
Viswanathan, Kasinath; Früh, Klaus; DeFilippis, Victor (2010) Viral hijacking of the host ubiquitin system to evade interferon responses. Curr Opin Microbiol 13:517-23
Douglas, Janet L; Viswanathan, Kasinath; McCarroll, Matthew N et al. (2009) Vpu directs the degradation of the human immunodeficiency virus restriction factor BST-2/Tetherin via a {beta}TrCP-dependent mechanism. J Virol 83:7931-47
Mansouri, Mandana; Viswanathan, Kasinath; Douglas, Janet L et al. (2009) Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. J Virol 83:9672-81
Thibodeau, Jacques; Bourgeois-Daigneault, Marie-Claude; Huppe, Gabrielle et al. (2008) Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Eur J Immunol 38:1225-30
Pantanowitz, Liron; Fruh, Klaus; Marconi, Sharon et al. (2008) Pathology of rituximab-induced Kaposi sarcoma flare. BMC Clin Pathol 8:7
Viswanathan, Kasinath; Fruh, Klaus (2007) Viral proteomics: global evaluation of viruses and their interaction with the host. Expert Rev Proteomics 4:815-29
Rose, Patrick P; Bogyo, Matthew; Moses, Ashlee V et al. (2007) Insulin-like growth factor II receptor-mediated intracellular retention of cathepsin B is essential for transformation of endothelial cells by Kaposi's sarcoma-associated herpesvirus. J Virol 81:8050-62
Mansouri, Mandana; Douglas, Janet; Rose, Patrick P et al. (2006) Kaposi sarcoma herpesvirus K5 removes CD31/PECAM from endothelial cells. Blood 108:1932-40

Showing the most recent 10 out of 12 publications