Rhesus rhadinovirus is a gamma-2 herpesvirus that is closely related to human herpesvirus 8 (HHV- 8)/Kaposi's sarcoma-associated herpesvirus (KSHV). In simian immunodeficiency virus (SIV) infected rhesus macaques (RM), RRV is associated with B cell hyperplasia and persistent lymphadenopathy that closely resemble multicentric Castleman's disease (MCD). More recently, RRV is found to be associated with non- Hodgkin's lymphoma (NHL), another disease manifestation that HHV-8 is found to be associated in a percentage of HIV-1 infected individuals. The close genetic similarity between RRV and HHV8 and the similar disease manifestations observed in animals/individuals infected with these viruses in conditions of immune deficiency, suggests that RRV infection of RM is an excellent animal model to identify HHV8 determinants of pathogenesis. Thus, the long-term goal of this application and the underlying hypothesis driving these studies are that RRV is directly associated with the B cell disease manifestations mentioned above in SIV-infected RM. To address this goal the following Specific Aims are proposed:
Specific Aim 1 : Identify differences between pathogenic and non-pathogenic isolates of RRV.
Specific Aim 2 : Construct a pathogenic bacterial artifical chromosome (BAG) of RRV strain 17577 from c3 to facilitate the generation of mutants in RRV.
Specific Aim 3 : To develop transposon mutagenesis for the RRV BAG to identify viral ORFs associated with RRV-associated disease-like patterns in vitro.
Specific Aim 4 : In vivo pathogenesis of mutant RRVs with targeted mutations defined ORFs identified in SA3 associated with distinct in vitro properties. The results form these proposed studies should provide new insight into how RRV induces RRV-associated disease, and serve as a means to elucidate the role of HHV8 in HHV8-associated disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075922-12
Application #
7407528
Study Section
Special Emphasis Panel (ZRG1-AARR-A (04))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-07-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
12
Fiscal Year
2008
Total Cost
$595,989
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
Estes, Jacob D; Wong, Scott W; Brenchley, Jason M (2018) Nonhuman primate models of human viral infections. Nat Rev Immunol 18:390-404
Skalsky, Rebecca L; Barr, Sarah A; Jeffery, Andrew J et al. (2016) Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family. J Virol 90:9350-63
Morin, Gabriela; Robinson, Bridget A; Rogers, Kelsey S et al. (2015) A Rhesus Rhadinovirus Viral Interferon (IFN) Regulatory Factor Is Virion Associated and Inhibits the Early IFN Antiviral Response. J Virol 89:7707-21
Estep, Ryan D; Rawlings, Stephanie D; Li, Helen et al. (2014) The rhesus rhadinovirus CD200 homologue affects immune responses and viral loads during in vivo infection. J Virol 88:10635-54
Estep, Ryan D; Wong, Scott W (2013) Rhesus macaque rhadinovirus-associated disease. Curr Opin Virol 3:245-50
Estep, Ryan D; Hansen, Scott G; Rogers, Kelsey S et al. (2013) Genomic characterization of Japanese macaque rhadinovirus, a novel herpesvirus isolated from a nonhuman primate with a spontaneous inflammatory demyelinating disease. J Virol 87:512-23
Robinson, Bridget A; Estep, Ryan D; Messaoudi, Ilhem et al. (2012) Viral interferon regulatory factors decrease the induction of type I and type II interferon during rhesus macaque rhadinovirus infection. J Virol 86:2197-211
Robinson, Bridget A; O'Connor, Megan A; Li, He et al. (2012) Viral interferon regulatory factors are critical for delay of the host immune response against rhesus macaque rhadinovirus infection. J Virol 86:2769-79
Messaoudi, Ilhem; Estep, Ryan; Robinson, Bridget et al. (2011) Nonhuman primate models of human immunology. Antioxid Redox Signal 14:261-73
Estep, Ryan D; Messaoudi, Ilhem; Wong, Scott W (2010) Simian herpesviruses and their risk to humans. Vaccine 28 Suppl 2:B78-84

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