Viruses cause an array of disease manifestations ranging from acute respiratory disease, intestinal diarrhea, hemorrhagic fevers, hepatitis, cancer, and chronic autoimmune disease and in some instances death. One virus that was recently identified to be associated with cancer in humans in 1995 is human herpesvirus 8 (HHV8)/Kaposi's sarcoma-associated herpesvirus (KSHV). An accumulation of scientific evidence now substantiates HHV8 as the etiological agent responsible for classical and acquired immunodeficiency disease syndrome (AIDS)-related Kaposi's sarcoma (KS), as well as other lymphoproliferative disorders (LPDs) in immunocompetent and human immunodeficiency virus (HIV)-infected humans. Despite all of this scientific evidence it is difficult to fully understand how the virus causes disease without the ability to follow a natural infection. As such, alternative in vivo models that are readily accessible and can recapitulate HHV8 infection and associated disease are absolutely needed to identify viral determinants of pathogenesis and how these specific determinants, either viral open reading frames (ORFs) or other viral-encoded macromolecules are involved in HHV8-mediated pathogenesis. Here, we propose to utilize a closely related and relevant virus that can manifest similar biological outcomes in its natural host. The genome of the virus, referred to as rhesus rhadinovirus (RRV) has been characterized and shown to be essentially colinear and encodes most of the viral ORFs thought to be associated with pathogenesis. More importantly, in vivo studies show that RRV infection in its natural host recapitulates many, if not most of the properties of HHV8, including persistence and LPDs. The long term goals of the proposed research project are to better understand how HHV8 interacts with its host, utilizing RRV and experimental infection its natural host. This will be accomplished by a series of experimental in vivo infections and characterization of the host immune response. Additionally, the role of specific ORFs of RRV will be interrogated by creating a number of defined recombinants utilizing the RRV-bacterial artificial chromosome (RRV-BAC) that we successfully generated and shown to be infectious and pathogenic. Combining these types of in vitro and in vivo to address viral pathogenesis will enable researchers to dissect how viruses cause infection and disease in susceptible populations and how scientists can shift the pendulum in favor of the host.

Public Health Relevance

The incidence of KSHV infection and KSHV-associated disease in the developing and developed world will continue to grow as the population becomes immunodeficient due to HIV-1 infection or iatrogenic agents associated with organ transplantation. The results from the proposed studies utilizing the nonhuman primate animal model should help elucidate the role of the viral interferon regulatory factors in virus infection, persistence and disease, and provide new insights into the future development of therapies for KSHV- associated malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA075922-16
Application #
8230783
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1997-07-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
16
Fiscal Year
2012
Total Cost
$689,049
Indirect Cost
$268,897
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
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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; 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
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
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
Zhou, Fuchun; Li, Qiuhua; Wong, Scott W et al. (2010) Autoexcision of bacterial artificial chromosome facilitated by terminal repeat-mediated homologous recombination: a novel approach for generating traceless genetic mutants of herpesviruses. J Virol 84:2871-80
Umbach, Jennifer L; Strelow, Lisa I; Wong, Scott W et al. (2010) Analysis of rhesus rhadinovirus microRNAs expressed in virus-induced tumors from infected rhesus macaques. Virology 405:592-9
Orzechowska, B U; Manoharan, M; Sprague, J et al. (2009) Viral interleukin-6 encoded by rhesus macaque rhadinovirus is associated with lymphoproliferative disorder (LPD). J Med Primatol 38 Suppl 1:2-7

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