Preliminary studies in rhesus macaques (RM) reveal that animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus rhadinovirus (RRV) develop B cell hyperplasia compared to RM infected with SIV alone. RRV, like Kaposi's sarcoma-associated herpesvirus (KSHV), encodes an interleukin-6 (IL-6) homologue, which is thought to be a necessary growth factor for Kaposi's sarcoma and the B cell-derived malignancy referred to as body cavity based lymphomas or primary effusion lymphoma in AIDS patients also infected with KSHV. The long-term objectives of this study aim to evaluate the role of the RRV vIL-6 homologue in viral-mediated B cell hyperplasia in the context of an SIV infection. Preliminary studies provided in the application strongly suggest that RRV vIL-6 is involved in RRV- associated disease, and as such provides an extremely value animal model to define the role of the viral encoded IL-6 in virus-mediated pathogenesis and to evaluate a novel therapeutic approach, utilizing a recombinant vIL-6-Fc fusion protein to induce anti-RRV vIL-6 responses to inhibit disease progression. To address this, the following Specific Aims are proposed:
Specific Aim 1 : Vaccination of immunocompetent and immunodeficient rhesus macaques with vIL-6-Fc fusion and define host immune response by enzyme-linked immunosorbent assays, neutralizing antibody responses, and cellular immune responses to vIL-6.
Specific Aim 2 will define alternations in host response following RRV infection in vIL-6 vaccinated animals (immunocompetent and immunodeficient), utilizing the assays and procedures from Specific Aim 1 studies and the inclusion of studies with a recombinant RRV that encodes nonsense mutations in RRV ORF R2 (vIL-6). Finally, in Specific Aim 3 studies are proposed to evaluate the therapeutic potential of vIL-6 Fc fusion vaccination in animals infected with SIV and RRV. Parameters that will be measured include: viral load as defined by co-culture analysis and real time PCR;differential leukocyte counts in peripheral blood;serum protein electrophoresis for hypergammaglobulinemia;host and viral IL-6 by ELISA and bioassay;lymph node and bone marrow biopsies, and physical examination. 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 vIL-6 in virus infection and disease, and provide new insights into the future development of therapies for KSHV-associated malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
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Read-Connole, Elizabeth Lee
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Oregon Health and Science University
Schools of Medicine
United States
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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; 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
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