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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132638-05
Application #
8239901
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2008-05-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$523,041
Indirect Cost
$191,944
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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