ANTI-VIRAL IL-6 APPROACH TO MITIGATE KSHV-RELATED DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies in rhesus macaques (RM) reveal that animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus rhadinovirus (RRV), the homologue of Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8), develop B cell hyperplasia compared to RM infected with SIV alone. RRV, like KSHV, encodes an interleukin-6 (IL-6) homologue. The KSHV IL-6 homologue 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 IL-6 homologue in viral-mediated B cell hyperplasia in the context of an SIV infection. To address this we have developed two strategies. The first strategy involves creation of recombinant RRV that lacks the ability to express vIL-6. A recombinant RRV encoding nonsense mutations in the vIL-6 open reading frame has been created and is currently being characterized. Once characterized, this recombinant will be used to test whether vIL-6 is required for viral mediated pathogenesis. The second strategy involves vaccination of animals with a recombinant vIL-6-human Fc fusion protein as an antigen to induce an immune response against vIL-6. Our preliminary studies indicate that animals inoculated with the vIL-6 fusion protein and adjuvant develop a robust humoral response against vIL-6 capable of neutralizing vIL-6 activity. Challenge infection studies are currently underway and preliminary studies suggest the humoral response is capable of mitigating viral pathogenesis in the SIV-infected RM.