Kaposi's sarcoma is the leading cancer observed in individuals with AIDS. In vivo models that can recapitulate most/all aspects of Kaposi's sarcoma-associated herpesvirus (KSHV) infection and disease are absolutely required to develop and test new vaccines to prevent the increase in KSHV infection and disease. Currently, the rhesus macaque (RM) model of KSHV-like disease fulfills most of these aspects, as animals experimentally infected with the simian immunodeficiency virus (SIV) and rhesus macaque rhadinovirus (RRV) develop B cell lymphoproliferative diseases (LPD) similar to AIDS patients co-infected with KSHV. Importantly, RM exhibit similar immunological responses to RRV infection, as humans infected with KSHV. Specifically, RM infected with RRV possess low CD4+ and CD8+ T cell responses to the virus, which could be one host factor that allows the virus to maintain a persistent infection. In this application, we intend to test the properties of the newly developed rhesus cytomegalovirus (RhCMV) vaccine vector system to stimulate a robust T cell response in RM that can recognize RRV latency-associated nuclear antigen (LANA). Once the immune responses to RRV LANA are characterized in vaccinated animals, the animals will be challenged with RRV and monitored for virus infection and persistence. The long-term objectives of this study aim to evaluate the ability of RhCMV vectors to induce a strong T cell response to RRV-LANA and whether this T cell immunity is capable of clearing RRV infection and persistence in a relevant model of KSHV infection. To address this, the following Specific Aims are proposed:
Specific Aim 1 : Immunogenicity of RhCMV US8-11-LANA in rhesus macaques.
Specific Aim 2 : Protection of RhCMV US8-11-LANA-vaccinated animals against challenge with wild type RRV.
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 with the development of an effective vaccine to prevent and/or inhibit KSHV- associated disease.
