Cervical and anal cancers are a significant cause of death and illness among people worldwide, and are especially common among patients with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). At least 99% of anogenital malignancies are caused by sexually transmitted infections with human papillomaviruses (HPVs). Currently, there is no animal model for HPV-induced anogenital malignancies. We propose to create such a model using a recently identified papillomavirus (PV) found to cause sexually transmitted genital lesions and cancers in Rhesus monkeys. The virus was designated Rhesus PV type 1 (RhPV1) and sequence analysis revealed the genome to be genetically very similar to HPV16 and HPV31, HPV types that cause the majority of anogenital lesions and malignancies in humans. We will use our expertise with epithelial cell transfection and with the organotypic (raft) culture system to synthesize infectious RhPV1 virions in the laboratory. This study will enable us to establish a Rhesus macaque model for HPV-induced anogenital infection and malignancy.
The specific aims of this program are three-fold. First, we will establish an in vitro system for RhPV1 replication and the production of infectious virions by stably transfecting RhPV1 genomes into epithelial cells. These cells will behave as persistently infected cells and will be grown as differentiating epithelial raft tissues for the biosynthesis of RhPV1 virions. Second, we will examine the viral transcription and genome replication activities in these persistently infected cells grown as differentiating epithelial raft epithelial tissues. Third, we will use purified RhPV1 virions to study viral activities in newly infected low passage Rhesus genital epithelial cells in vitro. Following this proposed initial characterization of RhPV1 replication and infection in vitro, we foresee future in vivo experimental RhPV1 infections in SIV-infected and non-infected Rhesus monkeys. Such studies will permit essential studies into the pathogenesis of anogenital PV infections. This animal model will allow the study of the natural history of anogenital PV infections including transmission, immunology, acute and chronic pathology (neoplasia), and progression to malignancy of PV infections. Prophylactic and therapeutic agents could be evaluated in this model system.
| Tomai?, V; Gardiol, D; Massimi, P et al. (2009) Human and primate tumour viruses use PDZ binding as an evolutionarily conserved mechanism of targeting cell polarity regulators. Oncogene 28:1-8 |
