Altered biology of adeno-associated virus type 2 and human papillomavirus during dual infection of natural host tissue.

Abstract

Adeno-associated virus (AAV), a common genital virus, may have a "protective" role against human papillomavirus (HPV)-associated cervical cancer. Epidemiological studies indicate a negative correlation between AAV infection and the incidence of cervical cancer. In contrast, HPV is positively associated with cervical cancer. To investigate interactions between these two viruses we used the organotypic "raft" culture system. The raft culture system is capable of supporting the complete HPV life cycle. Raft tissues that were actively replicating HPV were superinfected with AAV type 2 (AAV-2). We observed a multiplicity of infection (m.o.i.)-dependent enhancement and inhibition of HPV DNA replication, concomitant with AAV-2 replication. The data suggest that at low m.o.i. of AAV-2 infection, HPV DNA replication was slightly increased compared to controls and AAV-2 replicated poorly. At high AAV-2 m.o.i., HPV DNA replication was reduced and AAV-2 replicated to high levels. AAV-2 replication was increased in the presence of HPV compared to primary human keratinocyte, squamous cell carcinoma, and HaCat raft cultures infected with AAV-2 alone. These data suggest that HPV may provide types of "enhancer/helper" functions for AAV-2 replication and progeny formation. Infection with AAV-2 had significant effects on epithelial morphology. During infection with low m.o.i. of AAV-2 the epithelium stratified to a greater extent than in controls. With high m.o.i. of AAV-2 infections, tissue cytopathic effects were observed, indicating an additional factor responsible for the effect of AAV-2 on HPV replication and infection. Our results demonstrate a complex interaction between AAV-2, HPV, and skin during dual infection.