The long term goal of this project is to develop antisense oligonucleotide therapy to treat latent human papillomavirus (HPV) infection. HPVs are the cause of benign and malignant tumors in man. These viruses establish both latent and active infection. Latency is characterized by continued maintenance of low copy numbers of viral DNA in the tissue, expression of very low levels of a subset of viral transcripts and absence of any clinical or histologic pathology. Active infection is characterized by abundant viral transcripts, formation of tumors, and production of large amounts of viral DNA and infectious virions. Latent infection is believed the source of recurrence in respiratory papillomatoses, associated with high levels of morbidity and significant mortality. There is no known therapy that eliminates latent infection.
The specific aims of this proposal are to test the hypothesis that antisense oligodeoxyribonucleotides (oligos) targeted against the HPV E1 mRNA can prevent HPV DNA replication, and thus reduce or eliminate latent HPV infection in laryngeal cells. We will also determine whether the same approach is effective in active infection in cells derived from laryngeal papillomas.
The specific aims are: 1. Determine whether antisense phosphorothioate oligos can reduce or eliminate latent HPV 11 DNA from cultured laryngeal cells. 2. Determine whether the same antisense oligos are effective in reducing or eliminating HPV DNA in cells cultured from laryngeal papillomas. 3. Determine whether the two cell types respond to antisense oligos by reduction in E1 transcript abundance, viral DNA replication, or both, to ascertain whether latent and active HPV infection respond in the same way. 4. Determine whether cells cultured on organotypic rafts, a model for epithelial tissues, respond to antisense oligos by reducing or eliminating HPV E1 RNA and reducing replication of DNA.
| Chow, Louise T; Broker, Thomas R; Steinberg, Bettie M (2010) The natural history of human papillomavirus infections of the mucosal epithelia. APMIS 118:422-49 |
