Darron R. Brown, M.D.
Professor of Medicine, Infectious Disease
Professor of Microbiology & Immunology
My laboratory is interested in human papillomavirus (HPV) as an infectious agent that leads to epithelial proliferation and, in some cases, genital tract malignancy. We are interested in basic biology of papillomaviruses as well as epidemiology of HPV infections, and clinical aspects of disease. Our recent work focuses on the effects of HPV infection on the cornified cell envelope (CCE). Because HPV is not a lytic infection, it is not clear how new virus is released from the desquamating keratinocyte, which usually has a thick and durable CCE. We showed that HPV 11 and HPV 59 (an oncogenic type) induce profound abnormalities of the CCE, including altered transcription of loricrin, the major CCE protein. We also have shown evidence that the HPV 11 E1^E4 spliced viral protein may be incorporated into the CCE, and may alter the physical properties of the CCE. This may be important, since the E1^E4 protein is detected in the same cells that produce infectious virus.We are investigating the epidemiology of genital tract HPV infection in adolescent women and in women infected with HIV. These studies are designed to provide insight into how some HPV infections persist and cause dysplasia, as compared to other infections that appear to clear. These studies relate to production of vaccines as well. To develop a prophylactic vaccine against HPV, we are investigating the possibility of using L1 protein virus like particles (VLPs) to generate protective immunity in cervicovaginal secretions of immunized women. An HPV 11 isolate was expressed as VLPs in yeast. These VLPs were then purified, and female monkeys were immunized by intramuscular injection. Neutralizing antibody, as determined by the neutralization of HPV 11 virions in the athymic mouse xenograft system was present in the serum, and more importantly in the cervicovaginal lavage fluid of these animals. Women immunized with this vaccine also produce neutralizing antibodies. We also studies HPV 16 VLPs as a vaccine and found a high degree of efficacy in preventing incident HPV 16 infection. HPV 16 is the most common type found in cervical cancers. We are currently conducting clinical trials of a quadrivalent VLP vaccine in conjunction with the Merck Research Laboratories.
Using the athymic mouse xenograft system, we have successfully propagated an oncogenic type (HPV 59) and have successfully grown this virus in culture. These cells contain episomal HPV 59 and produce infectious HPV 59 in a simple culture system upon differentiation. After approximately 30 passages, the cells obtain a malignant phenotype that is concurrent with HPV 59 integration into the keratinocyte genome. We recently performed a gene array experiment using early passage cells containing episomal HPV 59 DNA, late passage cells, containing integrated HPV 59 DNA, and primary human keratinocytes (PHKs) as control cells. The array studies indicated differences between PHKs, early, and late passage cells, including changes in angiogenic factors, growth factors and their signaling pathways, genes involved in the cell cycle, tumor suppressors and oncogenes. Studies are underway to determine the significance of these differences.
- Lehr E and Brown D. 2003. Human papillomavirus type 59 induces alterations of the cornified cell envelope proteins Virology 309:53-60.
- Lehr E, Qadadri B, Hall K, Brown C, and Brown D. 2003. HPV 59-immortalized keratinocytes express late genes and produce infectious virus after calcium stimulation. Virology 314:562-571.
- Lehr E and Brown D. 2002. How do human papillomaviruses escape the infected keratinocyte? Papillomavirus Reports 13:181-189.
- Lehr E and Brown D. 2004. Expression of small proline rich proteins in genital epithelium infected with human papillomaviruses J Med Virology 72:478-83.
- Brown D, Fife K, Wheeler C, Koutsky L, Lupinacci L, Railkar R, Dicello A, Li W, Smith J, Tadesse A, Jansen KU, Suhr G, and Barr E. 2004. Early assessment of the efficacy of an HPV 16 L1 VLP vaccine Vaccine 22(21-22):2943-52.
- Dillner J and Brown D. 2004. Can genital tract human papillomavirus infection and cervical cancer be prevented with a vaccine? Expert Reviews in Molecular Medicine Volume 5, http://www.expert-reviews.com/
- Brown D, Brown, C, and Lehr E. The human papillomavirus type 59 E1^E4 protein is cytoplasmic and translocates to the region of the cornified cell envelope in differentiated keratinocytes Intervirology (in press).
- B.S., 1975, State University of New York at Buffalo
- M.D., 1979, University of Rochester School of Medicine and Dentistry, Internship and Residency, 1979-1982
- Fellow in Medicine, Infectious Diseases Unit, University of Rochester School of Medicine and Dentistry; 1985-1988
- Diplomat, American Board of Internal Medicine; Internal Medicine 1981; Infectious Diseases 1988.