A majority of cases by sexually transmitted disease occur in people under the age of 24. Among these are infections by human papillomaviruses which are the causative agents of cervical cancer. Over 40 million people are infected with human papillomaviruses and a subset of these progress to cervical cancer. In college age female students, over 50 % are found to be infected with HPVs and over 25% acquire HPV in their first year of sexual activity. The goal of this proposal will be try to understand the basis for this high infection rate. I propose to examine the cellular parameters which influence susceptibility to papillomavirus infections and pathogenesis. The high frequency of infection of adolescent and young adults suggests that there by differences in the infection process between younger and older individuals. This proposal will first seek to identify the cellular factors that influence infectivity and then to determine if differences exist between adolescents and older individuals. The long term goal would be to use this information to prevent and treat infection by these viruses. Papillomaviruses target epithelial cells at a variety of body locations with each type exhibiting a high degree of specificity. Over seventy different HPV types have been identified and one third specifically target the genital tract. Among these are HPV types 16,18,31 and 34 which are associated with over 90% of cervical cancers and are referred to as """"""""high risk types"""""""". HPV infection is believed to occur through micro-wounds of the epithelia which expose basal cells to viral entry. Following infection, viral genomes are established as low copy episomes and the production of progeny virions is dependent upon epithelial differentiation. The integrin alpha6beta4 receptor has been proposed as a candidate receptor for HPVs but strong evidence supporting this hypothesis is lacking. My laboratory has recently developed methods to grow human papillomaviruses in tissue culture as well as methods to perform a genetic analysis of viral functions during the productive life cycle. I propose to use these methodologies to examine the process of HPV infection with an emphasis on the parameters controlling susceptibility to infection in adolescents. We will ask the following questions: 1). Can we develop a simple assay for HPV infectivity using recombinant virus technology? 2). What cellular proteins are involved in viral attachment and entry? 3) Are there differences between adolescents and older adults in levels of expression of the cellular factors involved in HPV entry?
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