Mechanistic Investigations of Ethnic Differences in HPV Variants

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DESCRIPTION (provided by applicant): Genotypic variants of HPV16 are defined as having less than 2% differences in the major capsid protein gene with respect to the prototype genome have been identified worldwide. A body of epidemiological and clinical data has emerged associating groups of HPV16 variants with differences in the clinical progression and aggressiveness of the cervical neoplasia. Representative variants from all major HPV16 variant lineages are detected in populations worldwide, although specific prevalences differ by geography. Infection and oncogenicity of specific HPV variants appears to vary geographically and also with the ethnic origin of the population studied. The greatest predictor of variant lineage is race. Variants, especially those associated with ethnic populations of African or Asian descent have a greater predisposition for persistence. Attempts have been made to correlate the differences in the clinical picture exhibited by HPV16 variants with the biology and life cycle of the virus. However, the majority of these studies have analyzed functions of specific genes or regions of the virus in isolation, such as the E6 gene product or the upper regulatory region. To unequivocally evaluate causal genetic effects, whole-genomes analyses are needed. There have been no whole-genome studies relating to the viral life cycle and infectivity, and how this may be related to the ethnicity. Our ability to reproduce in vitro the complete viral life cycle, including production of infectious virus, places us in a position to propose whole-genome analyses of the HPV16 variants. We also have the tools and expertise to investigate interaction of HPV16 variants with ethnic-specific host tissues. Our long-term goal is to understand ethnic differences in HPV variants using a whole-genome analyses, including infection prevalence and carcinogenicity. As far as we can tell this will be the first whole-genome analyses of any HPV variant. The specific objectives of this proposal are to compare European HPV16 variants with the two African HPV16 variant groups (African-1 and African-2) and the Asian American variant group. The central hypothesis is that ethnic associated variants differ mechanistically in infectivity and carcinogenicity and that these differences are especially acute in epithelial tissus of individuals of the ethnic backgrounds associated with the variant. We will pursue these studies in three specific aims: Specific Aim 1: Investigate differences in the carcinogenic proclivity of ethnic-specific HPV16 variants. Specific Aim 2: Compare infectivity of HPV16 variants ethnic-specific keratinocytes. Specific Aim 3: Identify genetic determinants responsible for ethnic-specific biological differences of HPV16 variants.