Epidemiology of HPV31 evolution and pathogenicity

Abstract

Cervical cancer ranks 3 rd among female malignancies globally, and 2nd in developing countries. Select, evolutionarily related, high-risk (HR) human papillomavirus (HPV) types are the known cause. Of over 180 characterized PV types, 12 phylogenetically related types have emerged as highly oncogenic (HR-HPVs). Comparison of viral genomes permits taxonomic classification of HPVs to genera, species and types. Phylogenetic topology validates clinical observations of HPV-related disease. All HR-HPVs sort to the Alphapapillomavirus genus. Species' designated related HPV genotypes that share a most recent common ancestor and 60 --70% genome identity. HR-HPVs primarily belong to either the Alphapapillomavirus 9 (HPV16-related) or Alphapapillomavirus 7 (HPV18-related) species, and individual types vary in prevalence and/or pathological risk. To identify emergent carcinogenic properties in circulating HR-HPVs, lower-level taxon is warranted. Isolates of the same HPV type with genomic nucleotide differences of 1 - 10% designate HPV variant lineages, and are reflective of host evolutionary events driven, by human geographic dispersal and population expansion. The virus hijacks highly efficient host DNA replication machinery, to ensure proofreading of viral DNA during replication, thereby securing a low viral mutation rate. Evolutionary models of HPV support carcinogenicity as an evolved trait. Establishment of fixed nucleotide polymorphisms acquired over time are associated with host populations, result in viral divergence. Epidemiological studies established nucleotide variations associate by HPV16 lineage and host geography, and differ in pathological risk. The natural history and clinical implications for remaining HR-HPV variants are first being identified. Furthermore, introduction of HPV vaccines may alter current HPV population dynamics. The hypothesis for this work is that selection for naturally occurring nucleotide polymorphisms, established though lineage fixation, may alter niche adaptation success, contributing to differences in carcinogenic risk in divergent HR-HPVs. This thesis focuses on the application of phylogenetics and molecular epidemiology to identify and characterize genetic determinants of HPV31 associated-pathogenesis. Studies were conducted using samples obtained from long-standing collaboration with the National Cancer Institute (NCI). HPV31 genome classification and methylation analysis were conducted using samples from the Persistence and Progression (PaP) repository from Kaiser Permanente California; vaccine analysis was conducted in samples obtained from the Costa Rica Vaccine Trial (CVT) co-sponsored by NCI and GlaxoSmithKline.