Human papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause over 5% of all human cancers, including cervical cancer and a subset of head and neck cancers. HPV-associated cancers result in a half of a million deaths every year, largely in underdeveloped countries.
While a majority of people becomes infected with HPV, most clear their infections and, of the remaining people with persistent infections, only small fractions develop pre-cancerous lesions and invasive cancers. Our research focuses on understanding how HPV interacts with the host factors to establish persistent infection and develop invasive cancers.
1. Establishment of persistent HPV infection
To establish persistent HPV infections, it is necessary for the viral genome to enter into the nucleus and establish its genome as a nuclear plasmid for long-term replication. Various host defense mechanisms are believed to play important roles for blocking and/or modulating the early establishment of HPV infections. These host mechanisms may include 1) physical barriers in virus trafficking through the cytoplasm and into the nucleus; 2) direct elimination of virus by host cell scavenger machinery such as autophagosomes; and 3) interference with viral gene expression and replication by host innate immunity. Using our HiP virus production technology, we discovered that HPV infection is modulated by a variety of host factors/mechanisms including host cell mitosis, autophagy, APOBEC3s, and other interferon-inducible proteins. We continue our research to further understand virus-host interactions and develop novel tools to prevent and eliminate HPV infection.
2. HPV-associated cancer progression
Initiated by HPV, HPV-associated cancers progress through a series of histopathologically characterized cytologic abnormalities (low-grade and high-grade intraepithelial lesions) to invasive cancer. To understand the molecular changes associated with each step in the progressive disease leading to invasive cancer, we have developed and performed functional genomics analyses of patient tissue specimens, from primary human cervical and head/neck tumor, precancerous or normal tissue. These studies revealed that each stage in the progressive disease is associated with a unique pattern of changes in gene expression. Genes upregulated specifically in early lesions were primarily associated with DNA replication/repair and cell proliferation. Interestingly, expression of markers in the IL-8 signaling pathway, which triggers chemotaxis and angiogenesis, differed only between low- and high-grade lesions. By far the greatest number of differences in gene expression was found between high-grade lesion and cancer, which included elevated levels of genes in the actin cytoskeleton signaling, fibrosis, tight junction, leukocyte extravasation, p38 MAP kinase, and vascular endothelial growth factor pathways. To better understand the underlying mechanisms and genetic determinants of cervical cancer progression, we are further 1) identifying host factors/pathways that contribute to cancer progression/regression and 2) developing key targets for treatment of HPV-associated cancers and novel biomarkers for diagnosis and prognosis, using in vitro cell culture systems, in vivo mouse models, and human patient specimens.