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 determining the mechanisms by which HPV modulates host immune defenses and drives cancer progression.
1. Virus-Host Interactions in 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. Immune Dysregulation during HPV-directed 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. During decades of HPV-associated cancer progression, HPV persists, evades host surveillance, and continuously contributes to host cell transformation. However, little is known about the mechanisms of disease progression driven by HPV, particularly in the context of host immunity. To understand the molecular mechanisms that drive HPV-positive cancer development, we analyzed global gene expression profiles of over 200 human cervical and head/neck tissues in different HPV status (HPV+ and HPV-) and disease stages (normal, early and late precancers, and cancer). The results have revealed a striking cascade of distinct HPV-specific molecular changes during cancer progression. The significantly altered genes are involved in cell cycle/DNA damage responses and innate/adaptive host immune regulations. We have further discovered that the HPV oncoprotein E7 dysregulates chemokine functions and the cytidine deaminase APOBEC3A that lead to antitumor immune suppression, cancer mutagenesis, and virus evolution.
We are currently investigating virus-mediated immune evasion during HPV-directed cancer progression, using in vitro cell culture systems, in vivo mouse models, and human patient specimens. Our studies in basic and translational sciences will lead to better understanding the novel mechanism of virus-induced immune suppression and developing new cancer immunotherapies.