Interdisciplinary HPV Prevention Center

Core A - Administrative

Leader: Cosette Wheeler, Ph.D.

1. Coordinate activities related to the development of the Center
2. Manage the fiscal resources of the Center
3. Maintain records, monitor and update compliance data related to Projects and Cores
4. Coordinate meetings among investigators and with external seminar speakers
5. Manage and schedule the travel and external reagent exchange and communications for the Center
6. Provide support for noncompetitive renewal reporting and preparation of an annual progress report
7. Manage requests for use of shared resources developed by the IHPC
8. Interface with all center activities to update the contents of the IHPC website

Core B - Virion Production & Infection Array

Leader: Michelle Ozbun, Ph.D.

The Virion Production and Infection Assay Core will enable the UNM IHPC to

• centralize the production of virions, psuedovirions, VLPs
• centralize equipment for virus particle production and for 3-D infection analyses
• centralize technical support and instrumentation for the Maestro Imager and real-time quantitative PCR
• establish and house the UNM IHPC shared specimen resource

The specific aims of the Virion Production and Infection Assay Core facility are to:

• Aim 1: Prepare VLPs for diagnositics, and PseudoV, and infectious virions for infections.
• Aim 2: Perform diagnostic experimental infections to assess serum infection neutralization titers.
• Aim 3: Carry out quantitative molecular diagnostic viral infectivity assays.
• Aim 4: Facilitate quantitative fluorescent imaging for infection quanitfication in cultivated tissues in vitro and in the rodent genital tract.
• Aim 5: Develop and house the IHPC's biospecimen shared resource generated through large-scale population-based sampling for anogenital HPV genotypes.

Core C - Biostatistics & Bioinformatics Core

The BBC will provide database support for the UNM IHPC research projects by:

• developing the IHPC central and project-specific relational databases including the NMHPVPR
• maintaining a master database for each project with appropriate backups and security checks
• assisting in development of protocols for data transmission
• interfacing and performing linkages to the NM-SIIS
• developing and maintaining the IHPC web site
• developing and running quality-control program checks
• monitoring study progress and distributing monthly status reports
• producing summary reports describing distributions and summary statistics for primary study variables

The BBC will provide statistical support for the UNM IHPC research projects by:

• assisting in the development and finalization of the study designs and protocols
• collaborating with study investigators in the development of forms and applications for collecting data
• working with the study investigators to develop detailed Manuals fo Procedures
• developing and writing statistical analysis subroutines as needed
• assisting with writing manuscripts and preparing presentations

Cosette Wheeler, Ph.D.

Leader Project #3, Director of IHPC

Cosette, the Program Director and Principal Investigator of NM-HOPES-PROSPR, is a UNM Regents Professor in the Departments of Pathology and Obstetrics and Gynecology at the University of New Mexico (UNM) Health Sciences Center. Her New Mexico research group has contributed for over 20 years to understanding the molecular epidemiology of human papillomaviruses (HPV) in cervical precancer and cancer. She has overseen a number of large-scale multidisciplinary population-based projects that have ultimately enabled advances in primary and secondary cervical cancer screening. She has authored over 150 peer-reviewed articles a number in top tier journals. In 2008 Sciencewatch (Thomson Reuters) ranked her citations over the past decade 7th in human papillomavirus contributions and in the top 1% in the field of clinical medicine.

Research Interests

Dr. Wheeler's interests and productivity have spanned many facets of HPV-related cervical disease from development of nucleic acid-based HPV diagnostics, HPV phylogeny and global molecular variation, host and viral genetic risk factors of cervical disease outcomes, and she has led groups supporting clinical trials to assess the utility of both HPV testing (US National Cancer Institute ALTS trial) and HPV vaccines (Merck Gardasil phase I, II and III and GSK Cervarix phase II and III). Within the Gardasil and Cervarix phase III pivotal efficacy trials, her clinical trials group acted as a lead enrollment site for the US and North America. Dr. Wheeler is currently the director of one of five US National Cooperative Research Centers in Sexually Transmitted Infections (STI-CRC), the UNM Interdisciplinary HPV Prevention Center funded by the National Institutes of Allergy and Infectious Diseases and she directs a UNM dedicated clinical trial facility, the House of Prevention Epidemiology (HOPE). In 2006 she was presented the American Society of Coloposcopy and Cervical Pathology (ASCCP) Distinguished Scientific Achievement Award.

Since 2006, Dr. Wheeler has directed a state-wide surveillance program in New Mexico that represents a one-of-a-kind US resource which captures all Pap and HPV tests, and all cervical, vulvar, and vaginal pathology under state regulations for all New Mexico residents. The goal of this monitoring program which interfaces with a state-wide immunization registry as well as health plan billing data for vaccine delivery is to assess real world HPV vaccine impact and effectiveness as a requisite to appropriate integration of screening and vaccination in the US.

Dr. Wheeler's laboratory has acted as a reference laboratory for the World Health Organization (WHO) and has developed international HPV DNA standards reagents for the WHO. These standards were considered necessary for monitoring global implementation of HPV vaccines. She has served as a Research Associate for the US National Research Council and as a scientific fellow for both the US National Science Foundation and the American Social Health Association and she has acted as an advisor to the US Centers for Disease Control and the American Cancer Society as well the International Agency for Research on Cancer's (IARC), Cancer UK, and the Instituto Nacional de Salud Publica, Cuernevaca, Mexico in support of their efforts to understand and prevent cervical cancer in developing countries.

Michelle Ozbun, Ph.D.

Leader Project #1, Co-I Project #2, Co-Leader Core B

Michelle is a Professor in the University of New Mexico's Department of Molecular Genetics and Microbiology and has a joint appointment in Obstetrics & Gynecology. As a post-doctoral fellow in Dr. Craig Meyers' laboratory at PennState University College of Medicine, she began studies on the human papillomavirus (HPV) life cycle, including the regulation of gene expression and viral genome replication during the differentiation-dependent viral life cycle in human skin equivalents derived via the organotypic (raft) epithelial tissue culture system.

Professor Ozbun's lab uses both the organotypic culture system and the 293TT transfection system to obtain infectious virions with which to study early infection events. Her work was first to assess HPV early infection and gene expression in human keratinocytes in vitro. Her laboratory has shown that HPV31 and HPV16, two carcinogenic HPV types with differential oncogenic capacity and prevalence in the population, use different mechanisms for entry into human keratinocytes. Michelle's research is focused on determining how HPVs interact with human keratinocytes and hijack the cells to establish persistent infections. This knowledge is important for developing and testing agents for preventing infection and transmission of these important human pathogens.

Research Interests

Papillomaviruses target cells in the stratified squamous epithelium in order to establish and complete their viral life cycles. According to current models, HPVs infect the mitotically-active basal cell layer of the skin through a micro-abrasion or wound in the epithelium. These progenitor cells of the skin support early viral gene expression required to set up a persistent infection (Figure 1). Laminin 5 (LN5) is a protein secreted by HKs onto the extracellular matrix (ECM) and basement membrane, and binds HPV particles with high affinity. This function appears to hold virions at the wound site for eventual transfer to the plasma membrane of adjacent susceptible keratinocytes. Studies in monolayer cell cultures identify heparan sulfonated proteoglycans (HSPGs), including syndecan-1 and syndecan-4, as cellular attachment factors. ?6-integrin and syndecans are candidate PV entry receptors. Of these, only the expression pattern of ?6-integrin could preferentially target particles to the basal layer (Fig. 1). LN5 cannot mediate viral entry as it is extracellular, and not a PM component of HKs. There is disagreement in the current literature over the requirement for specific attachment moieties, as well as the routes of internalization and cellular organelles involved in HPV infections. Although wounding of the epithelial barrier has long been known to augment infection in vivo, the physiological and molecular explanations for the involvement are rudimentary.

The long-term goals of the Dr. Ozbun's research program are to elucidate the cellular and viral mechanisms that regulate the process of infection and the replicative life cycles of papillomaviruses. Specific areas of interest include the following:

• Defining the cellular and viral components that are involved in the initial interactions that result in virus uptake in susceptible cells;
• Determining the aspects of the epithelial wounding process that enhance infection;
• Investigating the mechanisms of initial PV replication upon infection that lead to viral persistence;
• Identifying the viral and cellular determinants of host range and tissue tropism;
• Establishing a non-human primate model for the study of anogenital infection, persistence, and disease progression.

Our goals as part of the UNM Interdisciplinary HPV Prevention Center are to understand how molecular, cellular and structural changes associated with epithelial wounding contribute to HPV infections in physiologic relevant systems. We are using scratch wounding of monolayer cell cultures, wounded organotypic tissues, and the rodent genital tract models for infection.

Gill Woodall, Ph.D.

Project #4 Leader

W. Gill Woodall, Ph. D., is a Professor Emeritus of Communication and a past Senior Research Scientist in the Center on Alcoholism, Substance Abuse and Addictions (CASAA) at the University of New Mexico. He is an experienced NIH Principal Investigator, having served as a Principal Investigator or co-Investigator on twelve major NIH funded grant projects in the areas of drunk driving prevention, and Internet-based approaches to dietary improvement among minority rural adults, reduction of tobacco uptake among adolescents, reduction of risky alcohol consumption among college students, the development of web-based Responsible Beverage Service training in both on and off-site alcohol premises, the prevention of drug use, sexual debut and sexually transmitted disease among adolescents, and the increased adoption of HPV vaccine among early adolescent females. He has served as reviewer for the NIH Center for Scientific Review as a study section member and ad-hoc reviewer for 15 years. He has served on the New Mexico Governor’s DWI Leadership Task Force. He has also published extensively in the area of Nonverbal Communication, and is a co-author, with Dr. Judee Burgoon and Dr. David Buller, of a book on Nonverbal Communication.

Research Interests

The World Wide Web has had a dramatic impact on the everyday lives of many. In some sectors of life, the Internet has transformed how we communicate, how we see ourselves and how others see us, and how we think about a wide variety of issues. In the realm of Health Communication, the Internet is an important platform for the effective and accurate conveyance of health information. Such information, when framed by useful social theoretic al principles, can function to prompt the adoption of new health behaviors, practices, and policies. This is currently especially the case for Human Papillomavirus Vaccines, where the clarity of understanding of the vaccines has been clouded by misinformation and political misdirection. Project 4 will employ theoretically framed messages about the HPV Vaccines in an engaging web-based format for parents and young female adolescents in order to provide an informed basis for decision making about the uptake of the HPV vaccines.

Bryce Chackerian, Ph.D.

Leader Project #2

Bryce is an Associate Professor in the University of New Mexico's Department of Molecular Genetics and Microbiology. As a post-doctoral fellow in Dr. John Schiller's laboratory at the National Cancer Institute he began his work on using Virus-like particles (VLPs) as platform for antigen display. His laboratory has shown that VLP presentation can enhance the immunogenicity of numerous target epitopes, including epitopes derived from self-antigens, which are normally subject to the mechanisms of B cell tolerance. His work has focused on the development of new vaccines against infectious agents, as well as self-antigens involved in chronic diseases.

Research Interests

The immune system is remarkably adept at mounting strong responses against invading microorganisms such as viruses and bacteria. At the same time, it has developed mechanisms to avoid reacting against the body's own components. One the ways that the immune system is able to distinguish between foreign invaders and self-proteins is by being able to recognize and respond to the structure of pathogens. Virus particles, for example, typically consist of one or more proteins organized into a highly repetitive, particulate structure. These sorts of structures are highly stimulatory to the immune system, resulting in the induction of strong antibody and T-cell responses.

Many viral structural proteins have the intrinsic ability to self-assemble into virus-like particles (VLPs) that closely resemble authentic virions. These VLPs mimic the structures of the viruses from which they were derived, but, because they lack a viral genome, are not infectious. VLPs make excellent vaccines for several reasons. First, they are antigenically similar to the viruses from which they were derived, meaning that they can often induce antibodies that are capable of blocking viral infection. Second, because they aren't infectious, they have excellent safety profiles. Third, their multivalent structure is capable of inducing very strong antibody responses. Two VLP-based vaccines, for Hepatitis B virus and Human Papillomavirus, are currently approved clinically, and many more VLP-based vaccines are in clinical development.

VLPs can also be used as platforms to increase the immunogenicity of practically any antigen. Display of an antigen at high density on the surface of a VLP can dramatically enhance the immunogenicity of that antigen. This technique can be used to target antigens from pathogens and it can even be used to target self-antigens, which are normally not immunogenic. This finding has made it possible to develop new vaccines with the goal of deliberately inducing immune responses against self-molecules that are involved in chronic diseases, including cancer, Alzheimer's disease, and rheumatoid arthritis, among others. The Chackerian lab, in collaboration with Dr. David Peabody's laboratory at UNM, has exploited VLPs derived from a family of viruses that infect bacteria. These bacteriophages are safe, they cannot infect humans, they can be produced at high yields, and they are amenable to the techniques of protein engineering that make them a highly useful vaccine platform. The Peabody and Chackerian laboratories have developed techniques that allow them to link diverse antigens to VLPs of two bacteriophages, MS2 and PP7, making it relatively easy to apply the VLP technology to promising targets and develop new vaccines. Known B cell or T cell epitopes from antigens can be genetically displayed on VLPs. These recombinant particles can then be used directly as an immunogen to induce antibody or T cell responses against the target. We have developed VLP-based vaccines that target TNF-alpha (for Rheumatoid Arthritis), Amyloid-beta (Alzheimer's Disease), and CCR5 (HIV infection) and have been successfully tested in animal disease models.

The focus of our work as part of the UNM Interdisciplinary HPV Prevention Center is to develop second-generation vaccines against HPV that target the viral minor capsid protein, L2. Unlike current HPV vaccines, which only target a few strains of HPV associated with cancer, a vaccine targeting L2 could generate broad protection against a majority of HPV infections.