Overview
The Vaccine and Gene Therapy Institute (VGTI) at Oregon Health & Science University (OHSU) was established in March 2001 with the opening of the new OHSU West Campus Research Building. The overall mission of the VGTI is to develop research and teaching programs in accordance with the objectives and policies of OHSU. The founding goal of the VGTI was to assemble a multidisciplinary team of scientists to respond to the increasingly serious infectious disease threats facing the people of Oregon, the United States and the world as a whole, including AIDS, chronic viral infection-associated diseases, newly emerging viral diseases, and infectious diseases of the elderly.  Vaccine development, as well as development of novel immune and gene therapeutic approaches to these diseases are the major priorities of the faculty.  The founding of the VGTI was based on the increasing realization that progress in these areas of investigation requires high level expertise and experience in virology, immunology, animal models, pathology and clinical infectious disease, a combination that is rarely found in a single investigator. The strategy of the VGTI is to provide a close-knit collaborative environment for a group of independent scientists within these disciplines that could interact on a daily basis. Thus, a major founding principle of the VGTI is the expectation that each VGTI investigator not only establishes their own vigorous research program, but also devotes a portion of their research effort to comprehensive collaborative programs aimed at bringing diverse expertise to major clinical problems in infectious disease.   These VGTI programs are intended to span the continuum between basic and clinical science, in which discoveries are rapidly advanced from the level of molecular and cellular biology through animal models and ultimately into clinical testing – from lab bench to bedside. The development of this unique program in immunology and virology also provides an important training opportunity for graduate students and postdoctoral fellows at OHSU. Therefore, an important part of our mission is the training of young scientists in newer academic disciplines emerging at the VGTI.  Finally, many of the VGTI projects are clinically important and are focused towards the development of new therapies for disease. Therefore, another part of the institute’s mission is to transition these new vaccines, drugs, and assays to the public through corporate alliances. Thus, we anticipate that the VGTI will stimulate growth of the biotech industry in the greater Portland area.

Relationship of the VGTI with the Oregon National Primate Research Center (ONPRC) and the OHSU School of Medicine
The VGTI was formed to bridge scientific gaps at OHSU and take advantage of the existing faculty expertise and unique resources at the university resulting in synergistic interactions that would create a world class program in vaccines and new therapeutic approaches to disease. The formation of the VGTI as an independent entity was envisioned to be a scientific and fiscal marriage between the ONPRC and the OHSU School of Medicine (SOM). The rationale for this arrangement is explained below.

One of the unique resources at OHSU is the nonhuman primate model (NHP) that is an essential element of any clinically relevant investigations in the targeted areas of human disease. Thus, one high priority mission of the VGTI is to establish, maintain expertise in, and scientifically exploit NHP models of immunity and infection. To this end, the VGTI was formed in close association with the Oregon National Primate Research Center (ONPRC) with VGTI faculty providing the scientific leadership and staff for the ONPRC’s Division of Pathobiology and Immunology. This association is mutually beneficial providing new scientific programs for the ONPRC as well as strengthening ties between the ONPRC and basic science and clinical programs at the OHSU Portland campus.  All current VGTI faculty participate in NHP research and are ONPRC scientists; however, as the VGTI grows in the future, some of the programs will be more clinically based or may diverge into research areas that do not involve NHP. Therefore, some future faculty may be more intellectually and financially tied to other departments at OHSU rather than the ONPRC.

VGTI faculty scientific interests are also closely linked with the departments in the SOM including Molecular Microbiology and Immunology (MMI), Pathology, Pediatrics, Dermatology, Surgery, Medicine and the Oregon Cancer Institute. As VGTI-developed technologies mature, we anticipate that these approaches will be brought to the clinical arena via SOM programs.  Moreover, VGTI faculty are expected to contribute to the teaching, administrative and clinical missions of the SOM. For these duties, we anticipate that all VGTI faculty will have tenured or tenure track primary appointments in the SOM as Assistant, Associate or Full Professors as well as reimbursement for a portion of their salary. The VGTI relationship with the SOM provides the academic and clinical link between the ONPRC and the SOM and the MMI department serves as the academic base for the VGTI graduate program.

Faculty Recruitment
The VGTI was founded by Dr. Jay Nelson, a senior OHSU virologist who serves as the Institute’s director.  As the VGTI was a cooperative venture between the ONPRC and the SOM, Dr. Nelson’s recruitment of VTGI faculty was a joint effort between the immunology and virology faculty of the MMI department at OHSU and scientists at the ONPRC. One of the first VGTI faculty recruited was Dr. Louis Picker, an experienced immunologist, pathologist and AIDS investigator from UT Southwestern Medical Center in Dallas.  Dr. Picker was recruited as senior immunologist and co-director of the VGTI, as well as Chief of the ONPRC Pathobiology and Immunology Division. An additional six investigators were recruited to form the nucleus of VGTI’s investigative team, including Dr. Scott Wong, an NHP virologist from ONPRC, Dr. Michael Axthelm, a veterinary pathologist and NHP virologist from ONPRC, Dr. Ashlee Moses, a molecular virologist from OHSU, Dr. Janko Nikolich-Zugich, a cellular and molecular immunologist from Memorial Sloan-Kettering Cancer Center, Dr. Klaus Früh, a molecular immunologist and functional genomics expert from Johnson & Johnson Pharmaceuticals, and Dr. Mark Slifka, a viral immunologist from the Scripps Research Institute.  In addition to these primary VGTI faculty, two OHSU main campus-based affiliate investigators, Drs. David and Deborah Lewinsohn, were recruited into VGTI programs.  The individual interests and expertise of the founding VGTI investigators and affiliate investigators are described below, followed by the combination of this individual expertise into the original collaborative programs.

Jay Nelson, PhD (Director)
The long-term goal of Dr. Nelson’s laboratory is to understand the molecular basis of cellular interactions with persistent viruses that result in disease.  A major focus in the laboratory has been the identification of mechanisms involved in the pathogenesis of human and NHP cytomegaloviruses (CMV). CMV is a ubiquitous pathogen that is the major cause of morbidity and mortality in immunocompromised individuals, such as transplant and AIDS patients, and fetal infection is a leading cause of congenital birth defects as well. The virus has also been linked to vascular diseases such as atherosclerosis, transplant vascular stenosis (TVS) following solid organ transplant and restenosis following angioplasty. The topics that we are currently pursuing in the laboratory are as follows: 1) molecular mechanisms of CMV latency, persistence, and reactivation in macrophages and endothelial cells, 2) mechanisms of CMV-induced smooth muscle cell migration mediated by the viral chemokine receptor US28, 3) mechanisms of CMV-induced atherosclerosis and TVS in mouse and rat models, 4) mechanisms of CMV assembly and glycoprotein trafficking, 5) analysis of the CMV proteome, and 6) the use of recombinant CMV as a vaccine vector (this largely in the rhesus macaque model).Dr Nelson is also a scientific advisor for Virogenomics Inc. a genomics and drug discovery company based in Oregon.

Louis Picker, M.D. (Associate Director and ONPRC Division Head)
Dr. Picker’s laboratory is focused on four interrelated areas of T cell biology in human and nonhuman primates: 1) fundamental investigation into the physiology of T cell memory and effector responses, including the mechanisms controlling repertoire “selection” of the memory repertoire (e.g., response complexity and immunodominance), the development and consequences of functional heterogeneity (in cytokine synthesis, homing behavior, and activation threshold) among antigen-specific memory T cells, and the mechanisms responsible for memory T cell homeostasis and regeneration (including maintenance of effective T cell memory with aging), 2) determination of the immunologic basis of protective immunity against chronic viral pathogens (particularly HIV/SIV and CMV), 3) determinations of the mechanisms underlying the immunopathogencity of AIDS-causing lentiviruses, and 4) development of prophylactic and/or therapeutic vaccines and/or other immune based therapies for these pathogens.  His group has developed special expertise in the quantification and functional characterization of T cell populations in humans and nonhuman primates, particularly characterization of antigen-specific memory T cells and in vivo T cell dynamics, and exploits these technologies in the pursuit of these goals. Dr. Picker has collaborative/consultative relationships with several biotech companies, including Becton Dickinson Biosciences (Milpitas, CA), Corixa Corporation (Seattle, WA), Targeted Genetics (Seattle, WA), and Bioseek, Inc. (So. San Fransciso, CA).

Janko Nikolich-Zugich, MD, PhD (Senior Scientist)
The Nikolich laboratory is interested in the biology of cytotoxic T lymphocytes (CTL), specifically their antigen recognition, antiviral activity, homeostasis and senescence, and modulation of their function to achieve better vaccination. This group employs a combination of structural, molecular, transgenic, and functional approaches, with the emphasis on following and manipulating the CTL response in vivo.  The major projects are set up to understand the following topics: 1) CTL crossreactivity (ability to recognize multiple antigens) and positive selection (in mice; structure-function studies), 2) parameters of CTL efficacy in viral infection and vaccine development (in mice; in vivo infection, cell tracking and repertoire analysis), and 3) CTL dysregulation in immune senescence (in mice and NHP, with an increasing reliance on the latter model; homeostasis and cell population balance studies; repertoire maintenance; replicative senescence).  The above projects led to a coalescence of interests and approaches to improve vaccination outcomes in the elderly and other vulnerable populations; efforts are being expanded into the arena of flavivirus infection in young and old mice and NHPs (the West Nile virus and vaccination against it), and of poxvirus infection and vaccination in the same populations (vaccinia and monkeypox).

Klaus Frueh, PhD (Associate Scientist)
Dr. Frueh’s research aims at finding new strategies to intercept viral modulation of molecular pathways of the host. He is interested in mechanisms that allow herpesviruses and poxviruses to overcome innate and adaptive host responses as well as other aspects of host/pathogen relationships. As Director of the OHSU DNA microarray core facility, he also collaborates with Drs. Nelson and Moses to study transcriptional changes in virally infected cells with the aim to identify novel molecular targets required for viral disease progression. Viruses studied include HIV, KSHV, West Nile virus, Monkeypox, Hepatitis C virus, CMV, Japanese Encephalitis virus, and Yellow Fever virus.  In addition, Dr. Früh is working with Drs. Nikolich and Picker to use functional genomics to define cellular markers and mechanisms of immune senescence in the rhesus macaque aging model. His laboratory further houses the ONPRC proteomics facility which applies tandem-mass-spectrometry to high throughput protein identification. Dr. Frueh in member of the scientific advisory board of Znomics and Scientific Advisor of Virogenomics, both OHSU startup companies.

Michael Axthelm, DVM, PhD (Senior Scientist)
Dr. Axthelm’s research is focused on improving nonhuman primates (NHP) for use as models for human infectious diseases, improving NHP models for AIDS-related research, NHP virology and developing new NHP models for human viral diseases.  His laboratory is developing major histocompatibility complex-defined, specific pathogen free rhesus macaque breeding resources.  The overall goal is to enhance the rhesus macaque as a model for investigating viral pathobiology and immunobiology, and vaccine development relevant to human HIV infection and AIDS-related opportunistic infections.  Current research projects include 1) mapping HIV envelope determinants of pathogenicity (as determined by the ability to deplete CD4+ T lymphocytes and virus resistance to neutralization in the highly pathogenic simian-human immunodeficieny virus chimera, SHIV 89.6P), 2) investigation of the role of T cell dynamics in SIV infection, and delineation of viral mechanisms of pathogenesis targeting these dynamics, 3) development of RhCMV-vectored vaccines for SIV, 4) identification and characterization of new viral agents and viral-associated disease states in NHP, which currently include spontaneous multiple sclerosis-like demyelinating encephalomyelitis associated with a novel gammma-2 herpesvirus, and progressive multifocal leukoencephalopathy in immunosuppressed macaques associated with variant simian virus 40 polyomavirus.  Dr. Axthelm collaborates extensively with Division scientists (Drs. Picker, Lewinsohn, Nikolich and Wong) and outside scientists (Drs. Letvin, Sodroski, Koralnik, and Hirsch) in pursuit of these interests and supports virtually all of the Division’s scientific programs in his AIDS-related research animal support and virology core roles (see below).

Scott Wong, PhD (Associate Scientist)
The long-term goal of Dr. Wong’s laboratory is to understand how viruses cause disease, using viral infection of NHP as models for the analogous human disease.  His laboratory focuses on understanding how two simian herpesviruses, rhesus cytomegalovirus (RhCMV) and rhesus rhadinovirus (RRV), and an orthopoxvirus, monkeypox virus, cause disease in immunocompromised and immunocompetent rhesus macaques, respectively.  Utilizing molecular, genetic and virological techniques, his group examines how these viruses infect and replicate in cell culture, and how they cause illnesses in animals. He has shown that inoculation of immunocompromised monkeys with RhCMV and RRV results in disease symptoms that closely resemble those observed in humans infected with the human immunodeficiency virus (HIV). Utilizing this two-pronged approach, we are identifying the viral determinants that contribute to disease. The information that is generated from this research will be essential in the development of new vaccine strategies for preventing virus infection.  Dr. Wong’s group also plays a key role in the RhCMV vector program, focusing on determining potential mechanisms of vector pathogenicity and vector modification strategies that would abrogate this disease-causing potential without sacrificing vector immunogenicity.

Ashlee Moses, PhD (Assistant Scientist)
Dr. Moses is interested in HIV virology and pathogenesis, with a focus in two main areas: 1) AIDS-related cancer, and 2) brain and bone marrow dysfunction in HIV infection.  With regard to AIDS-related cancer, her group focuses on the role of the herpesvirus KSHV/HHV8 in mediating Kaposi’s sarcoma (KS) and on the pathogenesis of AIDS-related non-Hodgkin’s lymphoma (AIDS-NHL).  Her laboratory has used gene profiling to identify tumorigenic cellular genes induced by KSHV, and is interested in developing therapeutic strategies to interfere with this process.  In collaboration with Dr. Wong, Dr. Moses has extended this research to the rhesus macaque homologue of KSHV (RRV) with the goal of developing an NHP model to test therapeutic strategies.  In addition, Dr. Moses is investigating the role HIV endothelial cell infection plays in promoting the growth of AIDS-NHL. With regard to her brain and bone marrow studies, Dr. Moses is using in vitro models and the SIV-rhesus macaque animal model to study HIV/SIV infection of these tissue compartments and their function as viral reservoirs.  In collaboration with Drs Nelson and Früh, Dr Moses has recently extended her gene profiling studies to identify HIV-modulated cellular genes that may represent novel antiviral targets. Dr. Moses’ group also contributes to the projects studying RhCMV vectors and orthopoxvirus pathogenesis. In addition to collaborations with VGTI, ONPRC and MMI scientists, Dr Moses has established research partnerships with the Oregon Cancer Center, the Department of Dermatology and the Casey Eye Institute, and a corporate alliance with Virogenomics Inc. a Tigard-based genomics and drug discovery company.

Mark Slifka, PhD (Assistant Scientist)
Dr. Slifka’s laboratory has one main focus: understanding the fundamental mechanisms of immunological memory.  To do this, his group examines both T cell-mediated immunity and antibody-mediated immunity following acute viral infections.  These studies include animal models of arenavirus and poxvirus infections as well as clinical studies examining antiviral immunity following smallpox vaccination (with the vaccinia virus), monkeypox infection (from the monkeypox outbreak in Wisconsin in 2003), or after infection with smallpox itself (with >20 individuals who survived childhood smallpox infections currently on study).  Dr. Slifka’s laboratory is also part of a multi-center site that was recently awarded a 5-year NIAID contract entitled, “Atopic Dermatitis and Vaccinia Network (ADVN)” to study vaccinia and Yellow Fever Virus immunity in human volunteers.

Deborah Lewinsohn, MD (Affiliate Assistant Scientist)
Dr. Lewinsohn is a pediatric infectious disease specialist whose overall goal is the development of vaccines to protect infants and children from persistent pathogens, particularly HIV and Mycobacterium tuberculosis.  Her laboratory works on both characterization of the immune responses to these pathogens in human pediatric subjects, and on developing infant/juvenile NHP models of these infections.  Her group is currently comparing the immunogenicity and efficacy of an SIV vaccine candidate in infant versus juvenile rhesus macaques.  The overall goal of this work is to identify vaccine strategies that will induce durable T and B cell immunity in and provide protection for infants.  Her laboratory is also using the rhesus macaque model to explore differences in the immature vs. mature immune system with regard to dendritic cell (antigen presenting cell) biology with the goal of recognizing and understanding functional differences relevant to vaccine efficacy.

Established Scientific Programs:

1. AIDS Pathogenesis and Vaccine Development (L. Picker, J. Nelson, S. Wong, M. Axthelm, K. Früh, A. Moses, J. Nikolich-Zugich)
The AIDS epidemic represents one of medicine’s most pressing challenges, and in keeping with this, the development of an effective prophylactic HIV-1 vaccine and/or other immune-based therapies for HIV-1 infected individuals was made a primary focus of the VGTI’s research effort, involving nearly all faculty and representing the dominant focus of the Picker, Wong, Axthelm, and Moses laboratories.  This effort can be divided into three categories: 1) immunopathogenesis of SIV/HIV infection and development of immune- or gene-based therapies, 2) biology and treatment of opportunistic infections and AIDS-related malignancies, and 3) SIV/HIV vaccine development. 

2. Prevention and Treatment of Diseases Mediated by Herpes Family Viruses (J. Nelson, L. Picker, S. Wong, K Früh, A. Moses, M. Axthelm)
Herpes family viruses are ubiquitous and uniquely adapted viral “parasites” that account for or are suspected to contribute to a wide variety of human diseases, including aggressive destructive, local or systemic infections in immunocompromised or immunologically immature hosts, recurrent infections of normal hosts, malignancies, and chronic vascular and immunologic diseases.   VGTI investigators have long experience and considerable expertise in this area, particularly for cytomegalovirus and rhadinovirus groups.  Indeed, the combined expertise in both the virologic and immunologic aspects of these viruses are unique in U.S. medical schools.   VGTI research in this area focuses on mechanisms of Herpes family virus pathogenesis and immune evasion, immunobiology of Herpes family virus infections and exploitation of their unique immunogenicity for rationale vaccine development, and development of novel therapeutics for Herpes family virus-mediated diseases.

3. Infection and Immunity of Aged and Other Vulnerable Populations  (J. Nikolich- Zugich, L. Picker, M. Slifka, D. Lewinsohn, K. Früh)
Populations especially vulnerable to infection, including emerging infections and the agents of bioterrorism, encompass up to one-third of the U.S. population, and include the elderly, the immunosuppressed (those with congenital, acquired and iatrogenic immune deficiencies), and individuals under stress.  These individuals face two problems: increased morbidity and mortality in the face of numerous infectious pathogens, and poor responsiveness to many vaccines that effectively protect the immunocompetent population. The aim of this program, led by Dr. Nikolich-Zugich, is to exploit the NHP model to gain insight into the underlying immune deficiencies that face vulnerable populations, and to devise new vaccine and treatment approaches to protect these populations from infectious disease.

4. Systems Biology Approaches to Pathogen Therapeutic Target Discovery (K. Früh, J. Nelson, A. Moses, S. Wong)
Functional genomics and systems biology takes advantage of the completed human genome sequence by allowing the high throughput identification of proteomic and transcriptomics alterations. A major goal of the VGTI is to combine novel techniques such as DNA–microarrays or tandem mass-spectrometry with gene knockdown technology to identify novel therapies for infectious diseases and cancer. Examples are HIV, SIV, CMV, KSHV, RRV, and flaviviruses. Using this approach to target discovery, Drs Früh, Nelson and Moses implicated the KSHV-induced cellular gene c-Kit in the pathogenesis of Kaposi’s sarcoma. The Kit-inhibitor Gleevec is showing promise in pilot clinical trials as a KS therapeutic. Extending this approach to RRV by Dr. Wong allows exploitation of the NHP model. Drs. Nikolich-Zugich, Dr. Picker and Dr. Lewinsohn use DNA microarrays to develop a better understanding of the aging processes in the NHP immune system with the ultimate goal to optimize vaccination strategies for the elderly.

5. Prevention and Treatment of Diseases Mediated by Bioterrorism and Emerging Pathogens (J. Nelson, M. Slifka, S. Wong, K. Früh, J. Nikolich-Zugich, M. Axthelm)
The increasing threat of bioterrorism and the increasing realization of the dangers posed by emerging infectious diseases (e.g., West Nile virus infection; Severe Acute Respiratory Syndrome/SARS), have placed a national priority on understanding the diseases caused by these agents, and the development of vaccines by which vulnerable populations can be protected.  The VGTI faculty’s expertise in virology, immunology, pathology and NHP models are tailor-made for responding to this priority.  Indeed, we are currently extending our individual programs to include this area of investigation.  Targeted areas include Orthopoxviruses (Slifka, Wong, Früh), the SARS Coronavirus (Nelson, Wong), Arenaviruses (Slifka), Yellow Fever Virus (Slifka), West Nile Virus (Nelson, Nikolich-Zugich), and Francisella tularensis  (Axthelm). 

6.  NHP Model Development  (L. Picker, S. Wong, M. Axthelm, J. Nikolich-Zugich)
Effective use of NHP models for vaccine or pathogenesis research requires fundamental understanding of the “operational details” of the NHP immune system and state-of-the-art approaches and assays to evaluate various aspects of the immune response. Such expertise has been lacking in NHP models, and VGTI investigators, including Drs. Picker, Nikolich-Zugich, Axthelm, and Slifka, have committed to the development of the immunologic tools – reagents, protocols and physiologic information – necessary to support state-of-the-art NHP immunologic research.  An equally important VGTI goal is the expansion of NHP virology pathogenesis models, particularly viruses that emerge in the setting of SIV-induced immunodeficiency and contribute to the morbidity and mortality of simian AIDS.  Drs. Wong, Axthelm and Nikolich-Zugich have been the primary VGTI participants in this program, elucidating to date seven such NHP viral infections (including rhesus cytomegalovirus, rhesus rhadinovirus, Japanese macaque rhadinovirus, macaque lymphocryptovirus, a novel SIV recovered from Cercopithecus lhoesti, a variant of the polyomavirus SV-40 and simian varicella virus).  This work, both immunologic and virologic, is an important component of the VGTI faculty’s contribution to the ONPRC, and proves critical support for the faculty’s disease/vaccine/therapy-focused programs.