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Pacific NorthWest Regional Center of Excellence - Developmental Research Plan
NIH/NIAID
The goal of the PNWRCE is to develop novel vaccines and therapies against NIAID Category A-C pathogens using systems biology approaches and models that identify age-related immune system defects. The PNWRCE will solicit, identify and fund Developmental Research Projects that complement these themes.

Jay Nelson, PI
Pacific Northwest Regional Center of Excellence in Biodefense and Emerging Infectious Diseases NIH/NIAID
The first goal of the PNWRCE is to identify age-related immune system defects to develop new vaccines and supplemental therapies to enhance protection of individuals to NIAID Category A-C pathogens. A second goal of this center is to use systems genetic, chemical, and proteomics approaches to identify therapeutic targets for biodefense and emerging diseases.

Jay Nelson, PI

Molecular Aspects of Cytomegalovirus Latency NIH/NIAID
The long-term goal of this project is to develop an understanding of the cellular and molecular mechanisms involved in HCMV latency and reactivation, and, specifically, to identify the viral genes responsible for these viral phenotypes and to characterize the mechanisms and products encoded by these genes that promote growth in MDM and EC.

Jay Nelson, Co-PI

Mechanisms of immune vulnerability of the elderly to the West Nile virus NIH/NIAID
To use a succession of rodent, primate and human models to elucidate critical age-related defects in innate and adaptive responses to WNV.

Jay Nelson, PI

33rd International Herpesvirus Workshop NIH/NCI
The proposal is for travel funds for students and postdoctoral Fellows to attend and give presentations at the 33rd International Herpesvirus Workshop.

Jay Nelson, PI


The Role of the Cytomegalovirus Secretome in the Acceleration of Transplant Vascular Sclerosis NIH/NHLBI
In this project we propose the use of viral genetics to unravel the wound healing and angiogenesis mechanisms involved in CMV acceleration of TVS and CR.

Louis Picker, PI

Immune Correlates of Protection against HIV and SIV Infection Subcontract from Fred Hutchinson Cancer Research Center thru Bill and Melinda Gates Foundation and from the International AIDS Vaccine Initiative
Dr. Picker’s role in this project in to characterize the adaptive immune, innate immune, genetic and/or virologic parameters associated with the protection against pathogenic SIV provided by live attenuated SIV vaccines.

Louis Picker, Co-PI

Harnessing Innate Immunity to Enhance the Immunogenicity of T-Cell Inducing HIV Vaccines
Subcontract from Fred Hutchinson Cancer Research Center thru Bill and Melinda Gates Foundation (Global HIV/AIDS Vaccine Enterprise-Vaccine Discovery)
Dr. Picker’s role in this project is to test the ability of selected adjuvants (primarily toll-like receptor agonists) and microbial vectors, alone or in combination, to activate the innate immune system and generate cellular immune responses in the rhesus macaque.

Louis Picker, PI

IAVI HIV T Cell Vaccine Research & Development Program Subcontract from International AIDS Vaccine Zamb
Initiative thru Bill and Melinda Gates Foundation (Global HIV/AIDS Vaccine Enterprise-Vaccine Discovery)
Dr. Picker’s role in this large multi-center project is to compare the ability of SIV vaccine approaches using different viral vectors (focused on adeno-associated virus vectors) to provide immunologic protection against pathogenic SIV challenge in rhesus macaques and to provide flow cytometry expertise to the overall program.

Louis Picker, PI

IAVI GF Consortium - CMV Vector Design & Development
International AIDS Vaccine Initiative 

The major goal of this project is to develop gene-modified CMV vectors with enhanced efficacy and safety compared to wildtype and to compare optimized CMV vectors to other vaccine approaches in protection of rhesus macaques from pathogenic SIV challenge.

Louis Picker, PI

Role of memory T cell dynamics in SIV infection NIH/NIAID
The major goal of this project is to study the relationship between memory T cell turnover, immunity and disease progression in the SIV rhesus macaque model of AIDS.

Louis Picker, PI

Development of RhCMV vectors for SIV infection NIH/NIAID
The major goal of this project is to develop and assess RhCMV as a vaccine vector for SIV infection, and to investigate the hypothesis that a persistent vector engenders superior anti-SIV immunity than current strategies using disabled or acute vectors.

Louis Picker, Project Director
Vaccination and Immune Senescence in Primates NIH/NIA 

Dr. Picker's project within this PPG (#4) is entitled "Immune senescence and CMV immunity in primates" and examines the effect of aging on the rhesus macaque T cell response to the persistent herpesvirus RhCMV, and conversely the contribution of RhCMV immunity to global immune senescence.

Louis Picker, Co-PI

Evasion of antigen presentation by Rhesus Cytomegalovirus (RhCMV) NIH/NIAID
The major goal of this grant is to assess the role of viral encoded class I modulatory genes in the immunobiology of RhCMV infection.
Louis Picker, Senior Scientist and Head, Division of Pathobiology

Support for the operation of the Oregon National Primate Research Center
NIH/NCRR
Salary support only

Klaus Früh, PI

Immune Evasion by Gamma 2 Herpesviruses.
To understand the molecular mechanisms by which gamma 2 herpesviruses, particularly Kaposi’s sarcoma associated herpesviruses (KSHV), interfere with MHC class I antigen presentation and the implication of these mechanisms for viral pathology.

Klaus Früh, PI
Modulation of Innate Immune Responses by Cytomegalovirus. NIH/NIAID
The goal of this study is to identify how HCMV activates the interferon-response and how RhCMV inhibits this activation.

Klaus Früh, PI

Evasion of antigen presentation by Rhesus Cytomegalovirus. NIH/NIAID
The goal of this study is to identify and characterize RhCMV genes preventing MHC I antigen presentation and to examine the importance of these genes in vivo using a Rhesus Macaque model.

Klaus Früh, PI 

Mechanisms of T cell escape by Orthopoxviruses. NIH/NIAID
The goal of this project is to identify the mechanisms and viral genes that prevent T cell recognition of monkeypoxvirus- and cowpoxvirus-infected antigen presenting cells.

Klaus Früh, Interim-PI


Mechanism of immune vulnerability in the elderly to West Nile Virus. NIAID
To study age-related changes in the innate immune response to West Nile Virus

Klaus Früh, PI
Project 4.2
Pacific Northwest Regional Center of Excellence – Project 4.2: Kinase Networks Controlling Flavivirus Replication. 
NIAID
To use a high-throughput chemogenomics approach to identify and characterize kinase networks regulating flavivirus replication and innate immune responses to flaviviruses.

Michael Axthelm, PI 

Establishment of Specific Pathogen Free Rhesus Macaque Colonies NIH/NCRR
The major goal of this project is to expand and characterize a rhesus macaque breeding colony for production of genetically defined SPF rhesus macaques for AIDS-related research.

Michael Axthelm, PI


Establishment of Specific Pathogen Free Rhesus and Pigtail Macaque Colonies NIH/NCRR
The major goal of this project is to develop an expanded definition Indian specific pathogen free (SPF) rhesus macaque breeding colony to support research focused on AIDS-related opportunistic infections.

Michael Axthelm, Subproject PI

Thoracic Duct Drainage – A Model for the Study of Target Cell and Effector Cell Pools in Experimental SIV Infection NIH/NCRR
The goals of this project are to use T cell depletion and re-infusion to determine the effect of target cell pool size on the magnitude of initial SIV burst and on virus set point, and the phenotype, antigen specificity, turnover rates and trafficking patterns of lymphocyte subpopulations during primary SIV infection and after control of viremia with anti retroviral drug therapy.

Michael Axthelm, PI of Core B (Nonhuman Primate Core)


Vaccination and immune senescence in primates: Core B – Animal Core NIH/NIA
The goal of this project is to provide research support and veterinary services for nonhuman primates enrolled in this Program Project Grant

Michael Axthelm, Co-PI


Rhesus HHV-8 Homologue in AIDS-related Malignancies NIH/NCI
The major goals of this project are to 1) evaluate the role of immunosuppression in RRV strain 17577-associated disease; 2) develop techniques to genetically manipulate the RRV genome; and 3) identify viral determinants of pathogenesis.

Michael Axthelm, Co-PI


Role of Memory T cell Dynamics in SIV Infection: NIH NIAID
The major goal of this project is to characterize the nature and regulation of T cell turnover in various stages of SIV infection and to ascertain the impact of this regulation on viral dynamics and disease progression.

Michael Axthelm, Co-PI


CMV Vector Design and Development.
International AIDS Vaccine Initiative
The major goals are in vivo assessment of the immunogenicity, pathobiology and protective efficacy of “wild type” RhCMV vectors, with or without adenovirus (Ad) 5 boosting, and attenuated (gene-modified RhCMV vectors with or without AAV priming.

Michael Axthelm, Co-PI

Harnessing Innate Immunity to Enhance the Immunogenicity of T-cell Inducing HIV Vaccines
Bill and Melinda Gates Foundation thru Fred Hutchinson Cancer Research Center (McElrath)
The goal of this project is to test the ability of selected adjuvants (primarily toll-like receptor agonists), alone or in combination, to generate cellular immune responses in the rhesus macaque.

Michael Axthelm, Co-PI
Cell Vaccine Research and Development Consortium: Immune correlates of protection against HIV and SIV infection
Bill and Melinda Gates Foundation thru International AIDS
The major goals are in vivo assessment of the immunogenicity, pathobiology and protective efficacy of live attenuated SIV and SHIV vaccines with a focus on identifying immune correlates of protection.

Michael Axthelm, Co-PI 


Live Attenuated Vaccine Immune Correlates International AIDS Vaccine Initiative
This study increases the number of live attenuated vaccines under study in the Cell Vaccine Research and Development Consortium funded by the Bill and Melinda Gates Foundation. The major goals are in vivo assessment of the immunogenicity, pathobiology and protective efficacy of a live attenuated SIV vaccine (SIVmac239Δnef) with a focus on identifying immune correlates of protection.

Michael Axthelm, Co-PI 

Anti-viral IL6 approach to mitigate KSHV-related disease NIH/NCI
The major goal of this study aim is to evaluate the role of the rhesus rhadinovirus vIL-6 homologue in viral-mediated B cell hyperplasia in the context of an SIV infection.

Michael Axthelm, Co-PI and Subcontract PI
Oral Mucosal Vaccination against HIV Infection. NIH/NCI
The major goal of this subcontract is to evaluate the innate, adaptive cellular and humoral immune responses to SIV elicited by a DNA prime/replication-incompetent Ad5 vaccine given to rhesus macaques at two oral mucosal sites.

Michael Axthelm, PI of Nonhuman Primate Core Subproject 

Pacific NorthWest Regional Center of Excellence:
Core B – Nonhuman Primate Core NIH/NIA
The first goal of the PNWRCE is to identify age-related immune system defects to develop new vaccines and supplemental therapies to enhance protection of individuals to NIAID Category A-C pathogens. A second goal of this center is to use systems genetic, chemical, and proteomics approaches to identify therapeutic targets for biodefense and emerging diseases.

Scott Wong, PI

Rhesus HHV-8 homologue in AIDS-related malignancies NIH
The major goals of this study are to identify viral determinants that contribute with the development of RRV-associated disease in the SIV-infected rhesus macaque.

Scott Wong, PI
Subcontract
Biodefense Proteomics Research Programs: Identifying Targets for Therapeutic Interventions using Proteomic Technology NIH
The major goals of this study are to utilize proteomic techniques to identify novel monkeypox virus targets.

Scott Wong, Co-PI

Mechanisms of immune vulnerability of the elderly to the West Nile virus NIH
To use a succession of rodent, primate and human models to elucidate critical age-related defects in innate and adaptive responses to WNV.

Scott Wong, PI

Anti-viral IL-6 approach to mitigate KSHV-related disease NIH
The major goals of this study are to evaluate whether vaccination with a novel vIL-6/Fc fusion protein is capable of inducing host responses that can mitigate RRV-associated disease.
Scott Wong, Scientist
Support for the Oregon National Primate Research Center (ONPRC)
NIH/NCRR

Victor DeFilippis, PI

Evasion of Innate Immunity by Cytomegalovirus
American Heart Association

Daniel Streblow, PI

Mechanisms of CMV Latency in Accelerated Vascular Disease NIH: National Heart, Lung and Blood Institute
The goal of this project is to determine the viral latency mechanisms involved in rat cytomegalovirus (RCMV)-accelerated transplant vascular sclerosis (TVS), which is the hallmark vascular disease associated with chronic rejection of solid organ grafts.

Daniel Streblow, Co-PI

Chemokine Receptors in Vascular Disease NIH: National Heart, Lung and Blood Institute
The long-term goal of this project is to determine the role of viral pathogens in the development of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). One part of this project will examine mechanisms of US28 signaling that mediate smooth muscle cell migration. Another part of this project will identify cellular chemokines that mediate acceleraton of TVS.

Daniel Streblow, Co-PI 

The Role of CMV Secretome in the Acceleration of Transplant Vascular Sclerosis
NIH: National Heart, Lung and Blood Institute
The long-term goal of this project is to determine the role of human cytomegalovirus (HCMV) in the acceleration of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). HCMV is associated with TVS and CR in solid organ transplant patients and we have observed that RCMV significantly accelerates the development of TVS and CR in heart allografts in the rat transplant model. In this project we propose the use of viral genetics to unravel the WH and AG mechanisms involved in CMV acceleration of TVS and CR. The anticipation is that multiple HCMV genes are responsible for the induction of WH and AG and that we will be able to separate some of these processes to examine the effect of mutation of correlate RCMV genes in the acceleration of TVS.

Daniel Streblow, Co-PI

Cytomegalovirus Chemokine Receptors in Transplant Vascular Sclerosis
NIH: National Heart, Lung and Blood Institute
The long-term goal of this project is to determine the role of viral pathogens in the development of vascular diseases such as atherosclerosis, restenosis, and transplant vascular sclerosis (TVS). All of these diseases are the result of either mechanical or immune-mediated injury followed by inflammation and subsequent smooth muscle cell (SMC) proliferation and migration from the vessel media to the intima, which culminates in vessel narrowing. This proposal will continue our examination of the viral chemokine receptor (R33) during the development of disease.