Vaccination trials were conducted in outbred Saanen goats using recombinant vaccinia or plasmid DNA vectors expressing the caprine arthritis-encephalitis virus (CAEV) env gene or plasmid DNA expressing CAEV env and tat. Intradermal vaccination with plasmid DNA induced biased type 1 immune responses to vector encoded surface envelope (SU), whereas vaccinia induced type 2 responses. Subcutaneous boost with purified SU in Freund's incomplete adjuvant specifically expanded type 1 or type 2 memory established by initial immunizations with plasmid DNA or vaccinia. These goats together with sham vaccinated and non-vaccinated control goats were challenged intravenously with a molecular clone of tissue culture amplified CAEV. Preliminary results through 24 weeks postchallenge indicate that virus replication is restricted by type 1 immunity induced by plasmid DNA but not by type 2 responses induced by vaccinia. These data provide a basis to determine the role of qualitatively distinct immune responses to lentiviral SU in control of virus replication and disease progression. Therefore, the first objective of this proposal is to test the hypothesis that type 1 immunity induced by plasmid DNA restricts virus replication and prevents development of arthritis following CAEV challenge, whereas type 2 immunity induced by recombinant vaccinia fails to control virus replication and promotes development of arthritis. Proposed experimants expand the preliminary studies to a larger number of animals required for significant evaluation of virus load and disease progression. In addition, the challenge inoculum will be wild type virus derived from field cases of CAE arthritis. Additional goats were co- immunized with plasmid DNA expressing CAEV env with or without tat together with a second plasmid DNA encoding caprine interferon gamma (IFN). These studies provide preliminary evidence that synergistic effects of plasmid encoded Tat and IFN inhibit primary adaptive B cell responses to plasmid encoded SU without effect on activation of SU responsive Th1 lymphocytes. Significant control of CAEV replication by goats with this vaccine induced immunologic profile will support further studies on the role of Tat and IFN as vaccine components. Therefore, the second objective of this proposal is to evaluate virus replication following CAEV challenge of goats co-immunized with plasmid DNA expressing CAEV env and tat genes and caprine IFN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043718-07
Application #
6779043
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Serrate-Sztein, Susana
Project Start
1995-09-30
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
7
Fiscal Year
2004
Total Cost
$137,750
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Murphy, Brian; Jasmer, Douglas P; White, Stephen N et al. (2007) Localization of a TNF-activated transcription site and interactions with the gamma activated site within the CAEV U3 70 base pair repeat. Virology 364:196-207
Murphy, Brian G; Hotzel, Isidro; Jasmer, Douglas P et al. (2006) TNFalpha and GM-CSF-induced activation of the CAEV promoter is independent of AP-1. Virology 352:188-99
Hotzel, Isidro; Cheevers, William P (2005) Mutations increasing exposure of a receptor binding site epitope in the soluble and oligomeric forms of the caprine arthritis-encephalitis lentivirus envelope glycoprotein. Virology 339:261-72
Trujillo, Jessie D; Hotzel, Kathy J; Snekvik, Kevin R et al. (2004) Antibody response to the surface envelope of caprine arthritis-encephalitis lentivirus: disease status is predicted by SU antibody isotype. Virology 325:129-36
Trujillo, J D; Kumpula-McWhirter, N M; Hotzel, K J et al. (2004) Glycosylation of immunodominant linear epitopes in the carboxy-terminal region of the caprine arthritis-encephalitis virus surface envelope enhances vaccine-induced type-specific and cross-reactive neutralizing antibody responses. J Virol 78:9190-202
Hotzel, Isidro; Cheevers, William P (2003) Caprine arthritis-encephalitis virus envelope surface glycoprotein regions interacting with the transmembrane glycoprotein: structural and functional parallels with human immunodeficiency virus type 1 gp120. J Virol 77:11578-87
Cheevers, W P; Snekvik, K R; Trujillo, J D et al. (2003) Prime-boost vaccination with plasmid DNA encoding caprine-arthritis encephalitis lentivirus env and viral SU suppresses challenge virus and development of arthritis. Virology 306:116-25
Hotzel, Isidro; Cheevers, William P (2002) A maedi-visna virus strain K1514 receptor gene is located in sheep chromosome 3p and the syntenic region of human chromosome 2. J Gen Virol 83:1759-64
Hotzel, Isidro; Cheevers, William (2002) Differential receptor usage of small ruminant lentiviruses in ovine and caprine cells: host range but not cytopathic phenotype is determined by receptor usage. Virology 301:21-31
Hotzel, I; Cheevers, W P (2001) Host range of small-ruminant lentivirus cytopathic variants determined with a selectable caprine arthritis- encephalitis virus pseudotype system. J Virol 75:7384-91

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