Abstract

This proposal tests the hypothesis that a focused cell mediated immune response to immunization with a purified lentiviral surface (SU) glycoprotein will control virus replication and disease following challenge infection with homologous and heterologous virus. The research plan is to focus antigen specific T helper (Th) 1 lymphocyte responses by enhancing in vivo production of gamma interferon (IFN gamma) at the time of immunization. A vaccinia virus vector and plasmid DNA expressing IFN gamma cDNA will be evaluated to enhance IFN gamma production in vivo. This plan is based on well documented studies in mice demonstrating that crossregulatory cytokines specify the differentiation of Th1 and Th2 lymphocyte subsets from a common precursor at the time of antigen presentation, overriding the effects of other variables such as antigen dosage and MHC class II genotype. The lentiviral system to be studied is caprine arthritis-encephalitis virus (CAEV) in Saanen goats. The utility of the CAEV model for evaluating the role of Th1 responses to SU in immune control of lentivirus replication and disease is enhanced by preliminary data supporting the following: (1) CAEV infected goats have at least two populations of SU responsive CD4+ T lymphocytes with dichotomous antigen specific proliferative responses and patterns of IFNgamma gene expression analogous to Th1 and Th2 cells. (2) Dominance of CAEV SU responsive Th1 cells is specifically associated with restricted virus load and lack of disease progression. (3) The extent of CAEV replication and disease may be determined by differential activation of SU responsive Th1 or Th2 lymphocyte subsets at or near the time of infection. Thus, the anticipated results of this research will demonstrate the feasibility of using recombinant cytokines to focus antigen specific Th lymphocyte pathways in outbred species and provide an opportunity to directly examine the role of Th1 responses in immune control of a persistent lentivirus infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043718-03
Application #
2517499
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1995-09-30
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1999-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164

  Publications

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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