1. Research Proposal: The proposed research will utilize plasmid expression vectors to initiate a Type 2 immune response to lentiviral envelope proteins and determine if the induced Type 2 immune response leads to the development of clinical disease following homologous virus challenge. The long-term objective of this research is to identify critical lymphocyte-mediated immune effector mechanisms that allow lentiviral replication and initiation of clinical disease in outbred species. The lentiviral system to be studied is caprine arthritis encephalitis virus (CAEV) in goats. Goats become persistently infected with CAEV and either remain asymptomatic or progress to clinical disease characterized by arthritis. Symptomatic goats have intralesional memory and immunoglobulin producing B-lymphocytes, increased serum and synovial fluid titers of polyclonal IgG1 and CAEV SU reactive antibodies, and increased CAEV SU responsive Th2 lymphocytes compared to asymptomatic goats. These findings suggest that clinical disease in CAEV infected goals may be determined by a dominant viral specific type 2 immune response. The proposed specific aims permit investigation of the role of Type 2 cytokines, specifically IL-4, in the initial segregation of the immune response to a Type 2 profile and the progression of disease from lentiviral infections.
In specific aim 1, immunization with a mammalian expression vector that encodes CAEV SU in conjunction with a second expression vector encoding IL-4 will be used to stimulate antigen specific T helper lymphocytes and initiate a Type 2 immune response. Documented studies in mice have shown that intramuscular injection of expression vectors that encode IL-4 stimulate the development of Type 2 immune responses to co-immunized viral antigens.
In specific aim 2, the immunized goats will be infected with CAEV and disease progression evaluated. Anticipated results will demonstrate the use of recombinant cytokines to focus antigen specific T helper lymphocytes pathways in outbred species and provide an opportunity to directly examine the role of Type 2 responses in a persistent lentivirus infection. 2. Candidate: The candidate is a veterinarian completing a residency in comparative pathology and is a Ph.D candidate. In preparation for research, the candidate has completed graduate courses in biochemistry, molecular biology, mechanism of disease, and immunopathology. This proposal constitutes his doctoral research and will provide an excellent basis for future independent research in lentivirus infections.
| Morasco, B Joan; Sharma, Nidhi; Parilla, Jessica et al. (2003) Poliovirus cre(2C)-dependent synthesis of VPgpUpU is required for positive- but not negative-strand RNA synthesis. J Virol 77:5136-44 |
| Snekvik, K R; Beyer, J C; Bertoni, G et al. (2001) Characterization of caprine interleukin-4. Vet Immunol Immunopathol 78:219-29 |
