application): The goal of the candidate, Sean P. Troth, DVM, is to complete a mentored training program in retrovirus pathogenesis research. This training will culminate in both the Ph.D. degree and the opportunity for continued postdoctoral study. Dr. Troth's long term goal is to become a principal investigator employing animal models to investigate the pathogenesis of viral diseases of animal and human health importance. The research training program will be centered in the retrovirus research laboratory at Colorado State University, under the guidance of the sponsor Dr. Edward A. Hoover. The environment has a substantial record of extramural funding and trained post-DVM scientists. The candidate's training plan involves laboratory and didactic training in contemporary cellular and molecular research methods applied to an animal model of AIDS. The research proposed examines the distribution of the CXCR4 (X4) receptor and its role in infection by feline immunodeficlency virus (FIV). The four specific aims are: (1) to map the distribution of feline X4 in tissues and tissue cell phenotypes in cats; (2) to determine whether the feline X4 receptor mediates infection of natural feline cell populations by clinical FIV isolates; (3) to assess whether FIV infection of natural cell populations can be inhibited in vitro by the X4-specific bicyclam drug AMD 3100; (4) to determine whether FIV infection can be prevented or down-modulated in vivo by the bicyclam drug.
In aim 1, the investigator will study lymphoid, hemic, and mucosal cell populations using immunohistochemistry employing monoclonal antibodies cross-reactive with the human and feline X4 molecules and in situ hybridization using a riboprobe prepared to the cloned feline X4 sequence.
In aim 2, the investigators will infect cats with clinical FIV isolates and analyze lymphoid and mucosal cells and tissues by immunohistochemistry and flow cytometry using dual labeling cells for X4, phenotype, and viral proteins.
In aim 3, major cell phenotypes will be isolated from lymphoid and oral mucosal tissues of naive cats and inoculated in vitro with and-without the presence of AMD 3100 followed by assessment of virus replication by several methods. In the final aim, cohorts of cats will be treated with AMD 3100 at different times during or after mucosal exposure to FIV and monitored for inhibition of infection by several parameters. The results of these studies will provide information pertinent to lentivirus receptor usage and potential receptor-based prophylaxis and/or therapy of lentivirus infections.
| Troth, Sean P; Dean, Alan D; Hoover, Edward A (2008) In vivo CXCR4 expression, lymphoid cell phenotype, and feline immunodeficiency virus infection. Vet Immunol Immunopathol 123:97-105 |
