The overall goal of this investigation is to develop an animal model of the neurologic abnormalities associated with HIV infection using molecularly-clones (MC) strains of feline neurotropic retroviruses. A feline model of experimentally-reproducible, retrovirus-induced neurological disease will facilitate studies in three areas; determination of the precise cellular and electrophysiologic abnormalities directly attributable to retrovirus infection; identification of the viral genetic basis for retroviral infection of the central nervous system; and, most importantly, will allow the design and testing of therapies to counter the challenge of infections within the nervous system.
Specific aims for this five year project are: first, to characterize the neurological deficits and lesions in cats experimentally inoculated with neurotropic strains of feline leukemia virus (FeLV), and to determine the cellular tropism of these FeLVs in cell culture; second, to clone neurotropic FeLV-1390, identify the molecular differences between it and the minimally pathogenic strain of retrovirus (MC-FeLV-3281) from which it arose, and then to evaluate the pathogenicity of MC-FeLV-1390; third, to use the techniques refined in the FeLV studies to identify, isolate and molecularly characterize neurotropic strains of the recently discovered feline lentivirus (FIV), followed by characterization of the pathogenicity of MC-FIVs. This model system will allow the evaluation of anti-HIV therapies. The pathogenicity of neurotropic FeLVs will be evaluated in vitro in feline spinal cord, dorsal root ganglion, and schwann cell cultures and in vivo in specific pathogen free (SPF) cats. In vitro studies will be designed to identify neurotropic strains of feline retroviruses and to determine in which cell types they replicate and are cytopathic. Initial studies will focus on further characterization of strain FeLV-1390 that we recently isolated from a neurologically abnormal cat. Evaluation of infected cats will include prospective studies of electrophysiology (sequential conduction velocities of motor and sensory nerves and of evoked spinal cord potentials), immunological testing (functional studies), sequential neurological examinations and virus isolations (cerebral spinal fluid, blood, and bone marrow), and histopathology. Molecular studies of neurotropic FeLVs will include; identification of the viral genome present in the tissues of cat 1390 and cats inoculated with virus derived from this cat; molecular cloning of the FeLV-1390 neurotropic variant; and identification of the changes in this virus related to its minimally pathogenic parental virus (MC-FeLV-3281) through nucleotide sequence analysis. Additional sequence comparisons will be made to determine if FeLV-1390 arose through acquisition of endogenous sequences. Potentially neurotropic FIVs will be identified by performing neurologic and electrophysiologic exams of naturally-occurring cases of FIV which present to the Colorado State University Veterinary Teaching Hospital. FIVs will be isolated from cats with neurologic dysfunction, and the pathogenicity of these isolates will be evaluated in vitro and in vivo in order to identify a neurotropic strain of FIV for further study. FIV will be cloned from a strain that induces neurologic dysfunction in SPF cats. A biologically defined FIV model for lentivirus-induced neurologic disease will be established using MC-FIVs, and we will begin to define the genetic structures of neurotropic FIVs.
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| Mitchell, T W; Rojko, J L; Hartke, J R et al. (1997) FeLV envelope protein (gp70) variable region 5 causes alterations in calcium homeostasis and toxicity of neurons. J Acquir Immune Defic Syndr Hum Retrovirol 14:307-20 |
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