The long-term objective of this research proposal is to identify the effector genes required for the development of neurological diseases induced by HIV. We have recently generated transgenic mice expressing the whole HIV coding sequences in the CNS under the regulatory sequences (promoter) of the human neurofilament (NF/HIV) or of the myelin basic protein (MBP/HIV) gene. After a relatively long latency, these mice, bred in the C3H background, develop either neuropathies or a vacuolar myelopathy, respectively. Both diseases are pathologically very similar to the changes seen in HIV-infected individuals. We would like to identify modifier genes of these phenotype and more specifically, we intend: 1. To identify the more susceptible mouse background which will facilitate the optimal expression of the phenotype induced in NF/HIV and MBP/HIV transgenic mice. To achieve this goal, these transgenic mice will be bred for at least 6 generations with inbred mice of at least 15 strains. The phenotype will subsequently be analyzed at 6 and 10 months, in order to determine whether the expression of the transgene in a specific background induces more severe disease after a shorter latency. 2. To identify and map mouse gene(s) of resistance able to block the appearance of vacuolar myelopathy in MBP/HIV transgenic mice. To achieve this goal, the MBP/HIV mice will be bred with mice of several (15) inbred-strains to generate F1 mice. These F1 mice will be observed for at least 1 year and the pathology assessed. Mice of a strain offering a resistant phenotype in F1 (dominant) will then be used to generate backcross mice to map the putative gene(s) of resistance. Microsatellite markers will be used in correlation with the individual phenotype of each backcross transgenic mouse again observed for 12 months.
| Radja, Fatiha; Kay, Denis G; Albrecht, Steffen et al. (2003) Oligodendrocyte-specific expression of human immunodeficiency virus type 1 Nef in transgenic mice leads to vacuolar myelopathy and alters oligodendrocyte phenotype in vitro. J Virol 77:11745-53 |
