HIV-1 is the causative agent of AIDS and the AIDS dementia complex. HIV- 1 causes disease only in humans. There is no animal model to compare the pathogenicity of strains of HIV. Transgenic mice provide an animal model in which to examine the specific role of HIV genes and genetic elements in gene expression in vivo. Transgenic mice will be used to investigate the role of different HIV-LTR sequences in the activation of HIV gene expression during mouse development and in the adult mouse central nervous system (CNS). Specific cells in which HIV gene expression is activated will be identified; HIV gene expression during ontogeny will also be studied. The LTRs of three strains of HIV will be used HIV 111B the lymphotropic virus and HIV JR-FL and HIV JR-CSF two strains isolated from the CNS of an AIDS patient. Preliminary studies of the transgenic mice containing the three different LTR sequences indicate that there is differential gene expression from these LTRs and that activation of gene expression from the HIV JR-FL and HIV JR-CSF LTRs occur in CNS cells in the mouse embryo, neonate and adult. Experiments will be done to identify the specific cells expressing the HIV-LTR and to examine the effect of secondary factors on HIV expression. In vitro studies on the three HIV-LTRs will be done to identify the specific nucleotide sequences in the LTRs responsible for differential cellular activation. Characterization of the cellular factors that bind to the LTRs from specific cells will be done. Finally, using the HIV-LTR which expresses to the highest level in the CNS, HIV- LTR env transgenic mice will be constructed to investigate whether the gp120 toxicity observed in CNS cultures in vitro occurs in vivo. The HIV transgenic mice should allow the examination of the role of individual viral LTR and genes in HIV expression and cellular pathology in vivo.
| Craig, L E; Nealen, M L; Strandberg, J D et al. (1997) Differential replication of ovine lentivirus in endothelial cells cultured from different tissues. Virology 238:316-26 |
| Kurth, J; Buzy, J M; Lindstrom, L et al. (1996) In vivo transcriptional regulation of the human immunodeficiency virus in the central nervous system in transgenic mice. J Virol 70:7686-94 |
| Buzy, J M; Lindstrom, L M; Zink, M C et al. (1995) HIV-1 in the developing CNS: developmental differences in gene expression. Virology 210:361-71 |
