HIV-1 in the developing CNS: developmental differences in gene expression.

Abstract

HIV-1 infection of the CNS plays a direct role in the pathogenesis of AIDS dementia that frequently accompanies systemic AIDS. Both adult and pediatric AIDS are characterized by a high proportion of CNS disease. However, the pathogenic mechanisms responsible for AIDS dementia are not understood. A transgenic mouse model using the LTRs of two CNS-derived strains of HIV-1 (HIV-1JR-CSF and HIV-1JR-FL) has been developed to study HIV-1 gene expression in vivo. Analyses of expression in adult transgenic mice revealed expression in neurons in the CNS (J. R. Corboy, J. M. Buzy, M. C. Zink, and J. E. Clement, Science 258, 1804-1808, 1992). In this study, developmental analyses of HIV-1-directed gene expression in embryonic and newborn transgenic mice derived from the above lines revealed strikingly different levels and patterns of expression in the CNS and spinal cord compared with adult mice. Increased expression was observed in the newborn brain compared to the adult, and the neuroanatomical pattern of expression was markedly different than that observed in adult brain. Transient expression was detected in the dorsal root ganglia and spinal cord in embryos and newborns up to Day 14. In contrast to the expression in neurons in adult CNS, HIV-1-directed gene expression in the newborn brain was observed in neurons, endothelial cells, and macrophages. This difference in expression during development probably reflects temporally regulated cellular transcription factors in the CNS. This transgenic model suggests that HIV-1 replication in the CNS may use cellular transcription factors different from those in nonneural tissues. Studies are in progress to identify cellular transcription factors that may be responsible for the differential expression of the LTRs.