Peptide T, an octapeptide sequence found in the external envelope protein (gpl20) of the ARV isolate of human immunodeficiency virus (HIV), was investigated for its action in preventing neuronal death observed in mouse hippocampal cultures treated with purified gpl20. Cell counts of neuronspecific enolase-identified neurons revealed that peptide T application completely and potently antagonized gpl20-induced death. Analogs of the core pentapeptide sequence of peptide T, TTNYT, found in the second variable region of all gp120 isolates sequenced to date, were also tested and found to be similarly active. Investigations of structure activity relationships of related peptides suggested that the second and fourth positions in the core pentapeptide sequence were critical for biological activity in the neuronal survival assay. Antiserum against the peptide T sequence found in the the ARV isolate was found to prevent neuronal cell death in cultures treated with purified gp120 from the lllB isolate of HIV. These data indicate that the peptide T sequence is effective in preventing neuronal cell death associated with the envelope protein and provide a rationale for peptide T to be evaluated as a potential therapeutic agent for the neuropsychiatric and neurological sequelae of acquired immune deficiency syndrome.
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.
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