ANALYSIS OF THE DETERMINANTS OF NEUROTROPISM AND NEUROTOXICITY OF HFVIN TRANSGENIC MICE

The Bel-1 protein of human foamy virus (HFV) is a transactivator actin g on the U3 region of the long terminal repeat and on an internal prom oter (IP) immediately upstream of the bel genes. An HFV transgene call ed Delta gpe, containing both promoters and all bet genes, is expresse d in the central nervous system and induces neurodegeneration in mice. To dissect the role of individual promoters and bet genes on transgen e expression and neurotoxicity we generated transgenic mice with a con struct termed pL-bel1, which lacks the IP and the ancillary genes exce pt bel-1. L-bell mice transcribed the HFV transgene in more tissues th an Delta gpe mice, suggesting that CNS specificity is dictated by cis- acting elements not present in the pLbel-1 construct Unlike Delta gpe mice, L-bel1 mice did not develop neurodegenerative changes and did no t show induction of nitric oxide synthase expression, although both st rains expressed Bel-1 in the brain. Therefore, Bel-1 expression is not sufficient for neurotoxicity. Our results suggest that Bet, a fusion protein between bel-1 and bel-2 which is highly expressed in Delta gpe but not in L-bel1 mice, is a candidate for neurotoxicity. (C) 1996 Ac ademic Press, Inc.